Ovarian Carcinomas with Transitional Cell Carcinoma Pattern ELVIO G. SILVA, M.D., SUSAN S. ROBEY-CAFFERTY, M.D., TERRY L. SMITH, B.S., M.S., AND DAVID M. GERSHENSON, M.D.
Departments of Pathology, Biomathematics, and Gynecology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
TRANSITIONAL CELL CARCINOMA (TCC) has been only recently recognized as one of the main types of ovarian carcinoma.1 The absence of benign Brenner component separates TCC from malignant Brenner tumor.' In a previous study designed to evaluate the results of chemotherapy in a selected group of patients with high-grade ovarian carcinomas, we noticed that 18 patients with tumors composed predominantly of TCC responded excellently to chemotherapy.17 To test the validity of these ob-
Received May 17, 1989; received revised manuscript and accepted for publication September 6, 1989. Address reprint requests to Dr. Silva: Department of Pathology—Box 85, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030.
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servations, we reviewed 88 ovarian carcinomas that had a focal or diffuse TCC pattern. Materials and Methods We reviewed hematoxylin and eosin-stained microscopic slides from 934 ovarian carcinomas seen at The University of Texas M. D. Anderson Cancer Center between 1970 and 1983. We identified 88 cases containing a focal or diffuse TCC pattern (16 of which have been described previously17). The histologic requirements for the diagnosis of TCC were as follows: thick papillary proliferations, a smooth luminal border, and projection into empty cystic spaces. The epithelial cells forming the papillae were polygonal. Focally, spindle cells and glandular lumina were observed. The neoplasms were graded according to the World Health Organization (WHO) criteria for TCC of the urinary tract.15 Cases with areas of benign Brenner tumor were not included in this study. The tumors were staged according to the International Federation of Gynaecology and Obstetrics staging system." Clinical and follow-up data for a minimum of five years, or until the patient's death, were obtained for every patient. Survival intervals were computed from the date of initial surgery, and survival distributions were estimated by the method of Kaplan and Meier.12 Comparisons of survival rates among groups were accomplished by means of a log-rank test.13 Results The 88 patients with ovarian neoplasms ranged in age from 28 to 76 years (mean, 51 years). Eighty-one of the tumors were discovered during a pelvic examination, performed because of pelvic discomfort (45), because of increased abdominal girth (31), or as a routine examination (5). Among the remainder, five patients presented with pleural effusion and two with lymph node metastases, one supraclavicular and one inguinal. At presentation, disease in 15 patients was stage II; in 59, stage III; and in 14, stage IV.
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The authors report 88 cases of ovarian carcinoma containing areas of transitional cell carcinoma (TCC). The tumors were found in women 28-76 years old (mean, 51 years). Fifteen patients presented with stage II, 59 with stage III, and 14 with stage IV disease. Ten neoplasms were composed of only TCC, 48 were predominantly TCC, and 30 had foci of TCC but the predominant component was serous, endometrioid, undifferentiated, or unclassified adenocarcinoma. After the primary resection of the neoplasm, 76 patients received chemotherapy, 4 received chemotherapy and radiotherapy, and 5 received radiotherapy only; 2 refused further treatment and 1 patient died immediately after thefirstoperation. Estimatedfive-yearsurvival rates were 37% for the entire group and 41% for those who received chemotherapy. Favorable prognostic indicators, statistically significant, were low clinical stage, predominant TCC in the primary tumor, and a negative second-look operation. Other prognostic indicators were the amount of residual tumor after the first operation and tumor differentiation. When the primary neoplasm was predominantly TCC, another prognostic indicator was the type of carcinoma present in the metastases. Five-year follow-up shows that 56% of the patients whose metastases were predominantly TCC have no evidence of disease, whereas only 7% of the patients whose metastases are predominantly nonTCC are disease-free. The authors' study indicates that ovarian carcinomas containing predominant TCC pattern have an excellent response to different chemotherapy regimens. Tumor recurrences and lack of response to chemotherapy are often associated with a change in the histologic appearance of the metastatic lesion. (Key words: Ovary; Carcinoma; Transitional cell carcinoma) Am J Clin Pathol 1990;93:457-465
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but the metastases of 36 patients were histologically different from the primary neoplasm. In 20 of these 36 metastatic tumors, the proportion of the main histologic component was smaller than it was in the primary tumor but was still the main component in the metastases. However, in 16 patients whose primary neoplasms were predominantly TCC, the metastatic neoplasms were predominantly non-TCC—serous carcinoma in 15 (Figs. 2 and 3) and undifferentiated carcinoma in 1. Treatment All patients were treated with surgical resection of the neoplasm. In four patients, the tumor was completely resected. In 75 patients, however, the tumor resection was incomplete, leaving tumor nodules smaller than 2 cm in 40 patients and larger than 2 cm in 35 patients. In 9 patients the status of residual tumor was unknown. After resection of the tumor, 76 patients received chemotherapy, 5 received radiotherapy, and 4 received radiotherapy and chemotherapy. Two patients refused additional therapy, and one patient died immediately after thefirstoperation. Several different chemotherapy regimens were used, including hexamethylmelamine-doxorubicin-cyclophosphamide(28); melphalan-cisplatin (18); melphalan (19); cisplatin-doxorubicine-cyclophosphamide (6); hexamethylmelamine (6); doxorubicin (2); and cisplatin-cyclophosphamide (1). After chemotherapy, 48 patients had
FIG. 1. Moderately differentiated transitional cell carcinoma showing thick papillae projecting into empty spaces. Hematoxylin and eosin (X50).
