Advanced stage transitional cell carcinoma of the ovary

Advanced Stage Transitional Cell Carcinoma of the Ovary HELEN C, HOLLINGSWORTH, MD, SETH M, STEINBERG, PHD, STEVEN G, SILVERBERG, MD, AND MARIA J, MERINO, MD Primary transitional cell carcinoma (TCC) of the ovary has been recently recognized as a separate subtype of epithelial cancer. It has been proposed that recognition of such tumors is important on clinical grounds because of a favorable response to chemotherapy and an improved patient survival. The authors reviewed the histological and clinicopathologic findings of 58 patients with advanced stage (stages III and IV) ovarian cancer with a view to determining the frequency of TCC and confirming the favorable prognosis. O f these cases, 15 (26%) were reclassified as TCC; 13 were predominantly TCC, and 2 had a mixed pattern with approximately 50% of the tmnor being TCC. TCC patients ranged in age from 44 to 70 years of age (mean, 57). Ten of the patients had stage III disease, and five were stage IV. The tmnor was unilateral in 2 cases and bilateral in

11 (2 unknown). Tumor size varied between 3 and 23 cm. O f the stage III patients, five were optimally debulked, and five had residual disease. All patients received the same type of chemotherapy. The median overall survival was 28 months. There was no significant difference in the clinical outcome of patients with TCC compared with that of patients with serous carcinomas. These data suggest that TCC does not confer a favorable prognosis or better response rate to chemotherapy. HUM PATHOL 27:1267--1272. This is a US government work. There are no restrictions on its use. Key words: ovary, carcinoma, transitional cell carcinoma. Abbreviations: TCC, transitional cell carcinoma; OS, overall survival; DFS, disease-free survival; D O D , dead of disease; FIGO, International Federation of Gynecology and Obstetrics.

P r i m a r y t r a n s i t i o n a l cell c a r c i n o m a (TCC) of the ovary has r e c e n t l y b e e n r e c o g n i z e d as a separate subtype o f e p i t h e l i a l cancer. 1 Histologically, it is disting u i s h e d f r o m m a l i g n a n t B r e n n e r t u m o r by the a b s e n c e of a b e n i g n B r e n n e r c o m p o n e n t . 1 S u b s e q u e n t studies showed that T C C occurs fairly f r e q u e n t l y , i n o n e study c o n s t i t u t i n g 9.4% o f cases of ovarian cancer. 2 T h e s e studies also showed that T C C is associated with g o o d r e s p o n s e to c h e m o t h e r a p y a n d i m p r o v e d s u r v i v a l Y T h e a u t h o r s reviewed the histological a n d c l i n i c o p a t h o logic f i n d i n g s o f 58 p a t i e n t s with a d v a n c e d stage (stages III a n d 1V) o v a r i a n c a n c e r to d e t e r m i n e the f r e q u e n c y o f T C C a n d to c o n f i r m the favorable prognosis.

treated using dose-intensive induction therapy with cyclophosphamide and cisplatin; seven of these patients also received consolidative whole-abdominal radiation. 4 The remaining 22 patients were placed on a pilot protocol of a platinum-intense induction regimen consisting of cyclophosphamide, carboplatin, and cisplatin.

MATERIALS AND METHODS

Case Selection Cases were taken from two similar treatment protocols to limit the effect of treatment differences on outcome. A total of 80 patients were identified. All patients were referred to the Clinical Center, National Institutes of Health, newly diagnosed, with most having had initial workup and staging laparotomy at an outside institution. All tumors were advanced stage (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV). Of the original 80 patients, 22 were excluded, 16 because the primary tumor was unavailable for review, and 4 because of lack of sufficient follow-up information. Two other cases were determined to be serous tumors of low malignant potential. Of the remaining 58 patients, follow-up ranged from 0.5 months to 6 years, with three patients alive after more than 6 years. Thirty-six patients were From the National Cancer Institute, National Institutes of Health, Bethesda, MD; and the George Washington University,Washington, DC. Accepted for publication April 22, 1996. Address correspondence and reprint requests to MariaJ. Merino, MD, Laboratory of Pathology, National Cancer Institute, Building 10, Room 2N212, Bethesda, MD 20892. This is a US government work. There are no restrictions on its use,

