Background
The surface epithelial carcinomas and borderline tumors can be classified histopathologically into a simple 6 x 4 matrix. This does not address the relationship between different cells within the matrix or how these cells might be logically grouped,



the subject of this presentation. Both assignment of tumor grade and tumor cell type have historically been fraught with reproducibility problems. With regards to tumor grading, the recent introduction of a grading scheme for ovarian epithelial carcinomas based on tumor architecture, nuclear pleomorphism, and mitotic activity (reviewed in ref. 1) provides a significant advance in terms of both reproducibility and prognostication [1, 2, 3, 4, 5, 6] . Uniform application of grading will enhance our ability to reproducibly subclassify tumors and represents an important new tool in ovarian cancer translational research. Assignment of tumor cell type is highly "impressionistic", as noted by Hendrickson and Longacre, resulting in suboptimal reproducibility [7, 8, 9, 10] . It is likely that this lack of reproducibility is related to the difficulties in classification of higher grade carcinomas tumors rather than the low grade carcinomas; distinction between the cell type of low grade serous, mucinous and endometrioid tumors is usually straightforward, while grade 3 carcinomas lack the overt lineage specific differentiation that would allow their reproducible classification. One result of the difficulty in reproducibly subclassifying ovarian carcinomas is that tumor cell type typically does not influence treatment, independent of stage and grade. This does not mean that cell type is irrelevant. For example, grouping all borderline tumors together, as has been done in some studies, obscured important clinical and biological differences between different subtypes, e.g. serous borderline tumors vs. mucinous borderline tumors of intestinal type. Silverberg noted decreased chemoresponsiveness of mucinous and clear cell carcinomas, compared to serous or transitional cell carcinomas, and concluded that cell type, rather than grade may be a superior predictor of response to chemotherapy [1]. For tumor cell type to enter routine use in guiding patient treatment, however, it must be used in a way that allows more reproducible subclassification than is presently achieved.

