GYNECOLOGIC
ONCOLOGY
38, 90-98 (1990)
Ovarian Epithelial Tumors of Borderline Malignancy in Japan NOBUO NAKASHIMA, Department
of Laboratory
M.D.,’ TETSURO NAGASAKA, M.D., NOBORU OIWA, M.D., YOSHIHARU NARA, M.D., SHINJI FUKATA, M.D., TOSHIAKI FUKATSU, M.D., AND JUN TAKEUCHI, M.D. Medicine,
Nagoya
University School of Medicine, and Division University Hospital, Nagoya, Japan
of Pathology,
Clinical
Laboratory,
Nagoya
Received September 28, 1989
Seventy-onecasesof ovarian epithelial tumor of borderline malignancy have been surveyedfrom a clinicopathologic viewpoint. The majority of the borderlinetumors (73.2%)wereof the mutinous type, versusonly 16.9%of the seroustype. The other types-endometrioid (2.8%), Brenner (1.4%), and mixed type (5.6%)--were much rarer. Patients with mutinous tumors were significantly younger (mean age 42.6) than those with serous tumors (mean age 57.5) (P < 0.01). Of patients with mutinous tumors, 64.2%wereof reproductiveage(15-45 years),compared with 17%of patientswith seroustumors. Some78.8%of mutinous and 83.3%of serousborderlinetumors wereFIG0 stageI. Serous tumors were more frequently bilateral (66.7%) than mutinous tumors (9.8%). In mutinous borderline tumors, the extent of tumor spreadat the first laparotomyhad an intimate relationship to the prognosis,but in serousborderline tumors, it was insignificant. The survival rate of patients with mutinous borderline tumors was 69.3% at 5 years and 62.4% at 10 years (KaplanMeier method). Most patients with pseudomyxomaperitonei classifiedas borderline at the time of discovery died within 5 years of the operation. The prognosisof the seroustype was extremelyfavorable.Criteria for borderlinetumors of variouscell types and differencesin the clinicopathologic data of ovarian borderline tumors betweenJapan and other countries were discussed. 0 19!Xl Academic Press, Inc. INTRODUCTION The classification of ovarian epithelial tumor by FIG0 (1961) [l] and WHO (1973) [2] has introduced a distinct borderline category between benign and obviously malignant tumors, in contrast to the earlier benign and malignant categories. In 1929, Taylor reported on patients who had been considered terminal because the ovarian ’ To whom requests for reprints should be sent at the Division of Pathology, Clinical Laboratory, Nagoya University Hospital, 65 Tsnrumai-cho, Showa-ku, Nagoya 466, Japan.
90
0090~8258/90 $1.50 Copyright 0 1990by AcademicPress,Inc. All rights of reproductionin any form reserved.
tumors had extended beyond the ovaries with wide peritoneal implants at the primary laparotomy, but who had been alive and well for many years. The tumor histologically consisted of a characteristic papillary growth of the epithelium with relatively well differentiated cells in both the primary tumor and the implants [3]. First he recorded the tumor as “hyperplastic papillary cystadenoma” and then as “semimalignant” and “borderline” [4]. He noted that the borderline tumor was malignant because patients with the tumor occasionally died from a late recurrence of the tumor. The new concept of borderline tumor was accepted by both FIG0 and WHO, and an epithelial tumor of borderline malignancy was considered to be characterized by malignant biological behavior, yet remarkably good prognosis even if the tumor extended out of the ovary or metastasized to the lymph nodes. The greater disparity in clinical behavior generally observed between ovarian borderline and invasive tumors, than between grade I and higher-grade carcinomas of most organs justified the terminology “borderline” or “of low malignant potential” [5] found in FIG0 and WHO. For these reasons, correct discrimination between the borderline tumor and the obvious malignant or benign tumor is exceedingly important. On the other hand, the concept of the borderline tumor was originally established on the basis of serous tumors and then extended to other common epithelial tumors. The appropriateness of the term borderline for the other subtypes remains to be investigated. This article presents the clinicopathological findings for a borderline case in our files, discusses the histologic diagnostic criteria for common epithelial borderline tumors of various cell types, and also draws comparisons with the clinicopathological data reported in the literature of other nations.
EPITHELIAL
MATERIALS
TUMORS OF BORDERLINE
RESULTS
Histologic types of malignant common epithelial tumor are listed in Table 1, and the clinical staging of borderline tumors in Table 2. Seventy-one cases of borderline tumor accounted for 32% of common epithelial cancers. The majority of the borderline tumors (73.2%) were of the mutinous type, against only 16.9% of the serous type. The other types were much rarer: endometrioid (2.8%), Brenner (1.4%), and mixed type (5.6%). The borderline tumors (15-85 years, average 45) occurred, on average, 7 years earlier than invasive carcinomas (22-80 years, average 52), with approximately 55% occurring at reproductive age (15-45 years), 45% after age 45, and none before age 15. Eighty-two percent of borderline tumors were FIG0 stage I. The treatment of patients with epithelial borderline tumors in this series is shown in Table 3. Unilateral salpingo-oophorectomy was performed mainly in younger patients, who had unilateral stage IA tumor and in whom the preservation of fertility was important; average age of the patients was 36.4 ? 15.5 years. More aggressive surgical therapy was apt to be TABLE 1 Histological Distribution of Common Epithelial Carcinoma
Serous tumors Mutinous tumors Endometrioid tumors Clear cell tumors Brenner tumors Mixed epithelial tumors Undifferentiated carcinoma Unclassified epithelial tumors Total
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IN JAPAN
TABLE 2 Clinical Staging (FIGO) of Borderline Tumors
AND METHODS
Seventy-one cases of common epithelial borderline tumor were found among ovarian tumors on file in our laboratory for the 23 years from 1965 to 1987. Hematoxylin and eosin (H&E)-stained sections were available for review in each case. Some cases were examined with special stains, including periodic acid-Schiff (PAS), Mayer’s mucicarmine, Alcian blue, reticulum stain, and phosphotungstic acid-hematoxylin (PTAH) for basal body and cilia. Clinical information including follow-up data was obtained from the patients’ physicians. All ovarian tumors were classified in accordance with the WHO criteria for histological typing [2], and clinical staging was performed according to the system adopted by FIG0 [6]. Survival curves were calculated by the Kaplan-Meier method. For the comparison of survival rates, the Cox-Mantel test was used.
Type
MALIGNANCY
Borderline
Malignant
Total
12 52 2 0 1 4 0 0 71
73 20 26 25 0 1 2 2 149
85 72 28 25 1 5 2 2 220
Type
IA
IB and C
IIA
IIB and C
Serous Mutinous Endometrioid Brenner Mixed Total
3 39 2 I3 48
7 2
1 I
I
1 9
1
--10
I10
2
-
III
IV -
0
selected for older women or the few young patients with bilateral ovarian involvement; average age of the patients was 53.6 2 14.1 years. After surgical treatment, 25 of 71 patients with borderline epithelial tumor were administered chemotherapy. Before 1979, patients were given combination chemotherapy including mitomycin C, cyclophosphamide, 5-fluorouracil (5-FU), and the like; since 1980, cisplatin has been added. In some patients, an internal medicine such as HCFU (carmofur) was used. Radiotherapy was not administered to any patient. The survival rate of patients with whole borderline tumors (n = 45) was 75% at 5 years and 65% at 10 years [7]. Serous Borderline
Tumors
Twelve patients had serous borderline tumors. They ranged from 22 to 85 (average 57.5 +- 16.1) years in age; two (17%) were under the age of 45. Some 83.3% of serous borderline tumors were FIG0 stage I. Six of twelve patients presented with abdominal enlargement, three with abdominal pain, and two with irregular genital bleeding. One patient was detected by chance when she was treated for uterine corpus carcinoma. The symptoms were unknown in two patients. Tumor was bilateral in 8 (66.7%) of the 12 cases. Nine patients had tumors measuring 8 cm or less in their greatest diameter, while the other patients had larger tumors. The primary tumors were endophytic in all but one case, in which it was a combination of exophytic and endophytic growth. In I1 patients tumors were unilocular or multilocular. In one patient the tumor, with part of an adenofibromatous pattern, was solid and cystic in consistency. In all cases, papillary excrescences were observed on the inner surfaces of the cysts. No hemorrhage or necrosis was found. Microscopically, the tumor was characterized by the presence of tufts having cellular buds with a very thin or no stroma in the core. The epithelial cells demonstrated a slight to moderate grade of nuclear atypicality in all but one case, which was of high grade. Occasionally, nucleoli were prominent in focal areas of the tumor. Mitoses were generally few. Ciliated epithelial cells were found in 11 of 12 cases. In 5 of 12 cases, formation of psammoma bodies was a prominent feature. In 5 cases,
92
NAKASHIMA
ET AL.
