Ovarian Serous Borderline Tumors With Stromal Microinvasion: A Report of 21 Cases DEBRA A, BELL, MD, AND ROBERT E. SCULLY, MD The clinicopathologic features of 21 cases of otherwise typical serous borderline tumors that contained small foci of stromal invasion were reviewed. The mean age of the patients was 43 years and six of them were pregnant at the time of diagosis. Nineteen tumors were stage I, one was stage III (para-aortic lymph node involvement) and one was stage IV (parenchymal liver metastasis). The tumor invaded the stroma predominantly as individutal cells or nests or clusters of cells with abundant eosinophilic cytoplasm (17 cases), as small confluent nests with a cribriform pattern (two cases) and as rounded aggregates of papillae (two cases). Seven women were treated with bilateral salpingo-oophorectomy and hysterectomy; 13 had less than bilateral oophorectomy. Of the 17 patients for whom followup data were available, 16 were without evidence of disease 1 to 11 (mean, 5.2) years postoperatively, and one patient had a serous borderline tumor with microinvasion in a conserved contralateral ovary 2.8 years postoperatively, but was well 6 months after a partial oophorectomy. These data suggest that selous borderline tumors with microinvasion have a prognosis similar to that of the usual serous borderline tumor, and that conservation of the contralatera1 ovary and uterus may be acceptable therapy in young women Q who wish to preserve their fertility. HUM PATHOL21:397-403.
stromal invasion, possible microinvasion or pseudoinvasion of the stroma from the consultation files of one of us (R.E.S.) and the surgical pathology files of the Massachusetts General Hospital revealed 17 cases that fulfilled these criteria. Four additional cases were obtained by a screening examination of 36 consecutive cases of SBTs in the files of the Massachusetts General Hospital performed to assess the frequency of undetected stromal invasion. The clinical features of the cases were obtained from consultation correspondence, office charts, letters and oral communications with the patients’ physicians. The gross pathologic features were obtained from consultation correspondence and the original pathology reports. One to 33 (mean. 8) hematoxylin and eosin-stained slides of the ovarian tumors were reviewed and evaluated for alterations in cell type and percent of cells with such alterations, the number and sire of the invasive foci, the patterns of the invasive tumor (single cells, nests, papillary clusters) and the presence of lymphatic or vascular invasion. The stage of the tumor was recorded in accordance with the criteria of the International Federation of Gynecology and Obstetrics.” Followup data were obtained from gynecologists, pathologists, and tumor registries of the referring institutions.
1990 by W.B. Saunders Company.
Serous borderline tumors (SBTs) are defined by the World Health Organization as tumors characterized by epithelial proliferation greater than that seen in serous: cystadenomas and a lack of “destructive” stromal invasion.’ Since the original description of these tumors by Taylor, ‘Lhowever, a subset of serous borderline neoplasms that contain small foci of un-
RESULTS Clinical Findings The 21 patients ranged in age from 17 to 83 (mean 33) years. Fifty-two percent of them were 35 years of age or younger. Thirteen (62%) of them were premenopausal and six of these patients were pregnant at the time of operation.
equivocal infiltration of the stroma has been recognized.:‘-” To investigate the frequency and clinical significance of’ microinvasion, we reviewed the clinicopathologic features of 21 cases of otherwise typical SlBTs with this finding.
Operative Findings Eighteen of the tumors were confined to one ovary (stage IA); one of these tumors had ruptured at operation. One tumor involved both ovaries (stage IB), one patient had clusters of cells in a para-aortic lymph node that were similar to those in the invasive foci of the primary tumor (stage III), and one patient had a histologically confirmed metastatic SBT within the parenchyma of the liver (stage IV) at the time of presentation.