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Thirty-one tumors measured less than 10 cm in maximum dimension, 37 were between 10 and 15 cm, 7 were larger than 15 cm, and the size of 13 tumors was unknown. Grossly, in all tumors cystic areas alternated with solid foci. Ten neoplasms were composed of only TCC, and the TCC pattern was predominant in 48 additional primary tumors (Fig. 1). The other 30 tumors contained foci of TCC, but the predominant component was serous (10), endometrioid (3), undifferentiated (7), or unclassified adenocarcinoma (10). Mucin-producing glands were present in areas of the TCC pattern in 46 neoplasms; in 9 these glands were dilated, forming small cysts. Abundant lymphocytes were seen in foci of the TCC pattern in 22 neoplasms. In the areas of the TCC pattern, 12 tumors had fewer than 30 mitoses per ten high-powerfields(HPFs), 33 had between 30 and 50 mitoses per ten HPFs, and 43 neoplasms showed more than 50 mitoses per ten HPFs. Foci of highly anaplastic cells were seen in 22 tumors, and areas of necrosis were present in 58 tumors. Vascular invasion by tumor cells was seen in six neoplasms. Applying the WHO criteria for TCC of the urinary tract, we determined that 2 tumors were well differentiated, 30 were moderately differentiated, and 56 were poorly differentiated. The predominant histologic component in the primary tumor was also the major histologic type in 34 metastases,
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FIG. 2. A (upper). Ovarian transitional cell carcinoma showing several glandular spaces. Hematoxylin and eosin (X50). B (lower). Same case as A. Metastasis in omentum resected at the same time as the ovarian neoplasm. Irregular papillae with abundant psammomas, characteristic of serous carcinoma. Hematoxylin and eosin (X50).
a second-look operation that revealed no tumor in 28. Progressive or recurrent tumor was documented in 52 patients; in 20 it was found at the second-look operation.
Follow-up of the 88 patients revealed that 63 had died at times ranging from 1 to 108 months after surgery. This number includes three deaths attributable to causes other
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FIG. 3. A (upper). Ovarian transitional cell carcinoma, moderately differentiated. Hematoxylin and eosin (X50). B (lower). Same patient as in A. Metastasis in peritoneum found at autopsy after two years of chemotherapy. Papillary serous carcinoma. Hematoxylin and eosin (X50).
than ovarian carcinoma: one patient died immediately after surgical resection, one died of sepsis with no evidence of disease 13 months after surgical resection, and one died
ofleukemia 42 months after discovery of the ovarian neoplasm. The estimated five-year survival rate postsurgery for the whole group was 37%, whereas for patients who
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a poorer prognosis. Three of 12 patients with stage II, 41 of 56 with stage III, and 11 of 12 with stage IV disease died ofdisease (P < 0.01) (Fig. 5). A predominance of TCC was a favorable prognostic factor. Thirty of 51 patients whose tumor was predominantly TCC died ofdisease, whereas 25 of 29 with less than a 50% TCC component died of disease (P = 0.02) (Fig. 6). A negative second-look operation was also a favorable prognostic indicator. Eight of 28 patients without tumor at secondlook died ofdisease, whereas 17 of 20 patients with tumor present at that time died (P = 0.001). The eight patients who died ofdisease after a negative second-look operation died between 21 and 85 months (average, 45 months) after the second-look procedure. The 17 patients who died after a positive second-look operation died between 6 and 83 months (average, 20 months) after the operation. The amount of residual tumor after the first operation, although not prognostically significant, demonstrated a trend in the prognosis of this group of patients. Thirtysix patients had residual tumor larger than 2 cm in diameter after the primary resection; and 27 of them died
D
TOTAL DEAD 80 55 ALL CHEMO
FlG. 4. Survival curve for all patients.
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received chemotherapy it was 41%. The survival curve for the patients treated with chemotherapy is plotted in Figure 4. Of the 80 patients who received chemotherapy, 55 (69%) have died ofdisease and 25 (31%) are alive with no evidence of disease at 96 months. The patients that are alive and have no evidence of disease have been treated with hexamethylmelaminedoxorubicin-cyclophosphamide (8); melphalan-cisplatin (6); melphalan (7); cisplatin-doxorubicine-cyclophosphamide (1); hexamethylmelamine (1); doxorubicin (1); and cisplatin-cyclophosphamide (1). Seven of the eight patients who did not receive chemotherapy died ofdisease between 4 and 43 months after the primary neoplasm was discovered, and one died immediately after tumor resection. Five of the seven patients who died ofdisease had been treated with radiation only, and two had refused postsurgical treatment. Factors associated with survival for patients who received chemotherapy were clinical stage, the percentage of TCC component in the primary tumor, and the results of the second-look operation. Higher clinical stage carried
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STAGE STAGE I III STAGE III I I I
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FIG. 5. Survival curve according to clinical stage.