TABLE 3 Therapy for Ovarian Borderline Tumors and Prognosis No 1 2 3 4 5 6 7 8 9 10 11 12 13 I4 I5 16 17 18 19 20 21 22 23 24 2.5 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
Age
Histologic subtype”
22 36 48 48 57 61 63 66 67 67 70 85 15 I.5 16 17 21 21 23 24 24 28 30 30 31 31 33 33 34 34 35 36 37 38 39 39 40 40 40 41 41 42 43 43 44 46 48 50 51 52 52 56 56 58 61 62 65‘ 66 68
A2 A2,JAZ A2/A2 A2/A2 A2 A2/A2 A2 A2/Al A2/A2 A2/A2 A2/A2 A2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2/B2 B2 B2 B2 B2 + F2bl B2 F2blfI32 B2 B2 B2 B2 B2/B2 B2 + F2bl B2/B2 B2 B2 B2 B2 B2 B2 + F2bl B2
Stage
Surgical therapyb
IC IB III IB IA IB IA IA IB IB IB IIA IA IA IA IA IA IA IA IA IA IA IA IA IA IA IA IA IA IA IA IA2 IA IC IA IIB III IA III IA IA IA IA IA IA IIA IB IA 111 III III III IA IA IA IA IA IA2 III
us0 BSO-H BSO-H BSO-H BSO-H BSO-H us0 BSO BSO-H BSO BSO-H USO-H us0 uso+w us0 us0 us0 us0 us0 us0 us0 us0 us0 us0 USOfW uso+w us0 us0 us0 uso+w us0 US0 + my0 USO-H USO-H USO-H BSO-H oment BSO-H BSO us0 us0 USO-H uso+w BSO-H BSO-H us0 us0 us0 BSO-H BSO-H BSO-H BSO-H us0 us0 us0 BSO-H us0 BSO-H Probe
Postsurgical therapy’ MMC, 5FU, Ara-C CQ, 5FU, Ara-C None MMC, CPA, CHRM, TSPA None None None None None None None HCFU None None MMC, 5FU, Ara-C, CDDP None MMC, 5FU, Ara-C, CDDP
Survival‘+ (months) D 154 A 46 A 53
A 204 A 105 A 53 A 25 A 58 A 93 A 9 A A A A
10.5 34 25 74
None
A 117
MMC, 5FU, Ara-C None None MMC, 5FU, Ara-C, CDDP None None None None HCFU None
A 82 A 55 A 192 A 19
None CPA, ADM, MMC, CPA MMC, 5FU, CPA, ADM, None MMC, 5FU, HCFU
CDDP Ara-C, CDDP CDDP Ara-C,
None None None MMC, SFU, Ara-C, CDDP None MMC, CPA None MMC, 5FU, Ara-C, CDDP None None None None TF, PSK None None None
A 69 A 6
D 5 D 15 A44 D 6 A 36 A 85 A 23 A 228 A 74 A A A D D A
136 19 147 53 12 51
D 78 A 57 D 56 D60
EPITHELIAL
TUMORS OF BORDERLINE TABLE
No.
Age
60 61 62 63 64 65 66 67 68 69 70 71
71 71 72 74 74 46 49 57 25 27 29 44
Histologic subtype” B2 B2/B2 B2 B2 B2 c2 c2 E2 F2/F2 BI/F2 F2 F2
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3-Continued Surgical therapyh
Stage IA 111 III IA IA IA IA IA IB IA IA IA
MALIGNANCY
USO-H BSO-H USO-H us0 BSO us0 USO-H BSO-H BSO tm’ us0 USO-H
Postsurgical therapy’ None CDDP TF, 5FU None None None None 5FU, MMC, CPA CDDP. VLB, BLM CDDP, VLB, BLM None NCFU
Survivald (months) A 8 D 21
A 28 A 7 A 57 A
10
” Al, serous benign; A2, serous borderline; Bl, mutinous benign; B2, mutinous borderline; C2, endometrioid borderline; E2, Brenner borderline; F2, mixed epithelial borderline; F2bl, mature cystic teratoma; /, right and left side. * USO, unilateral salpingo-oophorectomy; BSO, bilateral salpingo-oophorectomy; -H, with total abdominal hysterectomy; + w, with wedge resection of the contralateral ovary; +myo, with myomectomy of the uterus; oment, omentectomy. ’ MMC, mitomycin C; 5FU, 5-fluorouracil; Ara-C, arabinoside C; CPA, cyclophosphamide; HCFU. carmofur; BLM, bleomycin; CQ. carboquone: CHRM, chromomycin; TSPA, thiotepa; CDDP, cisplatin; TF. tegafur; PSKE. Kurestin; VLB. Vinblastine; None, no postsurgical treatment. ” A, alive and well; D, dead ” Removal of only bilateral tumors. Five years after the operation she gave birth to a normal child.
tumors secreted a thick, mutinous fluid in some focal areas. Follow-up data were available in 8 patients; 7 were alive and well 25 months to 17 years (average 6.4 years) postoperatively, and the eighth patient, with a stage IC tumor died from the disease 13 years postoperatively. Mutinous
Borderline
Tumors
Fifty-four patients had mutinous borderline tumors. They ranged from 15 to 74 (average 42.3 ? 16.2) years in age; 34 (65%) were 45 years or younger. Of the mucinous borderline tumors, 78.8% were FIG0 stage I. Mutinous borderline tumors were bilateral in 9.8% of the cases. The median age for 41 patients with stage I tumors was 39.4 years and for 11 patients with stage II or III tumors, 53.4 years. Some 92% of the 52 patients had abdominal distension, 10% abdominal pain, and 6% irregular genital bleeding. Ninety-five percent of the mucinous borderline tumors were larger than 12 cm, and 56% measured more than 17 cm in greatest diameter; 85% occurred in the form of unilocular (2 cases) or multilocular (44 cases) cysts, which were always filled with mutinous fluid. There were two solid and cystic tumors, which associated with a mature cystic teratoma in one case and xanthoma-like nodule in another case. Five of nine cases of pseudomyxoma peritonei had no clear tumor boundary. There was no mention of associated mucocele of the appendix in clinical charts in any of the cases of pseudomyxoma peritonei. Microscopically, the mutinous borderline tumor is characterized by the presence of papillary growth and/or
small glands budding from adjacent loculi into the stroma. The epithelial cells lining the papillae and the glands showed a slight or moderate degree of nuclear atypicality (Figs. la and b). The epithelium was endocervical in 36% of cases, intestinal in 38%, and mixed endocervical and intestinal in the remaining 26%. The majority of tumors manifested benign and borderline features within the same specimen. In three patients, a mature cystic teratoma was present in the same ovary as the mutinous borderline tumor (intestinal type in one and endocervical type in two) and an xanthomatous nodule of stromal origin in another. We excluded from the present borderline series one mutinous borderline case with obvious sarcoma who died with gastric and pulmonary metastases of the sarcomatous component 7 months postoperatively. The opposite ovary contained a mature cystic teratoma in one case, and a benign mucinous tumor in another. There were inflammation, necrosis and/or calcification in the stroma in about 10% and stromal mutinous degeneration in 20% of cases. Follow-up information was available in 34 cases. Twenty-five were alive and well 6 months to 19 years (average, 6 years) postoperatively; 10 died within 5 months to 6.5 years (average, 2.6 years), and 7 of them had pseudomyxoma peritonei (stage III) at the time of discovery. They died within 6 months to 60 months (average, 32 months). By statistical analysis of the data, the 5-year survival rate for overall cases was estimated to be 69.3%, against 93% for stage I and 15% for stages II and III. Thus, there was a significant difference between stage I and the other stages (P < 0.001) (Fig. 2).
