Ovarian carcinoma of low malignant potential: Staging and treatment

Ovarian carcinoma of low malignant potential: Staging and treatment Jill G. Nation, M.D., and Garry V. Krepart, M.D. Winnipeg, Manitoba, Canada A review of 65 cases of ovarian carcinoma of low malignant potential registered at the Manitoba Cancer Treatment and Research Foundation over a 7'12-year period was undertaken. Eighty-four percent of patients presented with Stage I disease, which was confirmed by primary staging laparotomy in 25%. The average age at diagnosis was younger than that commonly found in patients with invasive carcinoma. Fourteen patients received postoperative chemotherapy, of whom 10 were evaluated with second-look laparotomy. No patient with macroscopic residual disease after initial surgery was cured by chemotherapy. This report emphasizes the need for a prospective controlled study to evaluate adjunctive chemotherapy in the treatment of these tumors. (AM J GasTET GVNECOL 1986;154:290-3.)

Key words: Ovarian cancer, low malignant potential, staging, treatment Epithelial ovarian carcinomas of low malignant potential have been studied with increasing interest over the past decade. The clinical entity was initially reported by Taylor' in 1929, and a pathologic definition was accepted by the International Federation of Gynecology and Obstetrics (FlGO) in 197F and by the World Health Organization in 1973.' However, the diagnosis is still associated with uncertainty with respect to both optimum surgical management and the need for postoperative therapy. Pathologically these tumors have been identified as intermediate between cystadenomas and cystadenocarcinomas.' Their clinical course is relatively benign in comparison to that of the invasive carcinomas. Stage I tumors have an excellent prognosis." Those tumors greater than Stage I demonstrate an indolent behavior with good survival rates, although studies with longterm follow-up illustrate they do have the capacity to metastasize and can be fatal." Epithelial carcinomas of low malignant potential comprise between 9.2%" and 20%7 of ovarian malignancies, and patients with these tumors tend to present at an earlier stage of disease than those with invasive carcinomas. The average age of patients at diagnosis is younger than in those with invasive carcinoma." Treatment has ranged from conservative surgical procedures to aggressive tumor-debulking in combination with adjuvant cytotoxic chemotherapy and/or From the Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Manitoba. Presented at the Forty-first Annual Meeting of The Society of Obstetricians and Gynaecologists of Canada, jasper, Alberta, Canada, June 10-15,1985. Reprint requests: Dr. G. V. Krepart, Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Women's Hospital, 735 Notre Dame Ave., Winnipeg, Manitoba, Canada R3E OL8.

290

radiotherapy. However, because of the good prognosis associated with these tumors, it has been difficult to evaluate the results of these various modes of treatment. This review was undertaken to study the clinical characteristics of patients with epithelial tumors of low malignant potential and to assess the value of staging procedures and subsequent cytotoxic chemotherapy on the clinical course. Material and methods

A retrospective review of the charts of 688 patients with ovarian carcinoma registered at the Manitoba Cancer Treatment and Research Foundation from July I, 1976, to December 31, 1984, was conducted. The records of 65 patients with a diagnosis of ovarian carcinoma of low malignant potential as defined by World Health Organization criteria" were selected for further study. All pathologic findings were confirmed by tissue review in the Department of Pathology either at Health Sciences Centre, Winnipeg, or at St. Boniface General Hospital, Winnipeg. All cases of epithelial ovarian tumors of low malignant potential were included. Results

The cases were evenly distributed over the study period and represented 9.4% of all patients with ovarian malignancies presenting during that time. The age at diagnosis ranged from 17 to 91 years. Thirty-five patients (53.8%) were <50 years of age at diagnosis. The most common presenting symptoms were lower abdominal discomfort (28.1 %) and increasing abdominal girth (20.3%), although 17.1 % were asymptomatic, with a mass being detected incidentally on routine examination. Surgical management was reviewed. Sixteen patients (25%) had a unilateral salpingo-oophorectomy only.