MATERIALS AND METHODS Tumors were classified as SBTs with microinvasion if they had the microscopic appearance of a typical SBT except for foci, each less than 0.3 cm in greatest dimension, of I urnor cells that infiltrated the stroma as single cells, nests of c,ells, or papillae. Review of all cases coded as SBTs with From the Department of Pathology, Harvard Medical School, ,tnd the James I Iomer Wright Pathology Laboratories of the Mas\achusetts General Hospital, Boston, MA. Accepted for publication .Allgust 23, 19x9. Presented in part at the 78th Annual Meeting of the US(knadian Academ\ of Pathology, San Francisco, CA, March 7,
Treatment Four patients were treated with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy, three with total abdominal hysterectomy and bilateral salpingo-oophorectomy, eight with unilateral salpingo-oophorectomy and contralateral ovarian biopsy or resection, five with unilateral salpingo-oophorectomy, and one with bilateral salpingooophorectomy and partial resection of a cystic liver metastasis. Three patients received postoperative
1989. Key u’r/~d~~ ovarian
serous borderline tumor. microinvasion, stromal inrasioll. Address correspondence and reprint requests to Debra A. Bell, MD, Departmrnt of Pathology, Massachusetts (ieneral Hospital. Fruit Street, Boston, MA 021 14. 6 1990 by W.B. Saunders Company. 0046-N 177iSOi? 104.0004$.i.O0/0
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chemotherapy; one of them received melphalan and two received cisplatin tin or cisplatin and cyclophosphamide.
10 courses of and doxorubi-
Pathologic Features The tumors were cystic and ranged in diameter from 4 to 29 (mean 13) cm in the 15 cases in which quantitative information was available. Tumor was present on the surface of the involved ovary in four of 16 women in whom the surface was identified. The microinvasion was present in one ovary in 19 cases and in both ovaries in one case; the ovarian distribution was not specified in a final case. In the unilateral cases, the contralateral ovary contained SBTs without invasion in two cases, serous cystadenomas in two cases, and fibromas in two cases; the contralateral ovary was normal histologically in 11 women. The conserved ovaries were described as normal on palpation and visual inspection by the operating gynecologist in the remaining five women. The ovarian tumors in each patient showed the typical histologic features of SBTs; broad and fine papillae lined by one to several layers of cells with atypical nuclei, and tufting of the neoplastic epithelium with the formation of solid cellular buds that appeared detached from the papillae were present. The epithelial cells were of two types. The first, of the type typically seen in serous neoplasms, was composed of cuboidal to pseudostratified columnar cells with occasional cilia, delicate cytoplasm, and ovoid nuclei. The second type of cell was cuboidal, columnar or hobnail-shaped with abundant dense eosinophilic cytoplasm and a round hyperchromatic nucleus, which often contained a single large nucleolus (Fig 1). These eosinophilic cells were present in all of the tumors, accounting for less than 10% to more
than 90% of the lining epithelial cells. Eosinophilic lining cells were present within one high power field of the invasive foci in 18 cases, within 2 mm in two cases, and in separate sections in one case. In each case, one of three histologic patterns predominated in the invasive foci. In 17 cases, the stroma of the tumor papillae was infiltrated predominantly by small, scattered foci of individual cells and small irregularly-shaped nests and papillary clusters of cells with dense eosinophilic cytoplasm and a round hyperchromatic nucleus with a single large nucleolus, resembling the eosinophilic cells of the lining epithelium (Figs 1 and 2). A clear zone or cleft was often present between the infiltrating cells and the stroma (Fig 2). No stromal reaction to the tumor cells was present except for a slightly increased number of mature stromal fibroblasts in the three cases with the largest aggregates. The number of foci ranged from one to eight in most cases and over 10 in four cases. The invasive foci were small and scattered and did not form measurable aggregates in 16 cases; in one case, they formed ill-defined aggregates that measured up to 2.5 mm in greatest dimension. Clusters of eosinophilic cells were present in spaces lined by flattened cells resembling lymphatics in four cases (Fig 2). In two cases, although individual eosinophilic cells and small nests of eosinophilic cells were present in the stroma, the histologic appearance was dominated by a second pattern, characterized by confluent nests of eosinophilic cells with a cribriform pattern (Figs 3 and 4). These foci measured 1 and 1.1 mm in diameter, respectively. In the final two cases a third pattern was encountered-a predominance of rounded aggregates of papillae lined by typical serous-type epithelial cells (Figs 5 and 6). These papillae were separated from the stroma by a clear zone or cleft (Fig 6). The aggregates measured 1.1 and 2.5 mm in greatest
FIGURE 1. Individual eosinophilic cells and small irregular nests of eosinophilic cells infiltrate the stroma between the glands of SBT. The non-invasive glands of the SBT are lined by typical columnar serous-type epithelial cells as well as polygonal or hobnail-shaped cells with abundant dense eosinophilic cytoplasm. [Hematoxylin-eosin stain, magnification x 313.)