94
NAKASHIMA
ET AL.
FIG. 1. (a) This borderline mutinous tumor contains papillae projecting into a cyst. The patient died from the disease 6.5 years postoperatively (case 54). x80. (b) Higher magnification of (a). Nuclear atypicahty is slight. x530.
Endometrioid, Clear Cell, and Brenner Borderline Tumors Endometrioid borderline tumor was discovered in one ovary in two patients, 46 and 49 years old. The tumors were 17 and 3 cm in greatest diameter, respectively. One of these patients presented with abdominal enlargement or an abdominal tumor; the other one was detected by chance in an operation for uterus myoma. The solid (one
Stage 1 n=24 *.__-______i Overall n=34 I-.. _.__.___.--.__..__”_.__._”.____._.__
Stage 2 & 3 n-10
0
5
to
case) or polyp-like (one case) nodules protruded into the lumen of the endometrioid cyst. Microscopically, the endometrioid tissue of the tumors closely resembled severely atypical hyperplasia or adenocarcinoma in situ of the uterine endometrium. In the endometrioid borderline tumors, the epith~lium was observed to undergo a transition from endometriosis to tumor tissue. The remaining endometriotic lining was focally atypical, consisting of cells with large, hyperchromatic nuclei. One case was alive and well 28 months posto~ratively; the other was lost to follow-up* No clear cell borderline tumor was found on file. Of seven Brenner tumors, one .57-year-old patient belonged to the borderline category and presented with abdominal distension. The tumor was unilateral, measuring 12 cm in greatest diameter (stage IA); it was a cyst with prominent papillary growth into the lumen. Microscopically, the tumor resembled noninvasive papillary transitional cell carcinoma of the urinary bladder, and it showed moderate nuclear atypia and some mitoses (Figs. 3a and b). No benign Brenner tumor was identified in the specimen. The patient was lost to follow-up.
Ii5
YEARS
FIG. 2. Survival of patients with mutinous borderline tumors according to clinical stage of tumor. The 5-year survival rate for overall cases was 69.3%, whereas the corresponding figure for stage I was 93% and for stages II and III, 15% (Kaplan-Meier method). Survival of patients with mutinous m~ignant tumors is aIso presented for comparison.
Mixed Borderline Tumors Five mixed borderline tumors were found in four patients, aged 25 to 44 (average, 31). The tumors were detected as an abdominal tumor in two patients, in one of whom it was associated with ascites; as abdominal pain in one patient; and by chance in another operation
EPITHELIAL
TUMORS OF BORDERLINE
MALIGNANCY
FIG. 3. (a) Borderline Brenner tumor. Papillary growth of transitional-like epithelial cells is observed (case 67). of (a). X 250.
in the last patient. All the tumors, which grew in the form of cysts containing papillary growths grossly resembling serous borderline tumor, were 8 cm or smaller in maximal diameter. These tumors were characterized by the presence of tufts lined by both mutinous cells and mutinous cells with cilia, which formed abundant mucin in the lumen. No intestinal differentiation was noted. Squamous cell foci were observed in one. Nuclear atypicality was slight and mitosis was rare. No peritoneal implants were found. Follow-up data on three patients were available from 7 to 42 months (average, 19.7 months). No patient died from the disease. One patient was lost to follow-up. DISCUSSION In diagnosing neoplasia of the common epithelial category, the idea is to pinpoint exactly a specific cell type and then distinguish the borderline tumors, because patients with a borderline tumor can be expected to have a much better prognosis than those with an obviously malignant tumor. Of course, in contrast to benign tumors, patients with a borderline tumor can be terminal. On the other hand, the prognosis of patients with a carefully distinguished borderline tumor should be quite favorable. The differential diagnosis of various cell types in a common epithelial category is relatively easier for experienced pathologists in borderline tumors than in obviously malignant tumors [5]. But, occasionally, a bor-
95
IN JAPAN
x
50. (b) Higher magnification
derline tumor with features intermediate between those of the serous and the mutinous forms exists. These tumors, which were uncovered in a review of tumors classified as serous borderline tumors, are placed in the mixed borderline category in the present series, and they apparently correspond to the mullerian mutinous papillary cystadenoma of borderline malignancy described by Rutgers and Scully [8] and the seromucinous borderline tumor noted by Bostwick er al. [9]. According to these reports, the prognosis of patients with these tumors is as favorable as that of patients with serous borderline tumors, and so it is assumed in the cases of the present series. There is general agreement regarding the basis of the definition of borderline tumor, but disagreement seems to exist over the application of a definition to each case. On review of our cases, the major difficulty experienced in differentiation is that criteria for cellular (nuclear) anaplasia and structural anaplasia without invasion have not been clearly defined by WHO, and much of the categorization has been subjective and is probably not reproducible. In a case not included in this borderline category, a small nodule about 0.7 cm in diameter was observed to protrude into an endometrioid cyst, and the tumor appeared to belong to the borderline category histologically. The patient died from peritonitis carcinomatosa 20 months after hysterectomy and bilateral salpingo-oophorectomy. Retrospectively, a cribriform pattern of glands with no invasion of the stroma was found in a small area. Although there is no WHO defi-
96
NAKASHIMA
nition (but see Fig. 248 in Ref. [2]), we agree with Hart [IO] that the obvious cribriform pattern should be regarded as an indication of invasive carcinoma. Only one Brenner borderline tumor resembles grade 1 papillary carcinoma of the urinary bladder (Figs. 3a and b), the features of which closely resemble those in the textbook [ 111.But this tumor has no features typical of a benign Brenner tumor. We placed this tumor in the borderline category, because it showed no invasion. But, according to Hart, who claimed that clear-cut malignant nuclear features should be regarded as carcinoma, irrespective of whether stromal invasion is identified [lo], it should have been placed in the malignant category because of the high degree of nuclear atypia. The diagnostic criteria for serous borderline tumor are considered to be defined properly in WHO, leaving trained pathologists [ 121with little disagreement regarding the diagnosis. Yet even experienced pathologists differ on the range of the mutinous borderline tumor. Hart and Norris [13] proposed that a stage I mutinous borderline tumor be classified as carcinoma when stratification of atypical cells into four or more layers was observed in the epithelial lining. Some disagree with this on the grounds that the classification would thus become more complex and difficult to use in practice [14], and with this we concur. Only one case fits this description in the present series and we placed it in the mutinous borderline category. Subjectivity is inevitable in differentiating borderline from benign mutinous tumors. When we examine retrospectively cases that succumbed to mutinous borderline tumor, there are some primary tumors with only epithelial proliferation and atypicality of a minor degree, which probably correspond to mutinous adenomas in WHO. Pathologists who have come across such a case are prone to widen the range of the borderline category. The relative frequency of mutinous borderline tumors is higher in our series than in other large series. We thought that more effort is needed to bring some objectivity to differentiation of mutinous borderline tumor. The frequency of endometrioid borderline tumors has been reported generally at about 1% that of common epithelial cancers [ 15,161,but in the series of Russell and Merkur it was 3.2%, which is higher than the 0.9% of our series. The relative frequency of endometrioid malignancy in the series of Russell and Merkur is also higher than in other studies. There may have been differences in applying the criteria for endometrioid tumors. Although there are some differences in applying the definition of borderline tumor, we consider that they do not prevent comparison of our data on the present series with data on other large series. Overall, borderline tumor, accounts for 32% of all epithelial malignancies in the present series, against 9.2-33% in other series [14,17,18].
ET AL.