High Grade Serous, Endometrioid, and Undifferentiated Carcinomas



Most ovarian carcinomas are high-grade serous, endometrioid or undifferentiated carcinomas. Seidman et al. reviewed 220 consecutive invasive ovarian epithelial carcinomas seen at Washington Hospital Center and found that 85% were of serous, endometrioid, or undifferentiated types, with a further 5% being of mixed type [11]. (The large majority of these tumors were considered to be of serous type). Considering only the advanced stage tumors (stage III and IV), the proportion considered serous, endometrioid, undifferentiated or mixed increased to 93%. A series of 102 cases of advanced stage ovarian epithelial carcinoma from our center were systematically reviewed with respect to tumor cell type and grade, and 93% were high grade (grade 2 or 3 by the Silverberg grading system) serous, endometrioid, undifferentiated or mixed carcinomas [12]. There were 5 cases of clear cell carcinoma and one each of low grade serous carcinoma and mucinous carcinoma in this series. Our understanding of genetic events underlying the genesis of this subset of ovarian tumors, that account for a disproportionate share of ovarian cancer mortality, was dramatically advanced with the discovery in the mid 1990s of the BRCA1 and BRCA2 genes. It is now appreciated that hereditable cases of ovarian carcinoma are more common than was originally thought, but it remains that the large majority of cases of ovarian cancer are sporadic, occurring in patients without a family history of ovarian cancer or any other identifiable risk factors. The breast carcinomas arising in patients with germline BRCA1 or BRCA2 mutations are morphologically distinct compared to sporadic breast cancers, are separable from sporadic breast cancers based on gene expression profiling, and respond differently to chemotherapeutic agents [13, 14, 15] . In striking contrast, the ovarian carcinomas associated with germline BRCA1 or BRCA2 mutations are indistinguishable from sporadic high grade ovarian carcinomas, based on morphology, gene expression profiling, and p53 mutation analysis [16, 17, 18, 19, 20, 21] ; the prognosis of familial vs. sporadic ovarian cancer remains controversial [22, 23, 24, 25, 26] . The molecular basis for this has been demonstrated by the studies of Hilton et al. and Geisler et al., who showed evidence of BRCA1 and/or BRCA2 loss of function in a large majority (84%) of ovarian carcinomas [27, 28] . In these important studies, a series of patients with high-grade ovarian carcinomas were characterized in detail with respect to BRCA1 and BRCA2 through assessment of mRNA levels, gene sequencing to identify both germ line and somatic mutations, loss of heterozygosity studies to identify allelic loss, and promoter hypermethylation assays to identify gene silencing through epigenetic means. In this series, 89% of the tumors were of serous or endometrioid type, 85% were stage III or IV, and 88% were grade 2 or 3. As expected, germ line and somatic mutations in BRCA1 or BRCA2 were relatively uncommon. Loss of function more commonly occurred through a combination of loss of heterozygosity and promoter hypermethylation, but the end result is that in most cases of high grade, advanced stage ovarian carcinoma there is loss of BRCA1 and/or BRCA2 function. We have recently shown that EMSY, a gene encoding a protein that binds and inactivates BRCA2, is amplified in 17% of high-grade ovarian cancers, thus identifying a relatively common genetic mechanism unrelated to the BRCA2 locus that can result in loss of BRCA2 function [29, 30] . EMSY amplification was not seen in grade 1 carcinomas, borderline tumors or mucinous carcinomas. The data presented demonstrate clearly that a central abnormality in the most common and lethal subset of ovarian carcinomas of both familial and sporadic type is loss of BRCA1/BRCA2 function with resulting inability to repair double strand DNA breaks. This correlates well with the very complex cytogenetic profiles of usual high grade ovarian carcinomas [31]. We have no reliable prognostic indicators for this group of patients and we have probably reached the limits of morphological subclassification so that meaningful stratification of patients within this group, with respect to either prognosis or prediction of response to therapy, will require molecular analysis.

Low Grade Serous Carcinomas and Serous Borderline Tumors



Serous carcinomas are predominantly high-grade tumors but rarely may be low grade. The low-grade serous carcinomas (and serous borderline tumors) frequently have mutations in BRAF and KRAS, which are rarely encountered in the high-grade carcinomas [32, 33, 34] . As well they lack p53 mutations, which are very commonly encountered in their high-grade counterparts [35]. Low grade serous carcinomas show fewer molecular abnormalities by both cytogenetic [31] and single nucleotide polymorphism [32] analysis, in comparison to high grade serous carcinomas. Gene expression profiling allows separation of both low grade serous carcinomas [36] and serous borderline tumors [37] from high grade serous carcinomas. It is clear that low-grade serous carcinomas are more closely related to serous borderline tumors than usual serous carcinomas, both in terms of clinical outcome and genetic events during carcinogenesis. What is less clear is whether we are able to reliably separate these two groups of tumors based on histopathological assessment. Based on the work of Singer et al., only tumors with grade 1 nuclear atypia, low grade architecture (typically micropapillary) and low-mitotic activity fall into the low-grade group, with respect to their genetic profile. We have recently, however, encountered two cases of high grade carcinoma in the recurrences of conventional serous borderline tumors. Both recurrences were of high architectural grade, intermediate nuclear grade and with intermediate numbers of mitotic figures (10 and 20 MF/10 HPF, respectively) [38]. While these cases show that progression to higher grade carcinoma can occur in serous borderline tumors or low grade carcinomas, this appears to be a rare event and in most cases separation of serous carcinomas into two groups should be possible based on routine histopathological assessment. The challenge then becomes determining the optimal therapy for advanced stage, low grade serous carcinomas.