0046-8177/96/2712-000550.00/0

Pathology Pathological review of case material was performed on all 58 cases. Gross features were retrieved from the original pathology reports, where available. Tumors were classified according to their predominant histology (defined as a single pattern constituting more than 50% of the tumor) as TCC, serous, clear cell, endometrioid, or undifferentiated. Histological criteria for the diagnosis of TCC were those used by Austin and Norris. 1 Briefly, they defined TCC as an invasive tumor closely resembling carcinoma of the bladder without a benign Brennen component. Minor areas of squamous carcinoma or adenocarcinoma are observed in up to half the cases. 1 Those that did not have a predominant pattern were classified as mixed carcinomas. A mean of five sections were reviewed per case (range, 1 to 16; median, 4). In addition to evaluation of histological subtype, tumors were given both a histological and cytological grade. TCCs were graded according to the World Health Organization criteria for the grading of bladder tumors. 5 Mitotic counts per 10 high power fields and the presence or absence of vascular invasion, necrosis, and associated inflammation were recorded. Three pathologists independently reviewed all cases. When disagreement occurred (four cases), all three pathologists reevaluated the case. A case was called TCC only if a consensus was reached. In cases in which TCC constituted 50% or more of the tumor, omental implants were also reviewed, if available. Implant histology was classified according to the predominant component, as discussed previously. Clinical follow-up information was obtained from chart reviews. The frequency of TCC in this population was determined, and the outcome in these cases was compared with that of other histological subgroups.

Statistical Analysis Data on 58 patients with stage III or IV ovarian cancer were provided. Overall survival (OS) was calculated from time

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TABLE 1.

Mean age (range) Stage III (Optimal debulking) Stage IV Cycles (mean) Radiation treatment (no. of patients) Bilateral Unilateral (unknown) Mean tumor size (cm) <3 3-10 10-15 >15 Unknown size

Clinical Data

All Cases (N= 58)

TCC (N= 13)

51 (18-71) 33 (17) 25 3.5 7 44 6 (8) 6.9 4 32 10 2 10

57 (44-70) 9 (4) 4 3.6 1 10 1 (2) 8.9 0 8 0 2 3

Mixed: TCC 50% (N= 2) 56 (49-64) 1 (1) 1 4.0 0 1 1 5.2 0 2 0 0 0

Serous (N= 25)

Other* (N= 18)

47 (18-69) 14 (5) 11 3.6 4 16 3 (6) 6.8 1 14 5 0 5

52 (32-71) 9 (7) 9 3.1 2 17 1 5.9 3 8 5 0 2

* Includes the following ovarian carcinomas: clear cell (7), endometrioid (3), mixed (3), undifferentiated (3), mucinous (1), and serous surface (1).

of diagnosis until date of death or last follow-up. Disease-free survival (DFS) was calculated from time of diagnosis until the time that disease recurrence was noted. In patients who never were rendered disease free, DFS was considered to have 0month duration. The probability of OS or DFS was determined by the Kaplan-Meier method, 6 and the significance of the difference between Kaplan-Meier curves was determined by the Mantel-Haenszel method. 7 All P values are two-sided and denoted by P2.