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SEROUS BORDERLINE TUMORS WITH MICROINVASION (Bell & Sadly]
FIGURE 2. A small, irregularly shaped nest of eosinophilic cells and an individual eosinophilIC cell are present in the stroma adjacent to several smoothly contoured non-invasive glands of an SBT. The infiltrative cells are surrounded by a cleft or clear zone devoid of lining cells. ,A nest of similar tumor cells is present in a lymphatic space lined by prominent endothelial cells. (Hematoxylin-eosin stain, magnification x 313.)
dimension. Blood vessel or lymphatic invasion or a stromal reaction to the tumor was not identified in these last four cases. The invasive foci in each of the 2 1 cases tiere present in the stroma of the tumor and did not invade the adjacent normal ovarian tissue. Follow-up
Data
Sixteen patients were alive without evidence of disease 1 to 1 1 (mean, 5.2) years postoperatively, including the woman with a documented hepatic metastatic tumor. She was alive and well 47 months after total abdominal hysterectomy, bilateral salpingooophorectomy, and omentectomy and combination chemotherapy. In one patient who had undergone a right salpingo-oophorectomy and left ovarian cystec-
FIGURE 3. Confluent nests of eosinophilic cells with a cribriform pattern are present in the stroma of a papilla of an otherwise typical SBT. (Hematoxylin-eosin stain, magnification x 50.1
tomy for an SBT with microinvasion of the right ovary and an SBT without invasion of the left ovary, a recurrent SBT with small foci of microinvasion developed in the left ovary 32 months postoperatively. She was well 6 months after a second left ovarian cystectomy. Two women were lost to follow-up, including the woman with a para-aortic lymph node metastasis. and two cases are too recent for a meaningful follow-up. Clinical Features of the Patients with Lymphatic Invasion The four women whose tumors contained lymphatic invasion were 19, 28. 30 and 36, years of age. Three of them were pregnant at the tune of opera-
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FIGURE 4. The cells lining the cribriform spaces are polygonal with round-to-oval nuclei and prominent nucleoli. [Higher power of Fig 3, Hematoxylin-eosin stain, magnification x 313.)
tion. Three of the tumors were confined to one ovary, and one woman had tumor in a para-aortic lymph node. All four women were treated with unilateral salpingo-oophorectomy. None received postoperative therapy. Two of them were alive and well at 11 and 42 months postoperatively, and two were lost to follow-up (including the patient with lymph node metastases). Assessment of Frequency Review of 36 consecutive unselected cases of SBTs from the files of the Massachusetts General Hospital revealed four (11%) with microinvasion. Three, seven and more than 10 foci of infiltrating eosinophilic cells were present in three of the tumors.
One tumor contained a 2.5 mm rounded posed of infiltrative papillae.
nodule
com-
DISCUSSION The most important feature that distinguishes SBTs from serous carcinomas is the presence of “destructive” stromal invasion in the latter.‘.’ In most serous carcinomas, the invasion is easily identified by the extensive presence of irregular, ill-defined nests of markedly atypical cells infiltrating a loose and edematous, myxoid, or desmoplastic stroma. In contrast, the epithelium lining the papillae of serous borderline tumors usually exhibits a sharp epithelialstromal junction, and when the epithelium dips into
FIGURE 5. A rounded aggregate of infiltrative popillae is present in the stroma of an SBT. (Hematoxylineosin stain, magnification x 79.)