Mucinous Carcinomas and Borderline Tumors (of intestinal type)



In an ongoing review of 3500 cases of ovarian carcinoma seen in Vancouver over the past 20 years it has become evident that in the 1980's, in particular, ovarian metastases of mucin producing adenocarcinomas from other body sites were frequently classified as primary ovarian mucinous carcinomas. There remain mucinous carcinomas that are true primary ovarian tumors rather than metastases, but they are uncommon. Seidman et al. found that only 6 of 220 carcinomas were mucinous carcinomas, and only one of these presented with advanced stage disease [11]. In our review of 102 advanced stage ovarian carcinomas seen at our institution, only one was mucinous [12]. Thus, with careful exclusion of metastases, mucinous carcinomas of the ovary are uncommon and the large majority are stage I tumors, requiring no additional therapy beyond surgical removal. Mucinous borderline tumors of intestinal type and mucinous carcinomas show an increasing frequency of KRAS mutations [39, 40, 41, 42] and, unlike the situation for serous tumors, individual tumors frequently show intratumoral heterogeneity with benign, borderline, and frankly malignant areas. Mucinous carcinomas have been reported to be less chemoresponsive than other ovarian carcinomas, but these older data must be interpreted with caution as an unknown number of these cases are probably metastatic and not primary ovarian carcinomas. We recently encountered a case of recurrent mucinous carcinoma in which conventional platinum/taxane chemotherapy had been ineffective; the tumor showed strong membranous immunoreactivity for Her-2 and a trial of Herceptin therapy resulted in a prompt response [43]. As for low grade serous carcinomas, optimal treatment of advanced stage mucinous carcinomas is not known, but consistent recognition of this group of tumors will allow assessment of response rates to conventional chemotherapy and trials of novel therapies to occur.

Low Grade Endometrioid Carcinomas and Borderline Tumors



Borderline and malignant endometrioid tumors arise in association with endometriosis in a significant percentage of cases, suggesting that they may arise from ectopic endometrial tissue rather than the ovarian surface epithelium. The low-grade endometrioid carcinomas of the ovary are characterized by mutations in the beta-catenin gene, an uncommon abnormality in high-grade ovarian carcinoma [44, 45, 46] . These low-grade endometrioid tumors typically present with early stage disease and have a favourable prognosis [45]. The diagnosis of high-grade endometrioid carcinomas is, based on our experience, irreproducible, with considerable morphological overlap with high-grade serous carcinomas. While endometrioid carcinomas accounted for 2-3% of advanced stage ovarian carcinomas in the Washington and Vancouver series [8, 9] , 23% of tumors were considered endometrioid in the Iowa series [28]. High-grade endometrioid carcinomas of the ovary are not separable from high-grade serous carcinomas based on either studies of genetic events or gene expression profiling [28, 37, 47] . Based on the available evidence it is doubtful whether there is a consistently recognizable set of high-grade endometrioid carcinomas that differ in any substantive way from high-grade papillary serous carcinomas. The challenge will be to define the boundary between the (usually) low grade tumors associated with endometriosis and beta-catenin deregulation and higher grade tumors associated with BRCA1/BRCA2 loss of function.

Clear Cell Carcinomas



Clear cell carcinomas are uncommon, often occur in association with endometriosis, and not infrequently are observed to arise in endometriotic cysts. Although depicted in the figure at right as showing a range of grades from borderline to grade 3, they are quite stereotypical in their appearance; even the "borderline" tumors, which lack invasion, show high grade cytological features, at least focally, and a consistent feature of clear cell carcinomas is a relatively low mitotic rate compared to other high grade ovarian carcinomas [1]. It is doubtful whether grading contributes significantly to subclassification of clear cell carcinomas, and according to WHO guidelines, these tumors are not graded. The gene expression profile of clear cell carcinomas is distinct from other types of ovarian carcinomas [47, 48] . Clear cell carcinomas occur in BRCA1 and BRCA2 mutation carriers. Although they frequently present with early stage disease, the prognosis of patients with clear cell carcinoma, when corrected for stage, appears to be somewhat worse than for patients with other subtypes of ovarian carcinoma [49]. Although this appears to be a well-defined subgroup of ovarian carcinoma, there are a number of unresolved questions. For example, do pure clear cell carcinoma differ significantly from those tumors showing mixed growth patterns (e.g. clear cell and serous differentiation)? Is BRCA1/BRCA2 loss of function as common as in high grade serous carcinomas? Do the tumors arising in endometriosis differ from those unassociated with endometriosis? Until these questions are answered it is uncertain whether this is a homogeneous group of tumors of whether there are clinically relevant subsets within this group.