The average age of patients with borderline tumor in the present series (45 years) is almost the same as that in the series of Kliman et al. (46 years) [17]. The survival rate of patients with borderline tumors has been reported to be 90-95% at 5 years and 70-90% at 10 years in several articles in the West [9,15-171, against a somewhat lower 75% at 5 years and 65% at 10 years in our series [7]. The poor prognosis of patients with pseudomyxoma peritonei clearly decreases the survival rate of patients with borderline tumors in our series. Serous and mutinous borderline tumors always constitute the majority of borderline tumors in any large series, accounting for 90% of the present series and 83100% [14,17-191 of other reported series. With respect to the relative frequency of mutinous borderline tumors, the 73% of all borderline tumors observed in this series and the 69% in another series in Japan [20] are higher than the 31-40% [ 14,18,21] observed in other series in the West. The ratio of serous borderline to mutinous borderline tumors is approximately 1:4 (if mixed-type tumors are included in the serous tumors, the ratio is 1: 3) in the present series and 1: 2 in the Japanese series [20], in contrast with 1:0.4-0.7 [14,18,21] in other nations; however, in the Kliman et al. series [17] it is 1: 1.3, which is relatively high for Western countries. Among borderline tumors, the mutinous borderline tumor is the most common type in Japan [20], but probably as a result of the much lower prevalence of serous tumors; also, disagreement in application of the criteria for mutinous borderline tumor is also considered to have somewhat widened the range. In our series the patients with serous borderline tumors were on average 57.5 years of age, considerably older than the patients (40-54 years) in several large series reported in the West [9,17,18,22]. The relatively older mean age of our patients may have been due in part to the rather small number of cases in our series. The age range (15-74 years; average, 42.3) for our 52 patients with mutinous borderline tumors is about ten years younger than that for several large series reported in the West [17,18,22,23]. The average age (35 years) of Hart and Norris’ patients [23] with stage I seems exceptionally young; however, it is near the mean (39 years) for the same type of patients in the present series. Patients with mutinous tumors were significantly younger (mean age, 42.6) than those with serous tumors (mean age, 57.5) (P < 0.01); of patients with mutinous tumors, 64.2% were of reproductive age (15-45 years), compared with 17% of patients with serous tumors in the present series. The prognosis for patients with serous borderline tumors has been reported to be extremely good in every country irrespective of age, clinical stage, or incomplete removal of tumor by operation. The distribution of clinical stage in patients with serous borderline tumors is
EPITHELIAL
TUMORS OF BORDERLINE
substantially no different: 7.585% of serous borderline tumors are stage I in other countries [9,14,15,17,21] versus 83% in our series. Serous tumors were more frequently bilateral than mutinous tumors in both the Orient and the West. Serous borderline tumors have been reported to be bilateral in 33-48% of patients [9,14,17,241 in other countries and 66.7% of patients in our series. More than 90% of patients survive 5 years and about 90% survive 10 years in Western countries [15,18,21] as well as in the present series, in which only 1 of 8 patients died from the disease 13 years postoperatively. For patients with mutinous borderline tumors, the extent of tumor spread at the first laparotomy had an intimate relationship with prognosis. Some 85-100% of mutinous borderline tumors are stage 1 in the West [9,14,15,18,23] versus 77% in our series. This figure is near that reported for mutinous borderline tumors by Kliman et ul. [17] and Russel and Merkur [ 141who reported 72% and 78% stage I cases, respectively. The 5year survival rate of patients with mutinous borderline tumors of all stages has been reported to be 92-98% by Aure et al. [15] and Chaitin et (~1.[23] and about 80% by Nieminen and Purola [21] and Nikrui [18]; the loyear survival rate is set at more than 90% by the first two reports; our corresponding figures are 69.3% at 5 years and 62.4% at 10 years. One reason for the low survival rate in our series is a higher rate of cases with pseudomyxoma peritonei at the time of first discovery, many of whom died from inanition or intestinal obstruction within relatively short periods. Kliman et ul. also reported that patients with pseudomyxoma peritonei fared badly [17], and the poor prognosis of the tumor apparently lowered the survival rate in their series. Borderline tumors other than serous and mutinous types are difficult to compare clinicopathologically because of the rarity of these cases in any series. In the present series, it had not been long since the postsurgical chemotherapy had been administered, and the number of patients with each epithelial subtype so treated was too small to evaluate the comparative merits of various agents. Thus, our experience is still insufficient to elucidate the role of chemotherapy for borderline epithelial tumors. Very long follow-up is clearly necessary before the efficacy (or ineffectiveness) of chemotherapy for borderline tumors becomes evident. SUMMARY The category of ovarian borderline tumors has been created by segregating a subgroup with an unusually good prognosis from the general group of common epithelial cancers [12]. Serous borderline tumors fit the category; mutinous borderline tumors would also fit it if patients with pseudomyxoma peritonei were excluded.
MALIGNANCY
IN JAPAN
97
Most cases of pseudomyxoma peritonei of borderline category at the time of discovery died within 5 years of their operation. Whether endometrioid, clear cell, and Brenner borderline tumors fit the category is too difficult to decide because of the rarity of these cases and the need for a larger sample. In comparison with Western countries, the relative frequency of mutinous borderline tumor is higher in Japan. However, the higher frequency in Japan is considered to be the result of a much lower prevalence of serous borderline tumors. REFERENCES I. Kottmeier, H. L. The classification and clinical staging of carcinoma of the uterus and vagina, J. Int. Fed. Gynecol. Ohstet. 1,
X3-93 (1961). 2. Serov. S. F., Scully, R. E., and Sobin, L. H. International
histological classijkation OJ‘ tumours. No. Y Histological typing OJ ovarian ~~~~oI(Ts,World Health Organization, Geneva (1973).
z Taylor, H. C. Malignant and semimalignant tumors of the ovary, Sarg. Gynecol. Ohstet. 48, 204-229 (1929). 4. Taylor, H. C., and Alsop. W. E. Spontaneous regression of peritoneal implantations from ovarian papillary cystadenoma, Amer. J. Gamer 16, 1305-1325 (1932). 5. Scully, R. E.. and Salazar, H. Problems in the histological typing of ovarian cancer. Validity of comparison of ovarian type-specific cancer incidence rdteS in several countries, in An internationa/ survey of distributions of histologic types of tamours of’ the testis and OI’LIY~(H. Stalsberg, Ed.), UICC Technical Report Series,
Vol. 75, UICC Geneva, pp. 123-135 (1983). 6. International Federation of Gynecology and Obstetrics. Changes in definitions of clinical staging for carcinoma of the cervix and ovary, Amer. J. Ohstet. G~necol. 156, 263-264 (1987). 7. Nakashima, N., Nagasaka, T., Fukata, S., Oiwa, N.. Nard, Y.. Fukatsu, T.. and Takeuchi, J. Study of Ovarian Tumors Treated at Nagoya University Hospital. 1965-1988, Gynecol. Oncol., 37, 103-111. 8. Rutgers, J. L., and Scully, R. E. Ovarian mullerian mutinous papillary cystadenomas of borderline malignancy. A clinicopathologic analysis, Cancer 61, 340-348 (1988). 9. Bostwick, D. G.. Tazelaar. H. D., Ballon, S. C., Hendrickson, M. R., and Kempson, R. L. Ovarian epithelial tumors of borderline malignancy. A clinical and pathologic study of 109 cases, Cancer 58, 2052-2065 (1986). IO. Hart, W. R. Ovarian epithelial tumors of borderline malignancy (carcinomas of low malignant potential), Hum. Pathol. 8, 541-549 (1977). 11. Scully, R. E. Tamours of the ovary and maldeveloped gonads, 2nd series, Armed Forces Institute of Pathology, Washington, DC (1979). 12. Scully, R. E. Common epithelial tumors of borderline malignancy (carcinomas of low malignant potential). BUM. Cancer (Paris) 69, 228-238 (1982). 13 Hart, W. R.,and Norris, H. J. Borderline and malignant mutinous tumors of the ovary. Histologic criteria and clinical behavior, Cancer 31, 1031-1045 (1973). 14 Russell, P., and Merkur, H. Proliferating ovarian “epithelial” tumours. A clinico-pathological analysis of 144 cases, Aust. N.Z. J. Ohstet. Gynaecol. 19, 45-51 (1979). 15 Aure. J. C., Hoeg, K., and Kolstad, P. Clinical and histologic
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studies of ovarian carcinoma. Long-term follow-up of 990 cases,
general hospital material, in An international
Obstet. Gynecol.
ofhistologic
37, 1-9 (1986).