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MONTHS of disease. Thirty-five patients had residual tumor smaller than 2 cm in diameter after the primary surgery, and 23 of them died of disease (P - 0.09). For patients whose primary tumor was predominantly TCC and who received chemotherapy, another prognostically determinant factor was the type of neoplasm present in the metastases. These metastatic foci were resected during the first operation, at the second-look operation, or at the time of a recurrence. Of 27 patients with predominantly TCC in the metastases, 12 died of disease. However, 13 of 14 patients whose metastases were predominantly serous (13) or undifferentiated (1) carcinoma died of disease (P = 0.02). Tumor differentiation was another prognostic factor, but it was associated with the percentage of TCC in the primary tumor. Poorly differentiated neoplasms responded better to chemotherapy than moderately differentiated tumors. Twenty-eight of 33 patients with moderately differentiated neoplasm died of disease, whereas only 25 of 46 patients with poorly differentiated tumors died. However, 73% of the poorly differentiated tumors
were TCC predominant, whereas moderate differentiation was associated with only 54% of the TCC-predominant neoplasms. Other factors investigated included degree of anaplasia and presence of necrosis, vascular invasion, glands in the TCC component, and lymphocytic infiltration in the TCC component; none demonstrated any prognostic value. There was no statistically significant difference in the survival rates of the patients according to the type of chemotherapy received; however, these were not designed as comparative studies. Disseminated carcinomatosis was the most common cause of death of disease. Extensive tumor involvement in the pelvis and abdomen produced intestinal and ureteral obstructions in most of the patients who died. Discussion The presence of areas resembling a poorly differentiated TCC has been rarely mentioned in ovarian carcinomas.19 Most studies have not included carcinomas with a TCC
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25 TCC 50%
MONTHS pattern as one of their histologic categories. 3~8'10'14,21'23 It is possible that several of the cases designated as malignant Brenner tumors were actually TCC.9,22,24 On the other hand, requiring the presence of a benign Brenner component to designate a neoplasm as a malignant Brenner tumor might be too strict. The benign part might have been overgrown by the malignant component. To our knowledge, only four authors have reported studies of ovarian carcinomas with a predominantly TCC pattern.'' I7,22,25 The study by Austin and Norris, designed to compare malignant Brenner tumors with TCC, was, to our knowledge, the first to propose TCC as a histologic type of ovarian carcinoma.' The studies by Young and Scully25 and Weiden and Gratama 22 compared urothelial and ovarian carcinomas of identical cell types. During a review of high-grade carcinomas of the ovary, we found that tumors with a predominantly TCC pattern responded best to chemotherapy.17 However, because our main goal in that study was to evaluate the response to chemotherapy of the different tumor types, we included only patients with residual tumor after the first operation
who had received at least six courses of chemotherapy. Most were drawn from a study of patients with ovarian carcinoma who underwent a second-look operation. This provided a precise evaluation of the response of the residual tumor to chemotherapy. Based on that study, we concluded that TCC of the ovary was the best responder to chemotherapy in that group of patients. The current study was designed to evaluate that observation in a larger group of ovarian carcinoma patients with TCC component regardless of their stages, treatments, the residual tumor, and second-look operation results. We have now reviewed all cases of ovarian carcinoma with a focal or predominant TCC pattern seen at M. D. Anderson Cancer Center between 1970 and 1983. This review showed that areas of TCC are present in 9.4% of ovarian carcinomas. Our study demonstrated an estimated five-year survival rate of 37% after surgery. This survival rate is better than the rates reported from several series of patients with ovarian carcinoma, including a threeyear progression-free survival rate of 29% in the series of Piver and associates,16 a four-year survival rate of 26% in
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FlG. 6. Survival curve according to the TCC component in the primary neoplasm.
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with vessels. These areas resemble the papillae of TCC. However, we have defined the term TCC to apply only to tumors having thick papillae projecting into empty spaces and without necrosis in the lumen. Furthermore, undifferentiated carcinoma also contains sheets of tumor cells without differentiation. Although TCC can be confused with granulosa cell tumor, the presence of thick papillae, the association with other types of miillerian carcinomas, and the absence of Call-Exner bodies and trabecular pattern are distinct histologic features. In addition, most patients with TCC are clinical stage II, III, or IV, which is exceptional for patients with granulosa cell tumor. Radiotherapy, an acceptable treatment for most lowstage ovarian carcinomas, is probably not appropriate for patients with TCC.6,7 The five patients treated only with radiation died of disease in less than 60 months. The tumors in three of these patients were clinical stage II; in one patient, stage HI; and in one, stage IV. In summary, although it has been reported that histologic typing of ovarian carcinomas is of limited prognostic value, we believe that ovarian carcinomas with a TCC pattern respond excellently to chemotherapy.2 Forty-one percent of the patients who received chemotherapy for these tumors survived longer than five years. Tumor recurrences and lack of response to chemotherapy are often associated with a change in the histologic appearance of the primary neoplasm, which becomes, in metastases, predominantly non-TCC.