Transitional Cell Carcinomas



Transitional cell carcinomas are the most recent addition to the WHO and ISGP classification of ovarian carcinomas so it is not surprising that they are the least characterized subtype. These are rare tumors; Silva et al. estimated that they account for 1% of ovarian carcinomas [50]. Transitional cell carcinomas may show a more favourable response to chemotherapy than other ovarian carcinomas, but this has not been a uniform finding [3, 50, 51, 52, 53, 54] . With a recently recognized tumor subtype there will be problems with reproducibility in diagnosis. Genetic abnormalities associated with transitional cell carcinomas have not been characterized and the immunophenotype of transitional cell carcinomas is not related to transitional cell carcinomas of the bladder [55]. Thus, definition of this subtype of ovarian carcinoma remains purely morphological [56]. How these tumor relate to other ovarian carcinomas remains to be determined.

Summary
Guided by recently gained insights into the genetic basis of different ovarian cancer subtypes it is possible, based on routine histopathological assessment of cell type and grade, to group ovarian carcinomas into clinically relevant subsets.

References

1. Silverberg SG. Histopathologic grading of ovarian carcinoma: a review and proposal. Int J Gynecol Pathol, 2000;19:7-15.
2. Shimizu Y, Kamoi S, Amada S, Hasumi K, Akiyama F, Silverberg SG. Toward the development of a universal grading system for ovarian epithelial carcinoma. I. Prognostic significance of histopathologic features – problems involved in the architectural grading system. Gynecol Oncol, 1998;70:2-12.
3. Shimizu Y, Kamoi S, Amada S, Akiyama F, Silverberg SG. Toward the development of an universal grading system for ovarial epithelial carcinoma: testing of a proposed system in a series of 461 patients with uniform treatment and follow-up. Cancer, 1998;82:893-901.
4. Ishioka S, Sagae S, Terasawa K, Sugimura M, Nishioka Y, Tsukada K, Kudo R. Comparison of the usefulness between a new universal grading system for epithelial ovarian cancer and the FIGO grading system. Gynecol Oncol, 2003;89:447-452.
5. Mayr D, Diebold J. Grading of ovarian carcinomas. Int J Gynecol Pathol, 2000;19:348-353.
6. Sato Y, Shimamoto T, Amada S, Asada Y, Hayashi T. Prognostic value of histologic grading of ovarian carcinomas. Int J Gynecol Pathol, 2003;22:52-56.
7. Hendrickson MR, Longacre TA. Classification of surface epithelial neoplasms of the ovary. In: Hendrickson MR, ed. Surface Epithelial Neoplasms of the Ovary. Philadelphia: Hanley and Belfus; 1993;189-254.
8. Cramer SF, Roth LM, Ulbright TM, Mazur MT, Nunez CA, Gersell DJ, Mills SE, Kraus FT. Evaluation of the reproducibility of the World Health Organization classification of common ovarian cancers. Arch Pathol Lab Med, 1987;111:819-829.
9. Lund B, Thomsen HK, Olsen J. Reproducibility of histopathological evaluation in epithelial ovarian carcinoma. APMIS, 1991;99:353-358.
10. Sakamoto A, Sasaki H, Furusato M, Suzuki M, Hirai Y, Tsugane S, Fukushima M, Terashima Y. Observor disagreement in histological classification of ovarian tumors in Japan. Gynecol Oncol, 1994;54:54-58.