RESULTS Patient Data T h e 58 patients studied r a n g e d from 18 to 71 years of age (mean, 51). Thirty-three cancers were stage III (22 stage IIIC), a n d 25 were stage IV. O f the stage III patients, 17 h a d optimal d e b u l k i n g of disease o n inidal laparotomy (residual disease < 2 cm in greatest d i m e n s i o n ) , whereas

16 h a d suboptimal d e b u l k i n g (residual disease > 2 cm in greatest d i m e n s i o n ) . I n general, patients received three or four cycles of c h e m o t h e r a p y (mean, 3). Seven patients also received a b d o m i n a l radiation. Clinical i n f o r m a t i o n for patients in the study is shown in Table 1. O f the 58 p a t i e n t s studied, 13 h a d TCC~predomin a n t t u m o r s (22%). M e a n age of this p a t i e n t g r o u p was 57 years. N i n e p a t i e n t s were stage III, a n d f o u r were stage IV. O f the stage III patients, f o u r were optimally d e b u l k e d , a n d five h a d b u l k y r e s i d u a l disease (Table 1). Patients received a m e a n of 3.6 cycles of c h e m o t h e r apy, a n d o n e also received a b d o m i n a l r a d i a t i o n . As can b e seen i n T a b l e 1, the T C C p a t i e n t s were a m e a n o f 10 years o l d e r t h a n those with serous t u m o r s . I n a d d i t i o n , two o t h e r p a t i e n t s h a d m i x e d t u m o r s i n which T C C c o n s t i t u t e d 50% o f the t u m o r . M e a n age was 56 years. O n e p a t i e n t was stage III, optimally d e b u l k e d , a n d o n e was stage IV.

FIGURE I. (A) The papillae are lined by epithelial cells more than 10 cell layers thick and with cellular features similar to TCC of bladder. (Hematoxylin-eosin stain; original magnification x150,) (B) Higher magnification of the papillary fronds, (Hematoxylineosin stain; original magnification ×200.) 1268

TRANSITIONAL CELL CARCINOMA OF OVARY (Hollingsworth et al)

FIGURE 2. Solid areas are commonly present in ovarian TCC. (Hematoxylin-eosin stain; original magnification x250.)

u n d e r 10 cm, a n d m e a n t u m o r size was s o m e w h a t larger in the TCCs t h a n in the serous t u m o r s (mean, 8.9 c m vs 6.8 cm). Histologically, the TCCs r e s e m b l e d transitional cell c a r c i n o m a o f the bladder. Five were g r a d e II, whereas the r e m a i n d e r were g r a d e III; three exhibited vascular invasion. Necrosis was rare or absent in seven a n d easily f o u n d in six o f the cases (Table 3). A m e a n o f 5.8 mitoses were f o u n d p e r 10 high p o w e r fields, a n d in f o u r cases a b n o r m a l mitoses were easily f o u n d . Five o f the cases were 100% TCC, the rest c o n t a i n e d 30% to 40% serous (two cases), 20% to 30% serous (three cases), a m i n o r serous (three cases), or 25% e n d o m e t r i oid (one case) c a r c i n o m a c o m p o n e n t . O m e n t a l implants were available for review in 9 o f the 13 T C C - p r e d o m i n a n t cases. O f these, five h a d p r e d o m i n a n t l y T C C histology in the implants. A n additional case h a d p r e d o m i n a n t l y s q u a m o u s cell carcin o m a in the implants; this case was i n t e r p r e t e d as consistent with s q u a m o u s differentiation in a transitional cell carcinoma.

Pathological Review

Statistical Analysis

I n d e p e n d e n t review o f the 58 cases by three pathologists was p e r f o r m e d . T h i r t e e n o f the cases were determ i n e d to be T C C (Figs 1 a n d 2), a n d an additional two o f m i x e d histology were f o u n d to have 50% T C C histology. Twenty-five o f the cases were d e t e r m i n e d to be serous, a n d the r e m a i n i n g 18 were o f different types (7 clear cell, 3 e n d o m e t r i o i d , 3 mixed, 3 undifferentiated, 1 m u c i n o u s , a n d 1 serous surface c a r c i n o m a ) . In addition, f o u r o f the serous cases c o n t a i n e d a m i n o r T C C c o m p o n e n t (Table 2). Most o f the 58 patients in the study h a d bilateral tumors; 6 were unilateral, a n d in 8 cases this information was unavailable (Table 1). In cases in which measurements were available (50 cases), 3 m e a s u r e d less than 3 cm, 34 m e a s u r e d between 3 a n d 10 cm, 11 were between 10 a n d 15 cm, a n d 2 were greater t h a n 15 cm. O f the TCCs, 10 were bilateral, 1 was unilateral, a n d 2 were o f u n k n o w n laterality. T u m o r size, w h e n known, r a n g e d f r o m 3 to 23 cm (mean, 8.9 cm). Most were