Ovarian carcinoma of low malignant potential

Volume 154 Number 2

Table II. Postoperative treatment according to stage

Table I. Distribution of histologic findings by stage of patients Histologic findings Stage

IA

Mucinous

32

IB

IC IIA

2

lIB

IIC III

1* 2

IV 37

I

291

Stage

Serous

Total

14 2 3

46 2 5

I

I

2 1* 5

2 1* 7

I

I

29

65

*One patient had mixed mucinous and serous elements, both of low malignant potential. Forty-two (65%) had a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Eleven patients (17%) had an omental biopsy or omentectomy and/or peritoneal washings for cytology as part of the initial surgical procedure. Fifteen patients (23%) underwent a primary staging laparotomy including peritoneal cytology, omentectomy, pelvic and precaval lymph node sampling, and multiple peritoneal biopsies. Fifty-five patients (84.6%) had Stage I disease. This was confirmed by primary staging laparotomy in 14 of these patients (25%). Two (3%) had Stage II disease, seven (10.7%) had Stage III disease, and one (1.5%) had Stage IV disease on the basis of a malignant pleural effusion. One case was upgraded from Stage I to Stage III as a result of a staging laparotomy. Two were downgraded from Stage II to Stage I. In both the latter cases the stage had been assigned initially on the basis of adhesions in the pelvis requiring sharp dissection, and subsequently primary staging laparotomy was negative. Five patients (7.6%) had cell-positive ascites at laparotomy. Twenty-three (35.3%) had peritoneal cytology performed, of which specimens four (17.3%) were positive for malignant cells. Thirty-four patients (52.3%) had an omentectomy or omental biopsies of which six (17.6%) were positive. Two of these six cases were subsequently upgraded from Stage I to Stage III on the basis of this microscopically positive omental biopsy in the absence of any other disease. Details of histologic findings according to stage are illustrated in Table I. Postoperative treatment is detailed in Table II according to stage. No patient received radiotherapy. The 14 patients in whom a primary staging laparotomy confirmed Stage I disease were not treated. The five patients who were treated with Alkeran were all diagnosed as having Stage I disease but with inadequate staging procedures. Rather than subject the patients to another laparotomy, a decision was made in conjunction with their referring physicians to treat them with Alkeran.

No. of patients

8 II III

42 5 2 I

2 3 I

IV

Treatment

Unknown No treatment Alkeran Alkeran No treatment Alkeran Adriamycin/cisplatin Adriamycinl Alkeran Hexamethylmelamine Adriamycin/cisplatin

Three of these patients subsequently had a second-look laparotomy, of which one was microscopically positive. Ten patients (five, Stage I; one, stage II; four, stage III) who had no evidence of disease clinically following chemotherapy underwent a second-look laparotomy. Of these procedures, five were positive and five negative. Details are included in Table III. All patients with disease greater than Stage I with macroscopic disease remaining after initial laparotomy had positive secondlook laparotomies after treatment. Two cases were upgraded on the basis of a single positive omental biopsy. One patient was treated with 12 courses of Alkeran (l mg/kg over 5 days) at monthly intervals and subsequently had a negative second-look laparotomy. The second patient, treated on the basis of a single microscopic focus of tumor in her omentum, also had a negative second-look laparotomy after treatment with hexamethylmelamine, Adriamycin and Alkeran for 13 courses. No patient with a negative second-look laparotomy has had a recurrence of disease. One patient with Stage III disease was not treated. Peritoneal studding was diagnosed pathologically as endosalpingiosis,· and the patient refused further treatment. She has been followed now for 60 months, remaining asymptomatic with no clinical evidence of disease. Follow-up in this study is short and ranges from 2 to 90 months. Present status of patients is documented in Table IV. It is of note that 21 patients were lost to follow-up, all of whom had Stage IA disease. However, in none of these patients was the stage confirmed by primary staging laparotomy. These patients were not evaluated by the gynecologic oncology service, many of them being diagnosed and treated in other parts of the province. However, their charts were sufficiently complete for this retrospective review. As long as they have remained in Manitoba, none have died of disease. No patient with disease greater than Stage I has been lost to follow-up. Of the six patients alive with disease, one is presently

292

Nation and Krepart

February, 1986 Am J Obstet Gynecol

Table III. Ovarian carcinoma of low malignant potential with second-look laparotomy Patient No.