11. Seidman JD, Horkayne-Szakaly S, Haiba M, Boice CR, Kurman RJ, Ronnett BM. The histologic type and stage distribution of ovarian carcinomas of surface epithelial origin. Int J Gynecol Pathol, 2004;23:41-44.
12. Parker RL, Yorida E, Cheang M, Huntsman DG, Miller D, Hoskins P, Gilks CB. Loss of p16 expression is of prognostic significance in high-grade advanced-stage ovarian cancer. USCAP 2004.
13. Armes JE, Venter DJ. The pathology of inherited breast cancer. Pathology, 2002;34:309-314.
14. Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L, Easton DF. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol, 2002;20:2310-2318.
15. Goffin JR, Chappuis PO, Begin LR, Wong N, Brunet JS, Hamel N, Paradis AJ, Boyd J, Foulkes WD. Impact of germline BRCA1 mutations and overexpression of p53 on prognosis and response to treatment following breast carcinoma: 10-year follow up data. Cancer, 2003;97:527-536.
16. Narod SA, Boyd J. Current understanding of the epidemiology and clinical implications of BRCA1 and BRCA2 mutations for ovarian cancer. Curr Opin Obstet Gynecol, 2002;14:19-26.
17. Boyd J, Sonoda Y, Federici MG, Bogomolniy F, Rhei E, Maresco DL, Saigo PE, Almadrones LA, Barakat RR, Brown CL, Chi DS, Curtin JP, Poynor EA, Hoskins WJ. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA, 2002;283:2260-2265.
18. Shaw PA, McLaughlin JR, Zweemer RP, Narod SA, Risch H, Verheijen RHM, Ryan A, Menko FH, Kenemans P, Jacobs IJ. Histopathologic features of genetically determined ovarian cancer. Int J Gynecol Pathol, 2002;21:407-411.
19. Werness BA, Ramus SJ, DiCioccio RA, Whittemore AS, Garlinghouse-Jones K, Oakley-Girvan I, Tsukada Y, Harrington P, Gayther S, Ponder BAJ, Piver MS. Histopathology, FIGO stage, and BRCA mutation status of ovarian cancers from the Gilda Radner Familial Ovarian Cancer Registry. Int J Gynecol Pathol, 2004;23:29-34.
20. Jazaeri AA, Yee CJ, Sotiriou C, Brantley KR, Boyd J, Liu ET. Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. J Natl Cancer Inst, 2002;94:990-1000.
21. Zweemer RP, Shaw PA, Verheijen RM, Ryan A, Berchuck A, Ponder BA, Risch H, McLaughlin JR, Narod SA, Menko FH, Kenemans P, Jacobs IJ. Accumulation of p53 protein is frequent in ovarian cancers associated with BRCA1 and BRCA2 germline mutations. J Clin Pathol, 1999;52:372-375.
22. Pharoah PD, Easton DF, Stockton DL, Gayther S, Ponder BA. Survival in familial, BRCA1-associated, and BRCA2-associated epitheial ovarian cancer. United Kingdom coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group. Cancer Res 1999;59:868-871.
23. Buller RE, Shahin MS, Geisler JP, Zogg M, De Young BR, Davis CS. Failure of BRCA1 dysfunction to alter ovarian cancer survival. Clin Cancer Res, 2002;8:1196-1202.
24. Boyd J, Sonoda Y, Federici MG, Bogomolniy F, Rhei E, Maresco DL, Saigo PE, Almadrones LA, Barakat RR, Brown CL, Chi DS, Curtin JP, Poynor EA, Hoskins WJ. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. JAMA, 2000;283:2260-2265.
25. Ben David Y, Chetrit A, Hirsh-Yechezkel G, Friedman E, Beck BD, Beller U, Ben-Baruch G, Fishman A, Levavi H, Lubin F, Menczer J, Piura B, Struewing JP, Modan B. J Clin Oncol, 2002;20:463-466.