Table 4 provides the survival data. Patients with T C C h a d a m e d i a n OS o f 23.7 m o n t h s , whereas patients with serous t u m o r s h a d a m e d i a n OS o f 29.3 m o n t h s (P2 = .78). M e d i a n DFS for T C C was 1.3 m o n t h s a n d for serous t u m o r s was 4.7 m o n t h s (P2 = .75). Stage was f o u n d to be a significant p r e d i c t o r o f OS (P2 = .0009) b u t n o t o f DFS. Histological subtype was n o t f o u n d to

TABLE 2.

Serous Carcinomas With a Minor TCC Component Patient No.

TCC (%) Age (yr) Stage Grade Architectural Cytological Follow-up (mo) OS (too) DFS (too)

1

2

25 48 IV

20 63 III-optimally debulked

3 3 30 30 22

3 3 32 32 13

3

4

10 54 III

Minor 47 III

2 2 39.5 39.5 19

2 3 16 16 0

TABLE 3. TCC ( N = 13) Tumor necrosis Absent Rare Easily found Vascular invasion Mitoses/10 HPFs (mean) (range) Abnormal mitoses Absent Rare Easily found Histological grade I II III Cytological grade I II III

Abbreviations: TCC, transitional cell carcinoma; OS, overall survival; DFS, disease-free survival.

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Histological Features Mixed: TCC 50% ( N = 2)

Serous ( N = 25)

4 3 6

1 1 0

9 10 6

3

1

6

5.8 (3-10) 4.8 (3-6.5)

3.7 (0.5-9)

0 9 4

0 2 0

10 8 7

N/A N/A N/A

N/A N/A N/A

12 10 3

0 5 8

0 0 2

6 9 10

Other ( N = 18)

3.] (0.5-7.5) 6

11 1

0 4 14

Abbreviation: HPFs, high power fields; N/A, not applicable.

HUMAN PATHOLOGY T,~BI.E 4. Patient No.

Volume 27, No. 12 (December 1996)

Description of Kaplan-Meier Plots Produced

Survival

Description

12-mo Estimate (95% CI)

36-mo Estimate (95% CI)

All patients Stage III Stage IV Serous TCC Other

.790 .968 .557 .840 .788 .718

.382 .539 .152 .348 .394 .410

11

OS OS OS OS OS OS Stage III OS OS OS Stage IV OS OS OS DFS DFS DFS DFS DFS DFS DFS DFS DFS DFS DFS DFS DFS DFS OS

12

OS

1

2 3 4

5

6 7 8 9

10

13 14

DFS DFS

Serous TCC Other Serous TCC Other All patients Stage III Stage IV Serous TCC Other Stage III Serous TCC Other Stage IV Serous TCC Other TCC primary with either: TCC omental implant Non-TCC omental implant Serous primary TCC primary with TCC omental implant Serous primary TCC primary with TCC omental implant in TCC primary with either: TCC omental implant Non-TCC omental implant

(.599, (.838, (.367, (.653, (.526, (.485,

.829) .994) .732) .936) .926) .873)

1.000 (N/A) .889 (.565, .980) 1.000 (N/A) .636 .600 .444 .299 .372 .200 .332 .229 .313

.525) .709) .389) .568) .675) .642)

.446 (.214, .705) .444 (.167, .762) .750 (.409, .929)

28.0 38.0 13.7 29.3 23.7 15.6 32.8 25.25 50.0

P2*

.0009 .78

.62

.848) .882) .733) .432) .547) .406) .536) .495) .550)