Disease status after initial laparotomy

Disease status after second-look laparotomy

Negative Negative Negative Negative Negative Microscopic Microscopic (I biopsy positive) Microscopic (I biopsy positive) Macroscopic «2 cm) Macroscopic «2 cm)

Positive Positive Negative Negative Negative Positive Negative Negative Positive Positive

Stage

1 2 3

IA IA IA

4 5 6

IB

7 8

III III III III

IC IIC

9

10

Table IV. Staging and present status in 65 cases of ovarian carcinoma of low malignant potential Stage

No. of cases

No evidence of disease

55

28

I

II

2

III

7

IV

1

Total

65

Alive with disease

<12 12 24

36

48 60 >60

Death from other cause

Lost to follow-up

6

21

6

21

2 3

4

31

6

Table V. Completed months of follow-up of known survivors Completed follow-up (mo)

Death from disease

No. of patients 2

6 8 6 2 3 17

undergoing chemotherapy and will be eligible for a second-look laparotomy within 6 months. The other five are alive and well, their disease status having been assigned on the basis of a positive second-look laparotomy in three patients and by clinical examination in two. Three of the five have been followed for >60 months, one for 52 months, and one for 15 months. The length of survival is tabulated in Table V.

Comment The proposal of the International Federation of Gynecology and Obstetrics in 1961 that epithelial tumors of the ovary be divided into three categories (benign, malignant, and intermediate) was followed by acceptance of the classification for usage in 1971. The intermediate group consists of cystadenomas with proliferative activity of epithelial cells and nuclear abnormalities but absence of infiltrating destructive growth." The World Health Organization recognized this classification and has referred to these tumors as carcinomas of low malignant potential or tumors of bor-

derline malignancy.' Several authors have suggested that the latter terminology be abandoned in favor of the former to emphasize the capacity of these neoplasms to cause death."' 10 Barnhill et al. II reported the histologic findings of 82% of 94 tumors of low malignant potential as being serous and 18% mucinous. Aure et al. 7 found 50% of 64 tumors to be mucinous and 46% serous, and these findings are supported in this study. The difference in reported percentages may reflect different distribution by stage, since the majority of early-stage tumors in this study were mucinous. Pathologic evaluation becomes extremely important in making a diagnosis, particularly of large mucinous lesions in which there can be considerable variation from one area of tumor to another. Hart and Norris l2 have recommended that one tissue block be taken for pathologic evaluation for each I to 2 em of the tumor's maximum diameter. It has been clearly established in several series that these tumors occur in a younger population of women than in those who develop invasive epithelial carcinomas. 5 . 7.13 The findings in this study concur. Eighty-one percent of tumors in this study were Stage I at diagnosis, which is similar to the result obtained by Aure et al. 7 although two series have reported only 53%5 and 50%" of patients with Stage I disease. Confirmation of stage by primary staging laparotomy has not been standard procedure in the literature. In this study 14 of 55 Stage I cases (25%) were confirmed by primary staging laparotomy. Several authors have advocated less radical surgery for this group of patients, particularly if retention of child-bearing capacity is an issue. 14 . 15 Unilateral salpingo-oophorectomy is adequate therapy if a