16. Santesson, L., and Kottmeier, H. L. General classification of ovarian tumours, in Ovarian cancer (F. Gentil and A. C. Junqueira, Eds.), UICC Monograph Series, Vol. 11, Springer-Verlag, Berlin/Heidelberg/New York, pp. 1-8 (1968). 17. Kliman, L., Rome, R. M.,and fortune, D. W. Low malignant potential tumors of the ovary. A study of 76 cases, Obstet. Gynecol. 68, 338-344 (1986). 18. Nikrui, N. Survey of clinical behavior of patients with borderline epithelial tumors of the ovary, Gynecol. Oncol. 12, 107-119 (1981). 19. Salazar, H. Epidermiological observations on histologic types of ovarian tumours at Magee-Women’s Hospital, a gynecological referral center in Pittsburgh, PA, USA, in An international survey of distributions of histologic types of tumours of the testis and ovary (H. Stalsberg, Ed.), UICC Technical Report Series, Vol. 75,
UICC Geneva, pp. 331-34.5 (1983). 20. Tateno, H., and Sasano, N. Ovarian tumours in Sendai, Japan
21. 22.
23.
24.
survey of distributions types of turnours of the testis and ovary (H. Stalsberg,
Ed.), UICC Technical Report Series, Vol. 75, UICC, Geneva, pp. 291-296 (1983). Nieminen, U., and Purola, E. Stage and prognosis of ovarian cystadenocarcinomas, Acta Obstet. Gynecol. &and. 49,49-55 (1970). Bjorkholm, E., Pettersson, F., Einhom, N., Krebs, I., Nilsson, B., and Tjernberg, B. Long-term follow-up and prognostic factors in ovarian carcinoma. The Radiumhemmet series 1958 to 1973, Acta Radiol. Oncol. 21, 413-419 (1982). Chaitin, B. A., Gershenson, D. M., and Evans, H. L. Mutinous tumors of the ovary. A clinicopathologic study of 70 cases, Cancer 55, 1958-1962 (1985). Katsube, Y., Berg, J. W., and Silverberg, S. G. Epidemiologic pathology of ovarian tumors. A histopathologic review of primary ovarian neoplasms diagnosed in the Denver Standard metropolitan statistical area, 1 July-31 December 1969and 1 July-31 December 1979, Int. J. Gynecol. Pathol. 1, 3-16 (1982).
ONCOLOGY
38, 90-98 (1990)
Ovarian Epithelial Tumors of Borderline Malignancy in Japan NOBUO NAKASHIMA, Department
of Laboratory
M.D.,’ TETSURO NAGASAKA, M.D., NOBORU OIWA, M.D., YOSHIHARU NARA, M.D., SHINJI FUKATA, M.D., TOSHIAKI FUKATSU, M.D., AND JUN TAKEUCHI, M.D. Medicine,
Nagoya
University School of Medicine, and Division University Hospital, Nagoya, Japan
of Pathology,
Clinical
Laboratory,
Nagoya
Received September 28, 1989
Seventy-onecasesof ovarian epithelial tumor of borderline malignancy have been surveyedfrom a clinicopathologic viewpoint. The majority of the borderlinetumors (73.2%)wereof the mutinous type, versusonly 16.9%of the seroustype. The other types-endometrioid (2.8%), Brenner (1.4%), and mixed type (5.6%)--were much rarer. Patients with mutinous tumors were significantly younger (mean age 42.6) than those with serous tumors (mean age 57.5) (P < 0.01). Of patients with mutinous tumors, 64.2%wereof reproductiveage(15-45 years),compared with 17%of patientswith seroustumors. Some78.8%of mutinous and 83.3%of serousborderlinetumors wereFIG0 stageI. Serous tumors were more frequently bilateral (66.7%) than mutinous tumors (9.8%). In mutinous borderline tumors, the extent of tumor spreadat the first laparotomyhad an intimate relationship to the prognosis,but in serousborderline tumors, it was insignificant. The survival rate of patients with mutinous borderline tumors was 69.3% at 5 years and 62.4% at 10 years (KaplanMeier method). Most patients with pseudomyxomaperitonei classifiedas borderline at the time of discovery died within 5 years of the operation. The prognosisof the seroustype was extremelyfavorable.Criteria for borderlinetumors of variouscell types and differencesin the clinicopathologic data of ovarian borderline tumors betweenJapan and other countries were discussed. 0 19!Xl Academic Press, Inc. INTRODUCTION The classification of ovarian epithelial tumor by FIG0 (1961) [l] and WHO (1973) [2] has introduced a distinct borderline category between benign and obviously malignant tumors, in contrast to the earlier benign and malignant categories. In 1929, Taylor reported on patients who had been considered terminal because the ovarian ’ To whom requests for reprints should be sent at the Division of Pathology, Clinical Laboratory, Nagoya University Hospital, 65 Tsnrumai-cho, Showa-ku, Nagoya 466, Japan.
90
0090~8258/90 $1.50 Copyright 0 1990by AcademicPress,Inc. All rights of reproductionin any form reserved.
tumors had extended beyond the ovaries with wide peritoneal implants at the primary laparotomy, but who had been alive and well for many years. The tumor histologically consisted of a characteristic papillary growth of the epithelium with relatively well differentiated cells in both the primary tumor and the implants [3]. First he recorded the tumor as “hyperplastic papillary cystadenoma” and then as “semimalignant” and “borderline” [4]. He noted that the borderline tumor was malignant because patients with the tumor occasionally died from a late recurrence of the tumor. The new concept of borderline tumor was accepted by both FIG0 and WHO, and an epithelial tumor of borderline malignancy was considered to be characterized by malignant biological behavior, yet remarkably good prognosis even if the tumor extended out of the ovary or metastasized to the lymph nodes. The greater disparity in clinical behavior generally observed between ovarian borderline and invasive tumors, than between grade I and higher-grade carcinomas of most organs justified the terminology “borderline” or “of low malignant potential” [5] found in FIG0 and WHO. For these reasons, correct discrimination between the borderline tumor and the obvious malignant or benign tumor is exceedingly important. On the other hand, the concept of the borderline tumor was originally established on the basis of serous tumors and then extended to other common epithelial tumors. The appropriateness of the term borderline for the other subtypes remains to be investigated. This article presents the clinicopathological findings for a borderline case in our files, discusses the histologic diagnostic criteria for common epithelial borderline tumors of various cell types, and also draws comparisons with the clinicopathological data reported in the literature of other nations.
EPITHELIAL
MATERIALS
TUMORS OF BORDERLINE
RESULTS
Histologic types of malignant common epithelial tumor are listed in Table 1, and the clinical staging of borderline tumors in Table 2. Seventy-one cases of borderline tumor accounted for 32% of common epithelial cancers. The majority of the borderline tumors (73.2%) were of the mutinous type, against only 16.9% of the serous type. The other types were much rarer: endometrioid (2.8%), Brenner (1.4%), and mixed type (5.6%). The borderline tumors (15-85 years, average 45) occurred, on average, 7 years earlier than invasive carcinomas (22-80 years, average 52), with approximately 55% occurring at reproductive age (15-45 years), 45% after age 45, and none before age 15. Eighty-two percent of borderline tumors were FIG0 stage I. The treatment of patients with epithelial borderline tumors in this series is shown in Table 3. Unilateral salpingo-oophorectomy was performed mainly in younger patients, who had unilateral stage IA tumor and in whom the preservation of fertility was important; average age of the patients was 36.4 ? 15.5 years. More aggressive surgical therapy was apt to be TABLE 1 Histological Distribution of Common Epithelial Carcinoma
Serous tumors Mutinous tumors Endometrioid tumors Clear cell tumors Brenner tumors Mixed epithelial tumors Undifferentiated carcinoma Unclassified epithelial tumors Total
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IN JAPAN
TABLE 2 Clinical Staging (FIGO) of Borderline Tumors
AND METHODS
Seventy-one cases of common epithelial borderline tumor were found among ovarian tumors on file in our laboratory for the 23 years from 1965 to 1987. Hematoxylin and eosin (H&E)-stained sections were available for review in each case. Some cases were examined with special stains, including periodic acid-Schiff (PAS), Mayer’s mucicarmine, Alcian blue, reticulum stain, and phosphotungstic acid-hematoxylin (PTAH) for basal body and cilia. Clinical information including follow-up data was obtained from the patients’ physicians. All ovarian tumors were classified in accordance with the WHO criteria for histological typing [2], and clinical staging was performed according to the system adopted by FIG0 [6]. Survival curves were calculated by the Kaplan-Meier method. For the comparison of survival rates, the Cox-Mantel test was used.