The association in a single neoplasm of TCC with other histologic types of miillerian carcinomas, including serous, undifferentiated, and unclassified adenocarcinoma, is probably an indication of the multipotential characteristic of the neoplastic cells. The association of primary carcinomas with a predominantly TCC pattern with predominantly non-TCC metastases may be the result of the metastatic potential of one of the components of the neoplasm or of the presence of independent primary tumors. Because, in our patients, the non-TCC was the predominant component in the metastases and the TCC was the main tumor type in the primary lesion, we believe that the most chemotherapy-resistant cell type is the one that metastasized. The recurrence after chemotherapy of a tumor composed predominantly of non-TCC elements when the primary tumor was predominantly TCC supports our view. Furthermore, tumor grade has been reported to increase after chemotherapy in patients with progressive ovarian carcinomas.4 The differential diagnosis of ovarian carcinomas with TCC pattern includes undifferentiated carcinoma and granulosa cell tumor. Undifferentiated carcinoma might simulate TCC only when areas of necrosis leave islands of tumor cells around a central zone of connective tissue
References 1. Austin RM, Norris HJ. Malignant Brenner tumor and transitional cell carcinoma of the ovary: comparison. Int J Gynecol Pathol 1987;6:29-39. 2. Baak JPA, Wisse-Brekelmans ECM, Langley FA, Talerman A, Delemarres JFM. Morphometric data to FIGO stage and histological type and grade for prognosis of ovarian tumours. J Clin Pathol 1986;39:1340-1346. 3. Chen SS. Survival of ovarian carcinoma with or without lymph node metastasis. Gynecol Oncol 1987;27:368-372. 4. Dauplat J, Nieberg RK., Philippe A, Hacker NF. Changes in the histocytological grading of epithelial ovarian carcinoma following treatment. Int J Gynecol Pathol 1988;7:12-22. 5. Einhorn N, Nilsson BO, Sjovall K. Factors influencing survival in carcinoma of the ovary: study from a well-defined Swedish population. Cancer 1985;55:2019-2025. 6. Fuller DB, Sause WT, Plenk HP, Menlove RL. Analysis of postoperative radiation therapy in stage I through III epithelial ovarian carcinoma. J Clin Oncol 1987;5:897-905. 7. Goldberg N, Preschel RE. Postoperative abdominopelvic radiation therapy for ovarian cancer. Int J Radiat Oncol 1988;14:425-429. 8. Griffin TW, Hunter RA, Cederbaum AI, et al. Treatment of advanced ovarian cancer with sequential combination chemotherapy. Cancer 1987;60:2150-2155. 9. Hallgrimsson J, Scully RE. Borderline and malignant Brenner tumours of the ovary: a report of 15 cases. Acta Pathol Microbiol Scand 1972;80:56-66. 10. Heintz APM, Van Oosterom AT, Baptist J, et al. The treatment of advanced ovarian carcinoma: clinical variables associated with prognosis. Gynecol Oncol 1988;30:347-358. 11. International Federation of Gynaecology and Obstetrics: Classifi-
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the study by Griffin and associates,8 and a five-year survival rate of 28% in the cases reviewed by Einhorn and associates.5 Similar to previous investigators, we have found that tumor stage and the results of the second-look operation are excellent prognostic indicators and that the amount of residual tumor after the initial operation is also an important consideration. 2 ' 5 ' 81014 ' 18 ' 20 ' 21 However, our study also showed that the percentage of TCC in the carcinoma is an important prognostic indicator. The presence of a TCC component of 50% or more in the primary tumor is an important indicator of favorable response to chemotherapy. Austin and Norris also recognized the effectiveness of chemotherapy for patients with TCC: in their study, only two of eight patients with TCC who had received chemotherapy had died of disease.1 However, despite the favorable prognosis conferred by TCC in a tumor, chemotherapy can fail when the carcinoma is more than 50% TCC or even composed only of TCC. In our series, the primary tumors resected from ten patients were pure TCC. Seven of these patients died of disease in less than five years, one patient lived for 62 months, and two are alive, one at 51 months with advanced disease and one disease-free at 109 months. The lack of response to the treatment in these patients with pure TCC might have been influenced by other factors. Four of these patients who died of disease had clinical stage IV disease (pleural involvement), two had omental metastases of predominantly serous carcinoma, and one had a clinical stage IIB disease but was treated with radiation alone.
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12. 13. 14. 15. 16.
17.
cation and staging of malignant tumors in the female pelvis. Acta Obstet Gynecol Scand 1971;50:1-7. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Journal of the American Statistical Association 1958;53:457-481. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemotherapy Report 1966;50:163-170. Miller DS, Ballon SC, Teng NNH, Seifer DB, Soriero OM. A critical reassessment of second-look laparotomy in epithelial ovarian carcinoma. Cancer 1986;57:530-535. Mostofi FK. Histological typing of urinary bladder tumours. In: International histological classification of tumours, No. 10. Geneva: World Health Organization, 1973:17. Piver MS, Lele SB, Marchetti DL, Baker TR, Tsukada Y, Emrich U. The impact of aggressive debulking surgery and cisplatinbased chemotherapy on progression-free survival in stage III and IV ovarian carcinoma. J Clin Oncol 1988;6:983-999. Robey SS, Silva EG, Gershenson DM, McLemore D, El-Naggar A, Ordonez NG. Transitional cell carcinoma in high-grade highstage ovarian carcinoma: an indicator of favorable response to chemotherapy. Cancer 1989;63:839-847. Rothenberg ML, Young RC. Changing concepts in the management of epithelial ovarian and cervical cancers. Med J Aust 1988; 148: 354-363.
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19. Scully RE. Tumors of the ovary and maldeveloped gonads. In: Atlas of tumor pathology, 2nd series, fascicle 16. Washington, D.C.: Armed Forces Institute of Pathology, 1978:146. 20. Sorbe B, Frankendal BO, Veress B. Importance of histologic grading in the prognosis of epithelial ovarian carcinoma. Obstet Gynecol 1982;59:576-582. 21. Swenerton KD, Hislop TG, Spinelli J, LeRiche JC, Yang N, Boyes DA. Ovarian carcinoma: a multivariate analysis of prognostic factors. Obstet Gynecol 1985;65:264-269. 22. van der Weiden RMF, Gratama S. Proliferative and malignant Brenner tumours (BT) and their differentiation from metastatic transitional cell carcinoma of the bladder: a case report and review of the literature. Eur J Obstet Gynecol Reprod Biol 1987;26:251260. 23. Wils J, Van Guens H, Baak J. Proposal for therapeutic approach based on prognostic factors including morphometric and flowcytometric features in stage III—IV ovarian cancer. Cancer 1988;61: 1920-1925. 24. Woodruff JD, Dietrich D, Genadry R, Parmley TH. Proliferative and malignant Brenner tumors: review of 47 cases. Am J Obstet Gynecol 1981;141:118-125. 25. Young RH, Scully RE. Urothelial and ovarian carcinomas of identical cell types: problems in interpretation. Int J Gynecol Pathol 1988;7:197-211.