Volume 154 Number 2

thorough staging procedure confirms Stage IA disease. 5 . 14 Two of five cases staged as IA without primary staging laparotomy subsequently had positive secondlook laparotomies emphasizing the need for adequate staging. Sixteen percent to 18% of borderline tumors are Stage II or greater. 4 . 7 The majority of advanced cases are serous in origin. Debulking of all gross tumor is advocated in more extensive disease. 5 Extra ovarian implants may arise by metastases or by in situ development from coelomic epithelium.' These implants rarely infiltrate deeply, and it may be possible to incise the peritoneum around a tumor nodule, thus removing it completely. Mortality from tumors of low malignant potential occurs almost exclusively in the presence of peritoneal implants. Russe1l 4 has suggested that there may be a subgroup of patients with Stage III disease whose implants show local invasion and whose lesions should be reclassified as invasive carcinoma. Treatment has been variable, and reports of more than a few uniformly treated cases with adequate follow-up are sparse. Julian and Woodruff' used radiotherapy in an unspecified number of cases, and Nikrui 6 reported adjuvant radiotherapy in 10 cases. The effectiveness of chemotherapy for advanced disease is unknown, a variety of different regimens having been used over the years. fi There have been no reports of prospective randomized trials for advanced disease to clarify this issue. 9 These tumors are characterized by indolent growth and may not respond to cytotoxic chemotherapy. Rapidly dividing cells are most affected by cytotoxic agents that act at different stages during the cell cycle to retard or prevent further mitoses. Cells that replicate very slowly are largely protected from the effects of these drugs unless they are in the critical stage when the drug is delivered. Survival rates reported in the literature indicate the good prognosis for patients with this tumor. 7 . II. 11 The crucial question is whether the various forms of treatment used have any effect on the disease. Although the number of patients with advanced disease is small and follow-up is relatively short, this study confirms the clinical impression that ovarian tumors of low malignant potential are difficult to treat. It is our clinical impression on the basis of this series that, in view of their excellent prognosis, patients with Stage I epithelial ovarian carcinoma of low malignant potential

Ovarian carcinoma of low malignant potential

293

confirmed by a primary staging laparotomy should not receive adjunctive therapy. Furthermore, in this series of 65 patients, 14 received chemotherapy and no patient with macroscopic disease at the conclusion of initial surgery had a negative second-look laparotomy after treatment, either with single-agent Alkeran or platinum-containing combination chemotherapy. These findings reiterate the need for a multicenter, prospective, randomized study that includes staging laparotomy, adequate sectioning of specimens, randomized postoperative chemotherapy or radiotherapy, and second-look laparotomy to histologically and surgically assess response. Only after this information is available and long-term follow-up is achieved will there be any consensus on whether further treatment is indicated for advanced stages of this tumor. REFERENCES 1. Taylor HC. Malignant and semimalignant tumours of the ovary. Surg Gynecol Obstet 1929;48:204. 2. Classification and staging of malignant tumors in the female pelvis. Acta Obstet Gynecol Scand 1971 ;50: I. 3. Serov SF, Scully RE, Sobin LH. International histological classification of tumors, No.9: histological typing of ovarian tumors. Geneva: World Health Organization, 1973. 4. Russell P. Borderline epithelial tumours of the ovary: a conceptual dilemma. Clin Obstet Gynaecol 1984; II :259. 5. Julian CG, Woodruff JD. The biologic behaviour of lowgrade papillary serous carcinoma of the ovary. Obstet Gynecol 1972;40:860. 6. Nikrui N. Survey of clinical behaviour of patients with borderline epithelial tumours of the ovary. Gynecol Oncol 1981; 12: 107. 7. Aure JC, Hoeg K, Kolstad P. Clinical and histologic studies of ovarian carcinoma. Obstet Gynecol 1971;37: I. 8. Santesson L, Kottmeier HL. General classification of ovarian tumours. In: Gentil F, Junqueira AC, eds. Ovarian Cancer. New York: Springer-Verlag, 1968:1. 9. Naus GJ, Seltzer V. Diagnosing tumours of low malignant potential. Contemp Ob/Gyn 1985;25:143. 10. McCaughey WT, Kirk ME, Lester W. et al. Peritoneal epithelial lesions associated with proliferative serous tumours of ovary. Histopathology 1984;8: 195. II. Barnhill D, Heller P, Brzozowski P, et al. Epithelial ovarian carcinoma of low malignant potential. Obstet Gynecol 1985;65:53. 12. Hart WR, Norris HJ. Borderline and malignant mucinous tumors of the ovary. Cancer 1973;31:1031. 13. Isarangkul W. Ovarian epithelial tumors in Thai women: a histological analysis of 291 cases. Gynecol Oncol 1984; 17:326. 14. Creasman WT, Park R, Norris H, et al. Stage I borderline ovarian tumors. Obstet Gynecol 1982;59:93. 15. Katzenstein AA, Mazur MT, Morgan TE, et al. Proliferative serous tumors of the ovary. Am J Surg Pathol 1978;2:339.