26. Cass I, Baldwin RL, Varkey T, Moslehi R, Narod SA, Karlan By. Improved survival in women with BRCA-associated ovarian carcinoma. Cancer, 2003;97:2127-2129.
27. Geisler JP, Hatterman-Zogg MA, Rathe JA, Buller RE. Frequency of BRCA1 dysfunction in ovarian cancer. J Natl Cancer Inst 2002;4(1):61-67.
28. Hilton JL, Geisler JP, Rathe JA, Hattermann-Zogg MA, DeYoung B, Buller RE. Inactivation of BRCA1 and BRCA2 in ovarian cancer. J Natl Cancer Inst, 2002;94:1396-1406.
29. Hughes-Davies L, Huntsman D, Ruas M, Fuks F, Bye J, Chin SF, Milner J, Brown LA, Hsu F, Gilks B, Nielsen T, Schulzer M, Chia S, Ragaz J, Cahn A, Linger L, Ozdag H, Cattaneo E, Jordanova ES, Schuuring E, Yu DS, Venkitaraman A, Ponder B, Doherty A, Aparicio S, Bentley D, Theillet C, Ponting CP, Caldas C, Kouzarides T. EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell, 2003;115:523-535.
30. Irving J, Brown L, Magliocco T, Longacre TA, Gilks B, Caldas C, Hunstman D. Amplification of a novel BRCA2-inactivating gene, EMSY, in high grade ovarian carcinomas. Mod Pathol, 2003;16:193A.
31. Pejovic T. Genetic changes in ovarian cancer. Ann Med, 1995;27:73-78.
32. Singer G, Kurman RJ, Chang HW, Cho SK, Shih IeM. Diverse tumorigenic pathways in ovarian serous carcinoma. Am J Pathol, 2002;160:1223-1228.
33. Singer G, Oldt R 3rd, Cohen Y, Wang BG, Sidransky D, Kurman RJ, Shih IeM. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst, 2003;95:484-486.
34. Singer G, Shih IeM, Truskinovsky A, Umudum H, Kurman RJ. Mutational analysis of K-ras segregates ovarian serous carcinomas into two types: invasive MPSC (low-grade tumor) and conventional serous carcinoma (high-grade tumor). Int J Gynecol Pathol, 2003;22:37-41.
35. Katabuchi H, Tashiro H, Cho KR, Kurman RJ, Hedrick EL. Micropapillary serous carcinoma of the ovary: an immunnohistochemical and mutational analysis of p53. Int J Gynecol Pathol, 1998;17:54-60.
36. Jazaeri AA, Lu K, Schmandt R, Harris CP, Rao PH, Sotiriou C, Chandramouli GV, Gershenson DM, Liu ET. Molecular determinants of tumor differentiation in papillary serous ovarian carcinoma. Mol Carcinog, 2003;36:53-59.
37. Gilks B, Vanderhyden B, Zhu S, van de Rijn M, Longacre TA. Distinction between serous borderline tumors and serous carcinomas based on mRNA expression profiling. Mod Pathol, 2003;16:190A.
38. Parker RL, Clement PB, Chercover DJ, Sornarajah T, Gilks CB. Early recurrence of ovarian serous borderline tumor as high grade carcinoma: a report of two cases. Int J Gynecol Pathol, in press.
39. Mok SC, Bell DA, Knapp RC, Fishbaugh PM, Welch WR, Muto MG, Berkowitz RS, Tsao SW. Mutation of the K-ras protooncogene in human ovarian epithelial tumors of borderline malignancy. Cancer Res, 1993;53:1489-1492.
40. Cuatecasas M, Villaneuva A, Matias-Guiu X, Prat J. K-ras mutations in mucinous ovarian tumors: a clinicopathologic and molecular study of 95 cases. Cancer 1997;79:1581-1586.
41. Mandai M, Konishi I, Kuroda H, Komatsu T, Yamamoto S, Nanbu K, Matsushita K, Fukumoto M, Yamabe H, Mori T. Heterogeneous distribution of K-ras-mutated epithelia in mucinous ovarian tumors with special reference to histopathology. Hum Pathol 1998;29-34-40.