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18.
TRANSITIONAL CELL CARCINOMA OF THE OVARY
Departments of Pathology, Biomathematics, and Gynecology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
TRANSITIONAL CELL CARCINOMA (TCC) has been only recently recognized as one of the main types of ovarian carcinoma.1 The absence of benign Brenner component separates TCC from malignant Brenner tumor.' In a previous study designed to evaluate the results of chemotherapy in a selected group of patients with high-grade ovarian carcinomas, we noticed that 18 patients with tumors composed predominantly of TCC responded excellently to chemotherapy.17 To test the validity of these ob-
Received May 17, 1989; received revised manuscript and accepted for publication September 6, 1989. Address reprint requests to Dr. Silva: Department of Pathology—Box 85, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030.
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servations, we reviewed 88 ovarian carcinomas that had a focal or diffuse TCC pattern. Materials and Methods We reviewed hematoxylin and eosin-stained microscopic slides from 934 ovarian carcinomas seen at The University of Texas M. D. Anderson Cancer Center between 1970 and 1983. We identified 88 cases containing a focal or diffuse TCC pattern (16 of which have been described previously17). The histologic requirements for the diagnosis of TCC were as follows: thick papillary proliferations, a smooth luminal border, and projection into empty cystic spaces. The epithelial cells forming the papillae were polygonal. Focally, spindle cells and glandular lumina were observed. The neoplasms were graded according to the World Health Organization (WHO) criteria for TCC of the urinary tract.15 Cases with areas of benign Brenner tumor were not included in this study. The tumors were staged according to the International Federation of Gynaecology and Obstetrics staging system." Clinical and follow-up data for a minimum of five years, or until the patient's death, were obtained for every patient. Survival intervals were computed from the date of initial surgery, and survival distributions were estimated by the method of Kaplan and Meier.12 Comparisons of survival rates among groups were accomplished by means of a log-rank test.13 Results The 88 patients with ovarian neoplasms ranged in age from 28 to 76 years (mean, 51 years). Eighty-one of the tumors were discovered during a pelvic examination, performed because of pelvic discomfort (45), because of increased abdominal girth (31), or as a routine examination (5). Among the remainder, five patients presented with pleural effusion and two with lymph node metastases, one supraclavicular and one inguinal. At presentation, disease in 15 patients was stage II; in 59, stage III; and in 14, stage IV.
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The authors report 88 cases of ovarian carcinoma containing areas of transitional cell carcinoma (TCC). The tumors were found in women 28-76 years old (mean, 51 years). Fifteen patients presented with stage II, 59 with stage III, and 14 with stage IV disease. Ten neoplasms were composed of only TCC, 48 were predominantly TCC, and 30 had foci of TCC but the predominant component was serous, endometrioid, undifferentiated, or unclassified adenocarcinoma. After the primary resection of the neoplasm, 76 patients received chemotherapy, 4 received chemotherapy and radiotherapy, and 5 received radiotherapy only; 2 refused further treatment and 1 patient died immediately after thefirstoperation. Estimatedfive-yearsurvival rates were 37% for the entire group and 41% for those who received chemotherapy. Favorable prognostic indicators, statistically significant, were low clinical stage, predominant TCC in the primary tumor, and a negative second-look operation. Other prognostic indicators were the amount of residual tumor after the first operation and tumor differentiation. When the primary neoplasm was predominantly TCC, another prognostic indicator was the type of carcinoma present in the metastases. Five-year follow-up shows that 56% of the patients whose metastases were predominantly TCC have no evidence of disease, whereas only 7% of the patients whose metastases are predominantly nonTCC are disease-free. The authors' study indicates that ovarian carcinomas containing predominant TCC pattern have an excellent response to different chemotherapy regimens. Tumor recurrences and lack of response to chemotherapy are often associated with a change in the histologic appearance of the metastatic lesion. (Key words: Ovary; Carcinoma; Transitional cell carcinoma) Am J Clin Pathol 1990;93:457-465
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but the metastases of 36 patients were histologically different from the primary neoplasm. In 20 of these 36 metastatic tumors, the proportion of the main histologic component was smaller than it was in the primary tumor but was still the main component in the metastases. However, in 16 patients whose primary neoplasms were predominantly TCC, the metastatic neoplasms were predominantly non-TCC—serous carcinoma in 15 (Figs. 2 and 3) and undifferentiated carcinoma in 1. Treatment All patients were treated with surgical resection of the neoplasm. In four patients, the tumor was completely resected. In 75 patients, however, the tumor resection was incomplete, leaving tumor nodules smaller than 2 cm in 40 patients and larger than 2 cm in 35 patients. In 9 patients the status of residual tumor was unknown. After resection of the tumor, 76 patients received chemotherapy, 5 received radiotherapy, and 4 received radiotherapy and chemotherapy. Two patients refused additional therapy, and one patient died immediately after thefirstoperation. Several different chemotherapy regimens were used, including hexamethylmelamine-doxorubicin-cyclophosphamide(28); melphalan-cisplatin (18); melphalan (19); cisplatin-doxorubicine-cyclophosphamide (6); hexamethylmelamine (6); doxorubicin (2); and cisplatin-cyclophosphamide (1). After chemotherapy, 48 patients had
FIG. 1. Moderately differentiated transitional cell carcinoma showing thick papillae projecting into empty spaces. Hematoxylin and eosin (X50).