SEROUS BORDERLINE rUMORS WITH MICROINVASION [Bell & Scully]
FIGURE 6. The infiltrative papillae are surrounded by a cleft or clear zone, (Hematoxylin-eosin stain, magnification x 125.)
the stronna, it does so as regularly distributed, smoothly contoured, sharply defined glands without a stromal reaction. A small number of tumors in the serous category fall between these two extremes, having the general appearance of a serous borderline tumor, but containing small foci of stromal invasion that do not elicit a discernible stromal reaction. We term these latter tumors SBTs with stromal microinvasion if the foci of invasion do not exceed 0.3 cm in greatest dimension. The lclassification and significance of small areas of stromal microinvasion in otherwise typical SBTs has been discussed only rarely in the literature.“,q Katzenstein and her coworkers” described several histologic patterns they interpreted as destructive stroma1 invasion which, they concluded, justified a diagnosis of well-differentiated serous cystadenocarcinoma. These patterns included infiltration of the stroma bv (1) glands with poorly-defined borders in an edematous stroma, (2) cell clusters and individual cells in a pale, loose stroma, (3) confluent backto-back glands and solid sheets of tumor cells, (4) small irregular tongues of cells extending from the base of glands accompanied by chronic inflammation and creating a pattern similar to that of microinvasive squamous carcinoma of the cervix, and (5) haphazardly distributed single cells and cell clusters often separated from the stroma by a clear zone or cleft. A sixth pattern of stromal involvement characterized by “unattached single epithelial cells scattered within the stromal stalks of the papillae, and at times even appearing to break off from glands” was not interpreted as indicating invasion.” Tavassoli, in her review of 18 patients with tumors of this type, 4 defined serous tumors of low malignant potential with microinvasion as tumors with all the clharacteristics of SBTs, except for the presence of foci of early invasion that did not evoke a These foci were composed of isostromal response.
lated cells and cell clusters with abundant eosinophilic or pink cytoplasm. Typical serous cells invaded the stroma in one tumor as a single papillary cluster. Since these foci were small and scattered, a maximum size dimension allowable in this category was not determined. In our study, we defined SBTs with stromal microinvasion as tumors with foci of invasion, each measuring less than 3 mm in greatest dimension, that were unassociated with a significant stromal reaction. Review of our cases revealed that one of three patterns of invasion predominated in each case. The most common pattern of scattered foci of infiltration of the stroma by eosinophilic cells, present in 17 of our cases, was similar to that seen in the cases described by Tavassoli.q Although isolated single eosinophilic cells were present in most of our cases of this !ype, nests of eosinophilic cells were present as well m all of our cases and in those described by Tavassoli.4 For this reason. these tumors would be classified as welldifferentiated serous cystadenocarcinomas according to the criteria of Katzenstein and her coworkers.g The clinical features of the tumors wit.11 this pattern of infiltration in our study and in that of Tavassoli4 were remarkably similar. The 18 women described by Tavassoli ranged from 22 to 80 years of age with a median age of 34.5 years; the median age of our 17 patients in this category was 38.5 years. Five women in Tavassoli’s study and six in ours had tumors that were discovered during pregnancy. Twelve of the 18 patients in Tavassoli’s series had stage I tumors, whereas 16 of 17 of the patients in the present series had tumor confined to one or both ovaries. One patient in each study had metastatic tumor in lymph nodes in the form of eosinophilic cells resembling those of the microinvasive foci seen in the ovarian tumor. All of the patients in this category in the present study for whom followup data were available were alive and well: one of 17 patients in Tavassoli’s 401
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course of action are emphasized by the patient in our study who underwent a right salpingo-oophorectomy and left ovarian cystectomy for a right-sided SBT with microinvasion and a left-sided SBT without invasion. She had a recurrent serous borderline tumor with microinvasion foci in her conserved left ovarian tissue 34 months postoperatively. Because of the indolent but real malignant potential of these tumors, the standard therapy in older women would be bilateral salpingo-oophorectomy and hysterectomy. The excellent survival rate of patients with microinvasive serous borderline tumors with surgical therapy alone also indicates that postoperative radiation or chemotherapy is unlikely to be of value. The major problem of clinical importance in the histologic diagnosis of SBTs with microinvasion is distinguishing them from serous carcinomas. The individual cells, nests and papillae of stromal microinvasion are often of the eosinophilic cell type, do not elicit a significant stromal response, and according to our definition, are less than 0.3 cm in greatest dimension. In contrast, serous carcinoma is typically characterized by irregular, ill-defined nests of markedly atypical cells with a solid or complex bridging pattern that usually elicit an edematous, myxoid, or desmoplastic stromal response. The eosinophilic cells in microinvasive