.255 (.075, .589) .300 (.059, .745) 0.000 (N/A) .175 (.094, .302) .236 (.120, .412) 0.00 (N/A) .071 (.014, .288) .152 (.043, .416) .313 (.145, .550)

18.4 9.3 10.5 3.8 6.4 0.5 4.7 1.3 2.0

.286 (.117, .546) .240 (.070, .570) .667 (.354, .879)

.071 (.013, .315) .120 (.022, .456) .667 (.354, .879)

4.5 2.5 41.2

.94

(.194, .713) (.036, .624) (N/A) (.436, .970)

0.00 (N/A) 0.00 (N/A) 0.00 (N/A) .333 (.097, .700)

2.7 0.0 0.0 24.0

.48

1.000 (N/A) .840 (.653, .936) .833 (.436, .970)

.500 (.095, .905) .348 (.175, .568) .333 (.097, .700)

20.0 29.3 24.0

.90

.332 (.176, .536) .333 (.097, .700)

.071 (.014, .288) .333 (.097, .700)

4.7 0.0

.333 (.097, .700)

.333 (.097, .700)

0.0

.436 0.200 0.000 .833

(.354, (.231, (.189, (.193, (.224, (.083, (.176, (.082, (.145,

(.257, (.360, (.048, (.178, (.169, (.212,

Months (Median)

.200 (.036, .624)

(N/A)

2.0

.81

.14 .75

.87 .49

.33

Abbreviations: CI, confidence interval; OS, overall survival; DFS, disease-free survival; TCC, transitional cell carcinoma. * The P2 values in plot numbers 3 to 5 and 8 to 9 represent comparisons between serous carcinoma and TCC only.

be a significant predictor of OS or DFS even when patients were c o m p a r e d within a given FIGO stage. It is clear that TCC does not confer a favorable prognosis in this g r o u p of patients. Six patients with TCC had TCC in their omental implants as well. Median OS in these six patients was 24 m o n t h s versus 20 m o n t h s for primary TCC with predominantly serous omental implants (P2 = .90). Median DFS in these two groups of patients was 0 and 2 months, respectively (P2 = .33). OS and DFS for primary serous carcinoma versus primary TCC with TCC omental implants were also not significantly different. The two patients with 50% TCC h a d serous carcinoma in their omental implants.

DISCUSSION The authors were interested in evaluating the frequency of TCC in a population of patients with high-

stage ovarian carcinoma. Fifty-eight patients were evaluated; 13 of t h e m had TCC as the p r e d o m i n a n t histological subtype (22% of cases). In addition, two others had a mixed histology c o m p o s e d of 50% TCC. Four other patients had TCC as a m i n o r c o m p o n e n t . In all, 19 patients had some transitional cell areas within their tumors. This compares favorably to the incidence of TCC in high-stage ovarian cancer r e p o r t e d by Robey et al, ~ who studied 53 cases and f o u n d 18 examples of TCC (34% of cases). A subsequent study of 934 ovarian cancers of all stages by that g r o u p showed 88 cases of TCC, an incidence of 9.4%. 2 Fifty-eight of these cases were TCC p r e d o m i n a n t ; the rest exhibited TCC as a m i n o r c o m p o n e n t . Given the higher percentage of TCC observed in high-stage cancers in both this study and that of Robey et al, 3 it is possible that TCC is m o r e often f o u n d in high-stage, m o r e aggressive lesions. In fact, most TCCs observed in the study of Silva et al 2 m e n t i o n e d previously were stage III a n d IV (83%).