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Thirty-one tumors measured less than 10 cm in maximum dimension, 37 were between 10 and 15 cm, 7 were larger than 15 cm, and the size of 13 tumors was unknown. Grossly, in all tumors cystic areas alternated with solid foci. Ten neoplasms were composed of only TCC, and the TCC pattern was predominant in 48 additional primary tumors (Fig. 1). The other 30 tumors contained foci of TCC, but the predominant component was serous (10), endometrioid (3), undifferentiated (7), or unclassified adenocarcinoma (10). Mucin-producing glands were present in areas of the TCC pattern in 46 neoplasms; in 9 these glands were dilated, forming small cysts. Abundant lymphocytes were seen in foci of the TCC pattern in 22 neoplasms. In the areas of the TCC pattern, 12 tumors had fewer than 30 mitoses per ten high-powerfields(HPFs), 33 had between 30 and 50 mitoses per ten HPFs, and 43 neoplasms showed more than 50 mitoses per ten HPFs. Foci of highly anaplastic cells were seen in 22 tumors, and areas of necrosis were present in 58 tumors. Vascular invasion by tumor cells was seen in six neoplasms. Applying the WHO criteria for TCC of the urinary tract, we determined that 2 tumors were well differentiated, 30 were moderately differentiated, and 56 were poorly differentiated. The predominant histologic component in the primary tumor was also the major histologic type in 34 metastases,
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FIG. 2. A (upper). Ovarian transitional cell carcinoma showing several glandular spaces. Hematoxylin and eosin (X50). B (lower). Same case as A. Metastasis in omentum resected at the same time as the ovarian neoplasm. Irregular papillae with abundant psammomas, characteristic of serous carcinoma. Hematoxylin and eosin (X50).
a second-look operation that revealed no tumor in 28. Progressive or recurrent tumor was documented in 52 patients; in 20 it was found at the second-look operation.
Follow-up of the 88 patients revealed that 63 had died at times ranging from 1 to 108 months after surgery. This number includes three deaths attributable to causes other
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FIG. 3. A (upper). Ovarian transitional cell carcinoma, moderately differentiated. Hematoxylin and eosin (X50). B (lower). Same patient as in A. Metastasis in peritoneum found at autopsy after two years of chemotherapy. Papillary serous carcinoma. Hematoxylin and eosin (X50).
than ovarian carcinoma: one patient died immediately after surgical resection, one died of sepsis with no evidence of disease 13 months after surgical resection, and one died
ofleukemia 42 months after discovery of the ovarian neoplasm. The estimated five-year survival rate postsurgery for the whole group was 37%, whereas for patients who
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a poorer prognosis. Three of 12 patients with stage II, 41 of 56 with stage III, and 11 of 12 with stage IV disease died ofdisease (P < 0.01) (Fig. 5). A predominance of TCC was a favorable prognostic factor. Thirty of 51 patients whose tumor was predominantly TCC died ofdisease, whereas 25 of 29 with less than a 50% TCC component died of disease (P = 0.02) (Fig. 6). A negative second-look operation was also a favorable prognostic indicator. Eight of 28 patients without tumor at secondlook died ofdisease, whereas 17 of 20 patients with tumor present at that time died (P = 0.001). The eight patients who died ofdisease after a negative second-look operation died between 21 and 85 months (average, 45 months) after the second-look procedure. The 17 patients who died after a positive second-look operation died between 6 and 83 months (average, 20 months) after the operation. The amount of residual tumor after the first operation, although not prognostically significant, demonstrated a trend in the prognosis of this group of patients. Thirtysix patients had residual tumor larger than 2 cm in diameter after the primary resection; and 27 of them died
D
TOTAL DEAD 80 55 ALL CHEMO
FlG. 4. Survival curve for all patients.
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24
36
48 60 MONTHS
72
84
96
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received chemotherapy it was 41%. The survival curve for the patients treated with chemotherapy is plotted in Figure 4. Of the 80 patients who received chemotherapy, 55 (69%) have died ofdisease and 25 (31%) are alive with no evidence of disease at 96 months. The patients that are alive and have no evidence of disease have been treated with hexamethylmelaminedoxorubicin-cyclophosphamide (8); melphalan-cisplatin (6); melphalan (7); cisplatin-doxorubicine-cyclophosphamide (1); hexamethylmelamine (1); doxorubicin (1); and cisplatin-cyclophosphamide (1). Seven of the eight patients who did not receive chemotherapy died ofdisease between 4 and 43 months after the primary neoplasm was discovered, and one died immediately after tumor resection. Five of the seven patients who died ofdisease had been treated with radiation only, and two had refused postsurgical treatment. Factors associated with survival for patients who received chemotherapy were clinical stage, the percentage of TCC component in the primary tumor, and the results of the second-look operation. Higher clinical stage carried
461
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A.J.C.P. • April 1990
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FIG. 5. Survival curve according to clinical stage.