foci may be mistaken for stromal decidual transformation, especially when a woman is pregnant. In general, stromal decidual cells may be identified by their smooth amphophilic cytoplasm, and delicate, vesicular, uniform nuclei. Finally, microinvasive foci may be difficult to detect in an SBT, especially at low power. In the examination of SBTs, special attention should be paid to the presence of epithelial elements within the connective tissue cores of the papillae. If they are not in the form of regularly distributed glands with or without intraglandular papillae, these elements should be carefully studied to exclude microinvasion. A helpful feature in this regard is identification of clear zones or clefts that are usually present between the infiltrating tumor cells and the stroma, and are not generally seen surrounding noninvasive branching glands of SBTs. Also, the infiltrative nests have irregular contours, unlike the smoothly contoured epithelial budding typically seen in SBTs. That these foci are not uncommon and are easily overlooked, even on careful examination, is documented by the discovery of four examples of stromal microinvasion on review of 36 consecutive serous borderline tumors at our hospital. The presence of eosinophilic cells lining the papillae and glands within a high-power field of the microinvasive foci in many of our cases, and the apparent direct connection of the overlying eosinophilic epithelium with cytologically similar invasive foci, suggest that this type of epithelium may have a higher propensity for invasion than the more typical serous lining cells usually seen in SBTs. A recently performed study from our institution (Cajigas H, LimTan SK, Scully RE. Unpublished observations, 1989) has shown an association of extensive eosinophilic cell change of the epithelium of ovarian SBTs with preg-
study died of tumor. These findings are also comparable to those of the seven cases with “noninvasive” stromal involvement by single eosinophilic cells (category 6) of Katzenstein and her coworkers.” The median age of those patients was 27.5 years; four of their tumors were stage I, two were stage II and one was stage III. All seven women were without evidence of disease from 4 to 21 years postoperatively. Although it is probable that some of the 13 patients classified as having well-differentiated serous cystadenocarcinomas by Katzenstein and coworkers had small foci of stromal invasion by nests of eosinophilic cells, comparison of the clinicopathologic features of their cases with ours is not possible because the pattern of invasion and the size of the invasive foci in those cases were not described in detail. The second and third patterns of microinvasion noted in this study, those of infiltration of the stroma dominated by aggregates of papillae or small confluent foci of tumor cells with a cribriform pattern, were seen in older women, aged 26, 67, 74 and 83 years. Three of these tumors were stage I and one was stage IV because of parenchymal liver involvement. All four women were without evidence of disease at 47, 60,97 and 130 months postoperatively. Both of these patterns would have been considered well-differentiated serous carcinomas by Katzenstein and coworkers.” Although 58% of the patients with serous carcinomas in Katzenstein and coworkers’3 study died of tumor, these figures are not comparable to our results because the well-differentiated serous carcinoma group in the Katzensteir? study was heterogenous, containing cases ranging from those with minimal microinvasion to overt serous carcinomas containing solid sheets of tumor or irregularly contoured nests of malignant cells that elicited a marked stromal reaction (categories 1, 2, and 3 as described previously). These types of stromal invasion were not discussed by Tavassoli.-’ Four of the 21 patients’ tumors showed lymphatic invasion, as assessed on hematoxylin and eosin-stained sections. Although the clinical significance of this finding is unclear due to the small number of cases, one of the four patients had metastatic tumor in a para-aortic lymph node, suggesting that lymphatic invasion in these tumors may be associated with spread beyond the ovary. Lymphatic invasion was not identified on immunoperoxidase stains for factor VIII in any of Tavassoli’s 18 cases.A The disease-free survival of all 16 of 17 patients with followup in the present study, 17 of 18 patients and in all 7 patients with in Tavassoli’s study,’ “noninvasive” stromal infiltration in the study of Katzenstein et al,” suggests that SBTs with stromal microinvasion are associated with an excellent prognosis, similar to that of SBTs without invasive foci. Furthermore, many of the women who were diseasefree were treated with limited surgical procedures, indicating that conservation of the contralateral ovary and uterus may be an acceptable procedure in young women with this type of tumor if preservation of reproductive potential is desired. The risks of this 402
SEROUS BORDERLINE TUMORS WITH MICROINVASION (Bell & Scully)
nancy, compatible with the large number of pregnant patients in this series and that of Tavassoli4 That 28% of the women with microinvasive SBTs in these series were pregnant, compared with 4% in the group of unselected women with SBTs without microinvasion from our hospital, raises the possibility that pregnant women are at greater risk of having stromal microinvasion in their SBTs than other women. Larger studies of SBTs in pregnant and nonpregnant patients are necessary to confirm this observation.