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TCC of the ovary has b e e n described recently as a distinct clinicopathologic e n t i t y / a l t h o u g h the creation of a category of urothelial carcinomas of the ovary had b e e n p r o p o s e d previously, s TCC resembles typical carcin o m a of the bladder, sometimes also containing a squamous or a d e n o c a r c i n o m a c o m p o n e n t . 9 Histologically, it is identical to malignant B r e n n e r tumor, differing f r o m that entity primarily by the lack of a benign Brenner c o m p o n e n t . In fact, the t u m o r had b e e n described in 1972 in a study of proliferative and malignant Brenner tumors by Miles and Norris. a° Austin and Norris 1 c o m p a r e d the clinical and pathological features of TCC with that of malignant B r e n n e r t u m o r and concluded that TCC is a m o r e aggressive neoplasm, sufficiently different to warrant separate categorization. Subsequently, Robey et al 3 reviewed 53 cases of high-grade, high-stage ovarian carcinoma, 18 of which had a TCCp r e d o m i n a n t histology. S Interestingly, 94% of those patients r e s p o n d e d to chemotherapy, and 83% were alive without disease, whereas 89 % of the n o n - T C C - p r e d o m inant cases developed t u m o r p r o g r e s s i o n / r e c u r r e n c e , and 77% were dead of disease (DOD). a It was concluded that TCC was an i m p o r t a n t histological type to recognize because of the favorable response to chemotherapy and because of the a p p a r e n t improved patient survival. In fact, Austin and Norris had also n o t e d a favorable response to c h e m o t h e r a p y in some cases of TCC. 1 In a subsequent study, Silva et al 2 again d e t e r m i n e d that a p r e d o m i n a n t TCC pattern in the primary t u m o r was a favorable prognostic indicator. Twenty-five of 29 patients with n o n - T C C - p r e d o m i n a n t tumors were DOD c o m p a r e d with only 30 of 51 patients with TCCp r e d o m i n a n t tumors (P = .02).2 In a continuation of the work of Silva and coworkers, Gershenson et al ~1 studied 62 cases of TCC retrospectively, matching each case with a serous carcinoma case of similar stage and a m o u n t of residual disease. Patients with TCC h a d a 37% complete response rate c o m p a r e d with 11% in patients with serous carcinoma. Median survival time was 52.3 months for TCC versus 22.0 months in patients with serous carcinoma. Progression-free survival time was better for the TCC patients as well. They concluded that TCC was m o r e chemosensitive a n d conferred a better prognosis than serous tumors. T h e authors were also interested in investigating a potential improved response to c h e m o t h e r a p y or an improved patient survival in these tumors. All patients were treated on one of two similar c h e m o t h e r a p y protocols, helping to eliminate t r e a t m e n t differences as a factor in outcome. In this g r o u p of patients, a TCCp r e d o m i n a n t histology did not confer a survival advantage c o m p a r e d with serous tumors (/)2 = .72). T h e presence of TCC did not improve DFS (P2 = .75). In this study, patients who had T C C - p r e d o m i n a n t histology did not fare any better than those with serous tumors. Silva et al 2 n o t e d that patients with tumors of pure, as o p p o s e d to p r e d o m i n a n t , TCC histology can do poorly. Seven of 10 cases were DOD in less than 5 years. They postulated that p o o r outcomes were influenced by