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MONTHS of disease. Thirty-five patients had residual tumor smaller than 2 cm in diameter after the primary surgery, and 23 of them died of disease (P - 0.09). For patients whose primary tumor was predominantly TCC and who received chemotherapy, another prognostically determinant factor was the type of neoplasm present in the metastases. These metastatic foci were resected during the first operation, at the second-look operation, or at the time of a recurrence. Of 27 patients with predominantly TCC in the metastases, 12 died of disease. However, 13 of 14 patients whose metastases were predominantly serous (13) or undifferentiated (1) carcinoma died of disease (P = 0.02). Tumor differentiation was another prognostic factor, but it was associated with the percentage of TCC in the primary tumor. Poorly differentiated neoplasms responded better to chemotherapy than moderately differentiated tumors. Twenty-eight of 33 patients with moderately differentiated neoplasm died of disease, whereas only 25 of 46 patients with poorly differentiated tumors died. However, 73% of the poorly differentiated tumors
were TCC predominant, whereas moderate differentiation was associated with only 54% of the TCC-predominant neoplasms. Other factors investigated included degree of anaplasia and presence of necrosis, vascular invasion, glands in the TCC component, and lymphocytic infiltration in the TCC component; none demonstrated any prognostic value. There was no statistically significant difference in the survival rates of the patients according to the type of chemotherapy received; however, these were not designed as comparative studies. Disseminated carcinomatosis was the most common cause of death of disease. Extensive tumor involvement in the pelvis and abdomen produced intestinal and ureteral obstructions in most of the patients who died. Discussion The presence of areas resembling a poorly differentiated TCC has been rarely mentioned in ovarian carcinomas.19 Most studies have not included carcinomas with a TCC
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0.3"
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TRANSITIONAL CELL CARCINOMA OF THE OVARY
D A
TOTAL 29 51
DEAD
25 TCC 50%
MONTHS pattern as one of their histologic categories. 3~8'10'14,21'23 It is possible that several of the cases designated as malignant Brenner tumors were actually TCC.9,22,24 On the other hand, requiring the presence of a benign Brenner component to designate a neoplasm as a malignant Brenner tumor might be too strict. The benign part might have been overgrown by the malignant component. To our knowledge, only four authors have reported studies of ovarian carcinomas with a predominantly TCC pattern.'' I7,22,25 The study by Austin and Norris, designed to compare malignant Brenner tumors with TCC, was, to our knowledge, the first to propose TCC as a histologic type of ovarian carcinoma.' The studies by Young and Scully25 and Weiden and Gratama 22 compared urothelial and ovarian carcinomas of identical cell types. During a review of high-grade carcinomas of the ovary, we found that tumors with a predominantly TCC pattern responded best to chemotherapy.17 However, because our main goal in that study was to evaluate the response to chemotherapy of the different tumor types, we included only patients with residual tumor after the first operation
who had received at least six courses of chemotherapy. Most were drawn from a study of patients with ovarian carcinoma who underwent a second-look operation. This provided a precise evaluation of the response of the residual tumor to chemotherapy. Based on that study, we concluded that TCC of the ovary was the best responder to chemotherapy in that group of patients. The current study was designed to evaluate that observation in a larger group of ovarian carcinoma patients with TCC component regardless of their stages, treatments, the residual tumor, and second-look operation results. We have now reviewed all cases of ovarian carcinoma with a focal or predominant TCC pattern seen at M. D. Anderson Cancer Center between 1970 and 1983. This review showed that areas of TCC are present in 9.4% of ovarian carcinomas. Our study demonstrated an estimated five-year survival rate of 37% after surgery. This survival rate is better than the rates reported from several series of patients with ovarian carcinoma, including a threeyear progression-free survival rate of 29% in the series of Piver and associates,16 a four-year survival rate of 26% in
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FlG. 6. Survival curve according to the TCC component in the primary neoplasm.
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with vessels. These areas resemble the papillae of TCC. However, we have defined the term TCC to apply only to tumors having thick papillae projecting into empty spaces and without necrosis in the lumen. Furthermore, undifferentiated carcinoma also contains sheets of tumor cells without differentiation. Although TCC can be confused with granulosa cell tumor, the presence of thick papillae, the association with other types of miillerian carcinomas, and the absence of Call-Exner bodies and trabecular pattern are distinct histologic features. In addition, most patients with TCC are clinical stage II, III, or IV, which is exceptional for patients with granulosa cell tumor. Radiotherapy, an acceptable treatment for most lowstage ovarian carcinomas, is probably not appropriate for patients with TCC.6,7 The five patients treated only with radiation died of disease in less than 60 months. The tumors in three of these patients were clinical stage II; in one patient, stage HI; and in one, stage IV. In summary, although it has been reported that histologic typing of ovarian carcinomas is of limited prognostic value, we believe that ovarian carcinomas with a TCC pattern respond excellently to chemotherapy.2 Forty-one percent of the patients who received chemotherapy for these tumors survived longer than five years. Tumor recurrences and lack of response to chemotherapy are often associated with a change in the histologic appearance of the primary neoplasm, which becomes, in metastases, predominantly non-TCC.