Cooley Dickinson Hospital, Northampton, MA; Sherry Parker, Tumor Registrar, Midland Memorial Hospital, and R. H. Hardy, MD, Midland, TX. The authors also thank Judith M. Shnider for excellent research and secretarial assistance.
REFERENCES 1. Serov SF, Scully RE, Sobin LH: Histological typing of ovarian tumours. in: International Histological Classification of Tumours, no. 9. Geneva, Switzerland, World Health Organization, 1973. pp. 37-38 2. Taylor HC: Malignant and semi-malignam (urnor? of the ovarv. Surg Gynec-ol Obstet 48:204-230. 1929 3. Katzenstein A-L A. Mazur MT. Morgan TE, et al: Proliferative serous tumors of the ovary. Histologic features and prognosis. Am J Surg Path01 2:339-355, 1978 4. Tavassoli FA: Serous tumor of low malignant potential with early stromal invasion (serous LMP with microinvasion). Mod Pathol 1:407-414. 1988 5. Russell P: The pathological assessment of ovarian neoolasm. III. The mahenant ‘eoithehal’ tumours. Patholocrv 11:493u j32. 1979 6. Oncology Committee of the Internal Federation of Gynecology and Obstetrics: Changes in definitions of clinical staging for carcinoma of the cervix and ovary: International Federation of Gynecologv and Obstetrics. Am J Obstet Gcnecol 156:263-264, 1987 7. Scully RE: Tumors of the ovxy and maldeveloped gonads, in: Atlas of Tumor Pathology, 2nd Serves. Fascicle 16.Washington, DC. Armed Forces Institute of Patholog). 1979, pp I 17.127
Acknou~l~~&~c~~: The authors thank the following individuals for generously contributing cases, clinical data and followup information: N. Nikrui, MD. C. Granai, MD. A. Fuller, MD, M. Etkin, MD, J. Dineen, MD, and H. Safaii, MD, Boston. MA; Y. S. Fu, MD, Los Angeles, CA; Nancy Reas. Tumor Registrar, University of California, Los Angeles Medical Center. Los Angeles, CA; J. T. Wharton, MD, Houston, TX; Tumor Registrar, Columbia Hospital, Milwaukee, WI; S. Carinelli, MD, Milan, Italy; B. Pritzker, MD, Vallejo, CA; E. Davis, MD, and C. R. Minick, MD, New York, NY: M. de Sousa Paino, MD, Araraguara, Brazil; B. Westphall, MD, Anderson, CA; Northern Laboratories. Redding, C4; 1). R. Duffell, MD, and the Tumor Registrar, Northwest Community Hospital, Arlington Heights, IL; A. Fabbri, MD, Wakefield, MA: V. Lynch, MD, Hamden, CT; M. Carcangiu. MD, New Haven, CT; I. F. Hitti. MD, Forest Hills, NY: G. R. Marrocco, MD, and the Tumor Registrar,
IT,
403
stromal invasion, possible microinvasion or pseudoinvasion of the stroma from the consultation files of one of us (R.E.S.) and the surgical pathology files of the Massachusetts General Hospital revealed 17 cases that fulfilled these criteria. Four additional cases were obtained by a screening examination of 36 consecutive cases of SBTs in the files of the Massachusetts General Hospital performed to assess the frequency of undetected stromal invasion. The clinical features of the cases were obtained from consultation correspondence, office charts, letters and oral communications with the patients’ physicians. The gross pathologic features were obtained from consultation correspondence and the original pathology reports. One to 33 (mean. 8) hematoxylin and eosin-stained slides of the ovarian tumors were reviewed and evaluated for alterations in cell type and percent of cells with such alterations, the number and sire of the invasive foci, the patterns of the invasive tumor (single cells, nests, papillary clusters) and the presence of lymphatic or vascular invasion. The stage of the tumor was recorded in accordance with the criteria of the International Federation of Gynecology and Obstetrics.” Followup data were obtained from gynecologists, pathologists, and tumor registries of the referring institutions.