Type
MALIGNANCY
Borderline
Malignant
Total
12 52 2 0 1 4 0 0 71
73 20 26 25 0 1 2 2 149
85 72 28 25 1 5 2 2 220
Type
IA
IB and C
IIA
IIB and C
Serous Mutinous Endometrioid Brenner Mixed Total
3 39 2 I3 48
7 2
1 I
I
1 9
1
--10
I10
2
-
III
IV -
0
selected for older women or the few young patients with bilateral ovarian involvement; average age of the patients was 53.6 2 14.1 years. After surgical treatment, 25 of 71 patients with borderline epithelial tumor were administered chemotherapy. Before 1979, patients were given combination chemotherapy including mitomycin C, cyclophosphamide, 5-fluorouracil (5-FU), and the like; since 1980, cisplatin has been added. In some patients, an internal medicine such as HCFU (carmofur) was used. Radiotherapy was not administered to any patient. The survival rate of patients with whole borderline tumors (n = 45) was 75% at 5 years and 65% at 10 years [7]. Serous Borderline
Tumors
Twelve patients had serous borderline tumors. They ranged from 22 to 85 (average 57.5 +- 16.1) years in age; two (17%) were under the age of 45. Some 83.3% of serous borderline tumors were FIG0 stage I. Six of twelve patients presented with abdominal enlargement, three with abdominal pain, and two with irregular genital bleeding. One patient was detected by chance when she was treated for uterine corpus carcinoma. The symptoms were unknown in two patients. Tumor was bilateral in 8 (66.7%) of the 12 cases. Nine patients had tumors measuring 8 cm or less in their greatest diameter, while the other patients had larger tumors. The primary tumors were endophytic in all but one case, in which it was a combination of exophytic and endophytic growth. In I1 patients tumors were unilocular or multilocular. In one patient the tumor, with part of an adenofibromatous pattern, was solid and cystic in consistency. In all cases, papillary excrescences were observed on the inner surfaces of the cysts. No hemorrhage or necrosis was found. Microscopically, the tumor was characterized by the presence of tufts having cellular buds with a very thin or no stroma in the core. The epithelial cells demonstrated a slight to moderate grade of nuclear atypicality in all but one case, which was of high grade. Occasionally, nucleoli were prominent in focal areas of the tumor. Mitoses were generally few. Ciliated epithelial cells were found in 11 of 12 cases. In 5 of 12 cases, formation of psammoma bodies was a prominent feature. In 5 cases,
92
NAKASHIMA
ET AL.
TABLE 3 Therapy for Ovarian Borderline Tumors and Prognosis No 1 2 3 4 5 6 7 8 9 10 11 12 13 I4 I5 16 17 18 19 20 21 22 23 24 2.5 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59
Age
Histologic subtype”
22 36 48 48 57 61 63 66 67 67 70 85 15 I.5 16 17 21 21 23 24 24 28 30 30 31 31 33 33 34 34 35 36 37 38 39 39 40 40 40 41 41 42 43 43 44 46 48 50 51 52 52 56 56 58 61 62 65‘ 66 68
A2 A2,JAZ A2/A2 A2/A2 A2 A2/A2 A2 A2/Al A2/A2 A2/A2 A2/A2 A2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2 B2/B2 B2 B2 B2 B2 + F2bl B2 F2blfI32 B2 B2 B2 B2 B2/B2 B2 + F2bl B2/B2 B2 B2 B2 B2 B2 B2 + F2bl B2
Stage
Surgical therapyb
IC IB III IB IA IB IA IA IB IB IB IIA IA IA IA IA IA IA IA IA IA IA IA IA IA IA IA IA IA IA IA IA2 IA IC IA IIB III IA III IA IA IA IA IA IA IIA IB IA 111 III III III IA IA IA IA IA IA2 III
us0 BSO-H BSO-H BSO-H BSO-H BSO-H us0 BSO BSO-H BSO BSO-H USO-H us0 uso+w us0 us0 us0 us0 us0 us0 us0 us0 us0 us0 USOfW uso+w us0 us0 us0 uso+w us0 US0 + my0 USO-H USO-H USO-H BSO-H oment BSO-H BSO us0 us0 USO-H uso+w BSO-H BSO-H us0 us0 us0 BSO-H BSO-H BSO-H BSO-H us0 us0 us0 BSO-H us0 BSO-H Probe
Postsurgical therapy’ MMC, 5FU, Ara-C CQ, 5FU, Ara-C None MMC, CPA, CHRM, TSPA None None None None None None None HCFU None None MMC, 5FU, Ara-C, CDDP None MMC, 5FU, Ara-C, CDDP
Survival‘+ (months) D 154 A 46 A 53
A 204 A 105 A 53 A 25 A 58 A 93 A 9 A A A A
10.5 34 25 74
None
A 117
MMC, 5FU, Ara-C None None MMC, 5FU, Ara-C, CDDP None None None None HCFU None
A 82 A 55 A 192 A 19
None CPA, ADM, MMC, CPA MMC, 5FU, CPA, ADM, None MMC, 5FU, HCFU
CDDP Ara-C, CDDP CDDP Ara-C,
None None None MMC, SFU, Ara-C, CDDP None MMC, CPA None MMC, 5FU, Ara-C, CDDP None None None None TF, PSK None None None
A 69 A 6
D 5 D 15 A44 D 6 A 36 A 85 A 23 A 228 A 74 A A A D D A
136 19 147 53 12 51
D 78 A 57 D 56 D60
EPITHELIAL
TUMORS OF BORDERLINE TABLE
No.
Age
60 61 62 63 64 65 66 67 68 69 70 71
71 71 72 74 74 46 49 57 25 27 29 44
Histologic subtype” B2 B2/B2 B2 B2 B2 c2 c2 E2 F2/F2 BI/F2 F2 F2
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IN JAPAN
3-Continued Surgical therapyh
Stage IA 111 III IA IA IA IA IA IB IA IA IA
MALIGNANCY
USO-H BSO-H USO-H us0 BSO us0 USO-H BSO-H BSO tm’ us0 USO-H
Postsurgical therapy’ None CDDP TF, 5FU None None None None 5FU, MMC, CPA CDDP. VLB, BLM CDDP, VLB, BLM None NCFU
Survivald (months) A 8 D 21
A 28 A 7 A 57 A
10
” Al, serous benign; A2, serous borderline; Bl, mutinous benign; B2, mutinous borderline; C2, endometrioid borderline; E2, Brenner borderline; F2, mixed epithelial borderline; F2bl, mature cystic teratoma; /, right and left side. * USO, unilateral salpingo-oophorectomy; BSO, bilateral salpingo-oophorectomy; -H, with total abdominal hysterectomy; + w, with wedge resection of the contralateral ovary; +myo, with myomectomy of the uterus; oment, omentectomy. ’ MMC, mitomycin C; 5FU, 5-fluorouracil; Ara-C, arabinoside C; CPA, cyclophosphamide; HCFU. carmofur; BLM, bleomycin; CQ. carboquone: CHRM, chromomycin; TSPA, thiotepa; CDDP, cisplatin; TF. tegafur; PSKE. Kurestin; VLB. Vinblastine; None, no postsurgical treatment. ” A, alive and well; D, dead ” Removal of only bilateral tumors. Five years after the operation she gave birth to a normal child.