other factors including stage IV disease (four patients), t r e a t m e n t by radiation therapy alone (one patient), and the presence of serous carcinoma in the omental implants (two patients). Five patients in this study had 100% TCC histology, and no significant difference was n o t e d in o u t c o m e c o m p a r e d with the other TCC cases. Silva et al 2 and Gershenson et al n r e p o r t that the type of t u m o r present in the metastases is also of prognostic value. In patients whose primary t u m o r was TCC p r e d o m i n a n t and who received chemotherapy, those whose implants were predominantly TCC fared better than those whose implants contained other histological types. O f 27 patients with predominantly TCC in the implants, 12 were DOD, whereas 13 of 14 patients with p r e d o m i n a n t l y serous or undifferentiated carcinoma in the implants were DOD. 2 The r e p o r t by Gershenson et al n confirmed this finding. In this study there was no prognostic advantage observed in patients with TCC primaries who also had a p r e d o m i n a n c e of TCC in their metastatic disease when c o m p a r e d with either patients with serous primaries or those TCC patients with nonTCC metastatic disease. O n e possible explanation of the difference between our results and those of the M.D. Anderson investigators2,3,~ 1 is diffe rent criteria for the diagnosis of TCC. Histological typing of ovarian tumors is notorious for interobserver disagreement12; however, the three pathologists in this study independently m a d e the diagnosis of TCC in each of these cases, and o u r finding of overall prevalence o f a TCC c o m p o n e n t (33%) is essentially identical to that of Robey et al 3 (34%) for highstage cases. Urothelial differentiation is relatively easy to identify, and the absence of a benign B r e n n e r comp o n e n t in a well-sampled t u m o r is verifiable. The major differential diagnostic considerations are metastatic TCC of urinary tract origin and undifferentiated carcinoma. N o n e of our patients had evidence of urinary tract involvement after extensive diagnostic workup. Undifferentiated carcinoma consists of sheets of undifferentiated cells rather than cells with urothelial features. As discussed by Silva et al, 2 extensive necrosis in an undifferentiated carcinoma could mimic papillae with central fibrovascular cores. TCC, however, exhibits true papillae, which project into empty spaces, without necrosis in the lumen. A n o t h e r possible explanation for the discrepancy between our results and those previously published could be caused by differences in c h e m o t h e r a p y regimens at the two institutions. In the studies of Robey et al a and Silva et al, 2 several different c h e m o t h e r a p y regimens were used to treat their patients, whereas all of our patients were treated on one of two similar cisplatinbased regimens. The patients studied by Gershenson et al, n however, all received cisplatin-based combination c h e m o t h e r a p y as their initial postoperative therapy. T h a t study concluded that TCC is m o r e chemosensitive than poorly differentiated carcinoma and that it is associated with a better prognosis. It seems that this population is closely m a t c h e d to ours, yet we did not find that our TCC patients did better overall or that the tumors in our study were m o r e responsive to chemotherapy.

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It is clear that m o r e study of this entity is warranted to further elucidate the biology a n d clinical behavior of ovarian TCC.

REFERENCES 1. Austin RM, Norris HJ: Malignant Brenner tumor and transitional cell carcinoma of the ovary: A comparison. IntJ Gynecol Pathol 6:29-39, 1987 2. Silva EG, Robey-Cafferty SS, Smith TL, et al: Ovarian carcinomas with transitional cell carcinoma pattern. AmJ Clin Patho193:457465, 1990 3. Robey SS, Silva EG, Gershenson DM, et al: Transitional cell carcinoma in high-grade high-stage ovarian carcinoma: An indicator of favorable response to chemotherapy. Cancer 63:839-847, 1989 4. Rothenberg ME, Ozols RF, Glatstein E, et al: Dose-intensive induction therapy with cyclophosphamide, cisplatin, and consolidarive abdominal radiation in advanced-stage epithelial ovarian cancer. J Clin Oncol 10:727-734, 1992

5. Mostofi FK, Sobin LH, Torloni H: International Histologic Classification of Tumors, No. 10: Histologic Typing of Urinary Bladder Tumors. Geneva, Switzerland, World Health Organization, 1973 6. Igaplan E, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 7. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chem Rep 50:163-170, 1966 8. Roth LM, Czernobilsky B: Ovarian Brenner rumors. II. Malignant. Cancer 56:592-601, 1985 9. Roth LM, Gersell DJ, Ulbright TM: Ovarian Brenner tumors and transitional cell carcinoma: Recent developments. I n t J Gynecol Pathol 12:128-133, 1993 10. Miles PA, Norris HJ: Proliferative and malignant Brenner tumors of the ovary. Cancer 30:174-186, 1972 11. Gershenson DM, Silva EG, Mitchell MF, et al: Transitional cell carcinoma of the ovary': A matched control study of advance& stage patients treated with cisplatin-based chemotherapy. AmJ Obstet Gynecol 168:1178-1187, 1993 12. Silverberg SG: Prognostic significance of pathologic features of ovarian carcinoma. Curr Top Pathol 78:85-109, 1989

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