42. Garrett AP, Lee KR, Colitti CR, Muto MG, Berkowitz RS, Mok SC. K-ras mutation may be an early event in mucinous ovarian tumorigenesis. Int J Gynecol Pathol, 2001;20:244-251.
43. Ludwick C, Gilks CB, Miller D, Yaziji H, Clement PB. Aggressive behaviour of stage I ovarian mucinous tumors without destructive stromal invasion. USCAP 2004.
44. Palacios J, Gamallo C. Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas. Cancer Res, 1998:58:1344-1347.
45. Gamallo C, Palacios J, Moreno G, Calvo de Mora J, Suarez A, Armas A. Beta-catenin expression pattern in stage I and II ovarian carcinomas: relationship with beta-catenin gene mutations, clinicopathologic features, and clinical outcome. Am J Pathol, 1999;155:527-536.
46. Wu R, Zhai Y, Fearon ER, Cho KR. Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas. Cancer Res, 2001;61:8247-8255.
47. Schwartz DR, Kardia SL. Shedden KA, Kuick R, Michailidis G, Taylor JM, Misek DE, Wu R, Zhai Y, Darrah DM, Reed H, Ellenson LH, Giordano TJ, Fearon ER, Hanash SM, Cho KR. Gene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas. Cancer Res, 2002;62:4722-4729.
48. Schaner ME, Ross DT, Ciaravino G, Sorlie T, Troyanskaya O, Diehn M, Wang YC, Duran GE, Sikic TL, Caldiera S, Skomedal H, Tu IP, Hernandez-Broussard T, Johnson SW, O'Dwyer PJ, Fero MJ, Kristensen GB, Borreson-Dale AL, Hastie T, Tibshirani R, van de Rijn M, Teng NN, Longacre TA, Botstein D, Brown PO, Sikic BI. Gene expression patterns in ovarian carcinomas. Mol Biol Cell, 2003;14:4376-4386.
49. Tavassoli FA, Devilee P. (Eds). World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of the Breast and Female Genital Organs. IARC Press: Lyon 2003.
50. Silva EG, Robey-Cafferty SS, Smith TL, Gershenson DM. Ovarian carcinomas with transitional cell carcinoma pattern. Am J Clin Pathol, 1990;93:457-465.
51. Robey SS, Silva EG, Gershenson DM, McLemore D, el-Naggar A, Ordonez NG. Transitional cell carcinoma in high-grade high-stage ovarian carcinoma. An indicator of favorable response to chemotherapy. Cancer, 1989;63:839-847.
52. Gershenson DM, Silva EG, Mitchell MF, Atkinson EN, Wharton JT. Transitional cell carcinoma of the ovary: a matched control study of advanced-stage patients treated with cisplatin-based chemotherapy. Am J Obstet Gynecol, 1993;168:1178-1185, discussion 1185-1187.
53. Hollingsworth HC, Steinberg SM, Silverberg SG, Merino MJ. Advanced stage transitional cell carcinoma of the ovary. Hum Pathol, 1996;27:1267-1272.
54. Costa MJ, Hansen C, Dickerman A, Scudder SA. Clinicopathologic significance of transitional cell carcinoma pattern in nonlocaliezed ovarian epithelial tumors (stages 2-4). Am J Clin Pathol, 1998;109:173-180.
55. Logani S, Oliva E, Amin MB, Folpe AL, Cohen C, Young RH. Immunoprofile of ovarian tumors with putative transitional cell (urothelial) differentiation using novel urothelial markers: histogenetic and diagnostic implications. Am J Surg Pathol, 2003;27:1434-1441.
56. Eichhorn JH, Young RH. Transitional cell carcinoma of the ovary. A study of its morphology in 100 cases. Am J Surg Pathol, in press.