tumors secreted a thick, mutinous fluid in some focal areas. Follow-up data were available in 8 patients; 7 were alive and well 25 months to 17 years (average 6.4 years) postoperatively, and the eighth patient, with a stage IC tumor died from the disease 13 years postoperatively. Mutinous
Borderline
Tumors
Fifty-four patients had mutinous borderline tumors. They ranged from 15 to 74 (average 42.3 ? 16.2) years in age; 34 (65%) were 45 years or younger. Of the mucinous borderline tumors, 78.8% were FIG0 stage I. Mutinous borderline tumors were bilateral in 9.8% of the cases. The median age for 41 patients with stage I tumors was 39.4 years and for 11 patients with stage II or III tumors, 53.4 years. Some 92% of the 52 patients had abdominal distension, 10% abdominal pain, and 6% irregular genital bleeding. Ninety-five percent of the mucinous borderline tumors were larger than 12 cm, and 56% measured more than 17 cm in greatest diameter; 85% occurred in the form of unilocular (2 cases) or multilocular (44 cases) cysts, which were always filled with mutinous fluid. There were two solid and cystic tumors, which associated with a mature cystic teratoma in one case and xanthoma-like nodule in another case. Five of nine cases of pseudomyxoma peritonei had no clear tumor boundary. There was no mention of associated mucocele of the appendix in clinical charts in any of the cases of pseudomyxoma peritonei. Microscopically, the mutinous borderline tumor is characterized by the presence of papillary growth and/or
small glands budding from adjacent loculi into the stroma. The epithelial cells lining the papillae and the glands showed a slight or moderate degree of nuclear atypicality (Figs. la and b). The epithelium was endocervical in 36% of cases, intestinal in 38%, and mixed endocervical and intestinal in the remaining 26%. The majority of tumors manifested benign and borderline features within the same specimen. In three patients, a mature cystic teratoma was present in the same ovary as the mutinous borderline tumor (intestinal type in one and endocervical type in two) and an xanthomatous nodule of stromal origin in another. We excluded from the present borderline series one mutinous borderline case with obvious sarcoma who died with gastric and pulmonary metastases of the sarcomatous component 7 months postoperatively. The opposite ovary contained a mature cystic teratoma in one case, and a benign mucinous tumor in another. There were inflammation, necrosis and/or calcification in the stroma in about 10% and stromal mutinous degeneration in 20% of cases. Follow-up information was available in 34 cases. Twenty-five were alive and well 6 months to 19 years (average, 6 years) postoperatively; 10 died within 5 months to 6.5 years (average, 2.6 years), and 7 of them had pseudomyxoma peritonei (stage III) at the time of discovery. They died within 6 months to 60 months (average, 32 months). By statistical analysis of the data, the 5-year survival rate for overall cases was estimated to be 69.3%, against 93% for stage I and 15% for stages II and III. Thus, there was a significant difference between stage I and the other stages (P < 0.001) (Fig. 2).
94
NAKASHIMA
ET AL.
FIG. 1. (a) This borderline mutinous tumor contains papillae projecting into a cyst. The patient died from the disease 6.5 years postoperatively (case 54). x80. (b) Higher magnification of (a). Nuclear atypicahty is slight. x530.
Endometrioid, Clear Cell, and Brenner Borderline Tumors Endometrioid borderline tumor was discovered in one ovary in two patients, 46 and 49 years old. The tumors were 17 and 3 cm in greatest diameter, respectively. One of these patients presented with abdominal enlargement or an abdominal tumor; the other one was detected by chance in an operation for uterus myoma. The solid (one
Stage 1 n=24 *.__-______i Overall n=34 I-.. _.__.___.--.__..__”_.__._”.____._.__
Stage 2 & 3 n-10
0
5
to
case) or polyp-like (one case) nodules protruded into the lumen of the endometrioid cyst. Microscopically, the endometrioid tissue of the tumors closely resembled severely atypical hyperplasia or adenocarcinoma in situ of the uterine endometrium. In the endometrioid borderline tumors, the epith~lium was observed to undergo a transition from endometriosis to tumor tissue. The remaining endometriotic lining was focally atypical, consisting of cells with large, hyperchromatic nuclei. One case was alive and well 28 months posto~ratively; the other was lost to follow-up* No clear cell borderline tumor was found on file. Of seven Brenner tumors, one .57-year-old patient belonged to the borderline category and presented with abdominal distension. The tumor was unilateral, measuring 12 cm in greatest diameter (stage IA); it was a cyst with prominent papillary growth into the lumen. Microscopically, the tumor resembled noninvasive papillary transitional cell carcinoma of the urinary bladder, and it showed moderate nuclear atypia and some mitoses (Figs. 3a and b). No benign Brenner tumor was identified in the specimen. The patient was lost to follow-up.
Ii5
YEARS
FIG. 2. Survival of patients with mutinous borderline tumors according to clinical stage of tumor. The 5-year survival rate for overall cases was 69.3%, whereas the corresponding figure for stage I was 93% and for stages II and III, 15% (Kaplan-Meier method). Survival of patients with mutinous m~ignant tumors is aIso presented for comparison.
Mixed Borderline Tumors Five mixed borderline tumors were found in four patients, aged 25 to 44 (average, 31). The tumors were detected as an abdominal tumor in two patients, in one of whom it was associated with ascites; as abdominal pain in one patient; and by chance in another operation
EPITHELIAL
TUMORS OF BORDERLINE
MALIGNANCY
FIG. 3. (a) Borderline Brenner tumor. Papillary growth of transitional-like epithelial cells is observed (case 67). of (a). X 250.