The association in a single neoplasm of TCC with other histologic types of miillerian carcinomas, including serous, undifferentiated, and unclassified adenocarcinoma, is probably an indication of the multipotential characteristic of the neoplastic cells. The association of primary carcinomas with a predominantly TCC pattern with predominantly non-TCC metastases may be the result of the metastatic potential of one of the components of the neoplasm or of the presence of independent primary tumors. Because, in our patients, the non-TCC was the predominant component in the metastases and the TCC was the main tumor type in the primary lesion, we believe that the most chemotherapy-resistant cell type is the one that metastasized. The recurrence after chemotherapy of a tumor composed predominantly of non-TCC elements when the primary tumor was predominantly TCC supports our view. Furthermore, tumor grade has been reported to increase after chemotherapy in patients with progressive ovarian carcinomas.4 The differential diagnosis of ovarian carcinomas with TCC pattern includes undifferentiated carcinoma and granulosa cell tumor. Undifferentiated carcinoma might simulate TCC only when areas of necrosis leave islands of tumor cells around a central zone of connective tissue
References 1. Austin RM, Norris HJ. Malignant Brenner tumor and transitional cell carcinoma of the ovary: comparison. Int J Gynecol Pathol 1987;6:29-39. 2. Baak JPA, Wisse-Brekelmans ECM, Langley FA, Talerman A, Delemarres JFM. Morphometric data to FIGO stage and histological type and grade for prognosis of ovarian tumours. J Clin Pathol 1986;39:1340-1346. 3. Chen SS. Survival of ovarian carcinoma with or without lymph node metastasis. Gynecol Oncol 1987;27:368-372. 4. Dauplat J, Nieberg RK., Philippe A, Hacker NF. Changes in the histocytological grading of epithelial ovarian carcinoma following treatment. Int J Gynecol Pathol 1988;7:12-22. 5. Einhorn N, Nilsson BO, Sjovall K. Factors influencing survival in carcinoma of the ovary: study from a well-defined Swedish population. Cancer 1985;55:2019-2025. 6. Fuller DB, Sause WT, Plenk HP, Menlove RL. Analysis of postoperative radiation therapy in stage I through III epithelial ovarian carcinoma. J Clin Oncol 1987;5:897-905. 7. Goldberg N, Preschel RE. Postoperative abdominopelvic radiation therapy for ovarian cancer. Int J Radiat Oncol 1988;14:425-429. 8. Griffin TW, Hunter RA, Cederbaum AI, et al. Treatment of advanced ovarian cancer with sequential combination chemotherapy. Cancer 1987;60:2150-2155. 9. Hallgrimsson J, Scully RE. Borderline and malignant Brenner tumours of the ovary: a report of 15 cases. Acta Pathol Microbiol Scand 1972;80:56-66. 10. Heintz APM, Van Oosterom AT, Baptist J, et al. The treatment of advanced ovarian carcinoma: clinical variables associated with prognosis. Gynecol Oncol 1988;30:347-358. 11. International Federation of Gynaecology and Obstetrics: Classifi-
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the study by Griffin and associates,8 and a five-year survival rate of 28% in the cases reviewed by Einhorn and associates.5 Similar to previous investigators, we have found that tumor stage and the results of the second-look operation are excellent prognostic indicators and that the amount of residual tumor after the initial operation is also an important consideration. 2 ' 5 ' 81014 ' 18 ' 20 ' 21 However, our study also showed that the percentage of TCC in the carcinoma is an important prognostic indicator. The presence of a TCC component of 50% or more in the primary tumor is an important indicator of favorable response to chemotherapy. Austin and Norris also recognized the effectiveness of chemotherapy for patients with TCC: in their study, only two of eight patients with TCC who had received chemotherapy had died of disease.1 However, despite the favorable prognosis conferred by TCC in a tumor, chemotherapy can fail when the carcinoma is more than 50% TCC or even composed only of TCC. In our series, the primary tumors resected from ten patients were pure TCC. Seven of these patients died of disease in less than five years, one patient lived for 62 months, and two are alive, one at 51 months with advanced disease and one disease-free at 109 months. The lack of response to the treatment in these patients with pure TCC might have been influenced by other factors. Four of these patients who died of disease had clinical stage IV disease (pleural involvement), two had omental metastases of predominantly serous carcinoma, and one had a clinical stage IIB disease but was treated with radiation alone.
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12. 13. 14. 15. 16.
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cation and staging of malignant tumors in the female pelvis. Acta Obstet Gynecol Scand 1971;50:1-7. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. Journal of the American Statistical Association 1958;53:457-481. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemotherapy Report 1966;50:163-170. Miller DS, Ballon SC, Teng NNH, Seifer DB, Soriero OM. A critical reassessment of second-look laparotomy in epithelial ovarian carcinoma. Cancer 1986;57:530-535. Mostofi FK. Histological typing of urinary bladder tumours. In: International histological classification of tumours, No. 10. Geneva: World Health Organization, 1973:17. Piver MS, Lele SB, Marchetti DL, Baker TR, Tsukada Y, Emrich U. The impact of aggressive debulking surgery and cisplatinbased chemotherapy on progression-free survival in stage III and IV ovarian carcinoma. J Clin Oncol 1988;6:983-999. Robey SS, Silva EG, Gershenson DM, McLemore D, El-Naggar A, Ordonez NG. Transitional cell carcinoma in high-grade highstage ovarian carcinoma: an indicator of favorable response to chemotherapy. Cancer 1989;63:839-847. Rothenberg ML, Young RC. Changing concepts in the management of epithelial ovarian and cervical cancers. Med J Aust 1988; 148: 354-363.
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19. Scully RE. Tumors of the ovary and maldeveloped gonads. In: Atlas of tumor pathology, 2nd series, fascicle 16. Washington, D.C.: Armed Forces Institute of Pathology, 1978:146. 20. Sorbe B, Frankendal BO, Veress B. Importance of histologic grading in the prognosis of epithelial ovarian carcinoma. Obstet Gynecol 1982;59:576-582. 21. Swenerton KD, Hislop TG, Spinelli J, LeRiche JC, Yang N, Boyes DA. Ovarian carcinoma: a multivariate analysis of prognostic factors. Obstet Gynecol 1985;65:264-269. 22. van der Weiden RMF, Gratama S. Proliferative and malignant Brenner tumours (BT) and their differentiation from metastatic transitional cell carcinoma of the bladder: a case report and review of the literature. Eur J Obstet Gynecol Reprod Biol 1987;26:251260. 23. Wils J, Van Guens H, Baak J. Proposal for therapeutic approach based on prognostic factors including morphometric and flowcytometric features in stage III—IV ovarian cancer. Cancer 1988;61: 1920-1925. 24. Woodruff JD, Dietrich D, Genadry R, Parmley TH. Proliferative and malignant Brenner tumors: review of 47 cases. Am J Obstet Gynecol 1981;141:118-125. 25. Young RH, Scully RE. Urothelial and ovarian carcinomas of identical cell types: problems in interpretation. Int J Gynecol Pathol 1988;7:197-211.
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18.
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