in the last patient. All the tumors, which grew in the form of cysts containing papillary growths grossly resembling serous borderline tumor, were 8 cm or smaller in maximal diameter. These tumors were characterized by the presence of tufts lined by both mutinous cells and mutinous cells with cilia, which formed abundant mucin in the lumen. No intestinal differentiation was noted. Squamous cell foci were observed in one. Nuclear atypicality was slight and mitosis was rare. No peritoneal implants were found. Follow-up data on three patients were available from 7 to 42 months (average, 19.7 months). No patient died from the disease. One patient was lost to follow-up. DISCUSSION In diagnosing neoplasia of the common epithelial category, the idea is to pinpoint exactly a specific cell type and then distinguish the borderline tumors, because patients with a borderline tumor can be expected to have a much better prognosis than those with an obviously malignant tumor. Of course, in contrast to benign tumors, patients with a borderline tumor can be terminal. On the other hand, the prognosis of patients with a carefully distinguished borderline tumor should be quite favorable. The differential diagnosis of various cell types in a common epithelial category is relatively easier for experienced pathologists in borderline tumors than in obviously malignant tumors [5]. But, occasionally, a bor-
95
IN JAPAN
x
50. (b) Higher magnification
derline tumor with features intermediate between those of the serous and the mutinous forms exists. These tumors, which were uncovered in a review of tumors classified as serous borderline tumors, are placed in the mixed borderline category in the present series, and they apparently correspond to the mullerian mutinous papillary cystadenoma of borderline malignancy described by Rutgers and Scully [8] and the seromucinous borderline tumor noted by Bostwick er al. [9]. According to these reports, the prognosis of patients with these tumors is as favorable as that of patients with serous borderline tumors, and so it is assumed in the cases of the present series. There is general agreement regarding the basis of the definition of borderline tumor, but disagreement seems to exist over the application of a definition to each case. On review of our cases, the major difficulty experienced in differentiation is that criteria for cellular (nuclear) anaplasia and structural anaplasia without invasion have not been clearly defined by WHO, and much of the categorization has been subjective and is probably not reproducible. In a case not included in this borderline category, a small nodule about 0.7 cm in diameter was observed to protrude into an endometrioid cyst, and the tumor appeared to belong to the borderline category histologically. The patient died from peritonitis carcinomatosa 20 months after hysterectomy and bilateral salpingo-oophorectomy. Retrospectively, a cribriform pattern of glands with no invasion of the stroma was found in a small area. Although there is no WHO defi-
96
NAKASHIMA
nition (but see Fig. 248 in Ref. [2]), we agree with Hart [IO] that the obvious cribriform pattern should be regarded as an indication of invasive carcinoma. Only one Brenner borderline tumor resembles grade 1 papillary carcinoma of the urinary bladder (Figs. 3a and b), the features of which closely resemble those in the textbook [ 111.But this tumor has no features typical of a benign Brenner tumor. We placed this tumor in the borderline category, because it showed no invasion. But, according to Hart, who claimed that clear-cut malignant nuclear features should be regarded as carcinoma, irrespective of whether stromal invasion is identified [lo], it should have been placed in the malignant category because of the high degree of nuclear atypia. The diagnostic criteria for serous borderline tumor are considered to be defined properly in WHO, leaving trained pathologists [ 121with little disagreement regarding the diagnosis. Yet even experienced pathologists differ on the range of the mutinous borderline tumor. Hart and Norris [13] proposed that a stage I mutinous borderline tumor be classified as carcinoma when stratification of atypical cells into four or more layers was observed in the epithelial lining. Some disagree with this on the grounds that the classification would thus become more complex and difficult to use in practice [14], and with this we concur. Only one case fits this description in the present series and we placed it in the mutinous borderline category. Subjectivity is inevitable in differentiating borderline from benign mutinous tumors. When we examine retrospectively cases that succumbed to mutinous borderline tumor, there are some primary tumors with only epithelial proliferation and atypicality of a minor degree, which probably correspond to mutinous adenomas in WHO. Pathologists who have come across such a case are prone to widen the range of the borderline category. The relative frequency of mutinous borderline tumors is higher in our series than in other large series. We thought that more effort is needed to bring some objectivity to differentiation of mutinous borderline tumor. The frequency of endometrioid borderline tumors has been reported generally at about 1% that of common epithelial cancers [ 15,161,but in the series of Russell and Merkur it was 3.2%, which is higher than the 0.9% of our series. The relative frequency of endometrioid malignancy in the series of Russell and Merkur is also higher than in other studies. There may have been differences in applying the criteria for endometrioid tumors. Although there are some differences in applying the definition of borderline tumor, we consider that they do not prevent comparison of our data on the present series with data on other large series. Overall, borderline tumor, accounts for 32% of all epithelial malignancies in the present series, against 9.2-33% in other series [14,17,18].
ET AL.
The average age of patients with borderline tumor in the present series (45 years) is almost the same as that in the series of Kliman et al. (46 years) [17]. The survival rate of patients with borderline tumors has been reported to be 90-95% at 5 years and 70-90% at 10 years in several articles in the West [9,15-171, against a somewhat lower 75% at 5 years and 65% at 10 years in our series [7]. The poor prognosis of patients with pseudomyxoma peritonei clearly decreases the survival rate of patients with borderline tumors in our series. Serous and mutinous borderline tumors always constitute the majority of borderline tumors in any large series, accounting for 90% of the present series and 83100% [14,17-191 of other reported series. With respect to the relative frequency of mutinous borderline tumors, the 73% of all borderline tumors observed in this series and the 69% in another series in Japan [20] are higher than the 31-40% [ 14,18,21] observed in other series in the West. The ratio of serous borderline to mutinous borderline tumors is approximately 1:4 (if mixed-type tumors are included in the serous tumors, the ratio is 1: 3) in the present series and 1: 2 in the Japanese series [20], in contrast with 1:0.4-0.7 [14,18,21] in other nations; however, in the Kliman et al. series [17] it is 1: 1.3, which is relatively high for Western countries. Among borderline tumors, the mutinous borderline tumor is the most common type in Japan [20], but probably as a result of the much lower prevalence of serous tumors; also, disagreement in application of the criteria for mutinous borderline tumor is also considered to have somewhat widened the range. In our series the patients with serous borderline tumors were on average 57.5 years of age, considerably older than the patients (40-54 years) in several large series reported in the West [9,17,18,22]. The relatively older mean age of our patients may have been due in part to the rather small number of cases in our series. The age range (15-74 years; average, 42.3) for our 52 patients with mutinous borderline tumors is about ten years younger than that for several large series reported in the West [17,18,22,23]. The average age (35 years) of Hart and Norris’ patients [23] with stage I seems exceptionally young; however, it is near the mean (39 years) for the same type of patients in the present series. Patients with mutinous tumors were significantly younger (mean age, 42.6) than those with serous tumors (mean age, 57.5) (P < 0.01); of patients with mutinous tumors, 64.2% were of reproductive age (15-45 years), compared with 17% of patients with serous tumors in the present series. The prognosis for patients with serous borderline tumors has been reported to be extremely good in every country irrespective of age, clinical stage, or incomplete removal of tumor by operation. The distribution of clinical stage in patients with serous borderline tumors is
EPITHELIAL
TUMORS OF BORDERLINE
substantially no different: 7.585% of serous borderline tumors are stage I in other countries [9,14,15,17,21] versus 83% in our series. Serous tumors were more frequently bilateral than mutinous tumors in both the Orient and the West. Serous borderline tumors have been reported to be bilateral in 33-48% of patients [9,14,17,241 in other countries and 66.7% of patients in our series. More than 90% of patients survive 5 years and about 90% survive 10 years in Western countries [15,18,21] as well as in the present series, in which only 1 of 8 patients died from the disease 13 years postoperatively. For patients with mutinous borderline tumors, the extent of tumor spread at the first laparotomy had an intimate relationship with prognosis. Some 85-100% of mutinous borderline tumors are stage 1 in the West [9,14,15,18,23] versus 77% in our series. This figure is near that reported for mutinous borderline tumors by Kliman et ul. [17] and Russel and Merkur [ 141who reported 72% and 78% stage I cases, respectively. The 5year survival rate of patients with mutinous borderline tumors of all stages has been reported to be 92-98% by Aure et al. [15] and Chaitin et (~1.[23] and about 80% by Nieminen and Purola [21] and Nikrui [18]; the loyear survival rate is set at more than 90% by the first two reports; our corresponding figures are 69.3% at 5 years and 62.4% at 10 years. One reason for the low survival rate in our series is a higher rate of cases with pseudomyxoma peritonei at the time of first discovery, many of whom died from inanition or intestinal obstruction within relatively short periods. Kliman et ul. also reported that patients with pseudomyxoma peritonei fared badly [17], and the poor prognosis of the tumor apparently lowered the survival rate in their series. Borderline tumors other than serous and mutinous types are difficult to compare clinicopathologically because of the rarity of these cases in any series. In the present series, it had not been long since the postsurgical chemotherapy had been administered, and the number of patients with each epithelial subtype so treated was too small to evaluate the comparative merits of various agents. Thus, our experience is still insufficient to elucidate the role of chemotherapy for borderline epithelial tumors. Very long follow-up is clearly necessary before the efficacy (or ineffectiveness) of chemotherapy for borderline tumors becomes evident. SUMMARY The category of ovarian borderline tumors has been created by segregating a subgroup with an unusually good prognosis from the general group of common epithelial cancers [12]. Serous borderline tumors fit the category; mutinous borderline tumors would also fit it if patients with pseudomyxoma peritonei were excluded.
MALIGNANCY
IN JAPAN
97
Most cases of pseudomyxoma peritonei of borderline category at the time of discovery died within 5 years of their operation. Whether endometrioid, clear cell, and Brenner borderline tumors fit the category is too difficult to decide because of the rarity of these cases and the need for a larger sample. In comparison with Western countries, the relative frequency of mutinous borderline tumor is higher in Japan. However, the higher frequency in Japan is considered to be the result of a much lower prevalence of serous borderline tumors. REFERENCES I. Kottmeier, H. L. The classification and clinical staging of carcinoma of the uterus and vagina, J. Int. Fed. Gynecol. Ohstet. 1,
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