1990 by W.B. Saunders Company.
Serous borderline tumors (SBTs) are defined by the World Health Organization as tumors characterized by epithelial proliferation greater than that seen in serous: cystadenomas and a lack of “destructive” stromal invasion.’ Since the original description of these tumors by Taylor, ‘Lhowever, a subset of serous borderline neoplasms that contain small foci of un-
RESULTS Clinical Findings The 21 patients ranged in age from 17 to 83 (mean 33) years. Fifty-two percent of them were 35 years of age or younger. Thirteen (62%) of them were premenopausal and six of these patients were pregnant at the time of operation.
equivocal infiltration of the stroma has been recognized.:‘-” To investigate the frequency and clinical significance of’ microinvasion, we reviewed the clinicopathologic features of 21 cases of otherwise typical SlBTs with this finding.
Operative Findings Eighteen of the tumors were confined to one ovary (stage IA); one of these tumors had ruptured at operation. One tumor involved both ovaries (stage IB), one patient had clusters of cells in a para-aortic lymph node that were similar to those in the invasive foci of the primary tumor (stage III), and one patient had a histologically confirmed metastatic SBT within the parenchyma of the liver (stage IV) at the time of presentation.
MATERIALS AND METHODS Tumors were classified as SBTs with microinvasion if they had the microscopic appearance of a typical SBT except for foci, each less than 0.3 cm in greatest dimension, of I urnor cells that infiltrated the stroma as single cells, nests of c,ells, or papillae. Review of all cases coded as SBTs with From the Department of Pathology, Harvard Medical School, ,tnd the James I Iomer Wright Pathology Laboratories of the Mas\achusetts General Hospital, Boston, MA. Accepted for publication .Allgust 23, 19x9. Presented in part at the 78th Annual Meeting of the US(knadian Academ\ of Pathology, San Francisco, CA, March 7,
Treatment Four patients were treated with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy, three with total abdominal hysterectomy and bilateral salpingo-oophorectomy, eight with unilateral salpingo-oophorectomy and contralateral ovarian biopsy or resection, five with unilateral salpingo-oophorectomy, and one with bilateral salpingooophorectomy and partial resection of a cystic liver metastasis. Three patients received postoperative
1989. Key u’r/~d~~ ovarian
serous borderline tumor. microinvasion, stromal inrasioll. Address correspondence and reprint requests to Debra A. Bell, MD, Departmrnt of Pathology, Massachusetts (ieneral Hospital. Fruit Street, Boston, MA 021 14. 6 1990 by W.B. Saunders Company. 0046-N 177iSOi? 104.0004$.i.O0/0
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chemotherapy; one of them received melphalan and two received cisplatin tin or cisplatin and cyclophosphamide.
10 courses of and doxorubi-
Pathologic Features The tumors were cystic and ranged in diameter from 4 to 29 (mean 13) cm in the 15 cases in which quantitative information was available. Tumor was present on the surface of the involved ovary in four of 16 women in whom the surface was identified. The microinvasion was present in one ovary in 19 cases and in both ovaries in one case; the ovarian distribution was not specified in a final case. In the unilateral cases, the contralateral ovary contained SBTs without invasion in two cases, serous cystadenomas in two cases, and fibromas in two cases; the contralateral ovary was normal histologically in 11 women. The conserved ovaries were described as normal on palpation and visual inspection by the operating gynecologist in the remaining five women. The ovarian tumors in each patient showed the typical histologic features of SBTs; broad and fine papillae lined by one to several layers of cells with atypical nuclei, and tufting of the neoplastic epithelium with the formation of solid cellular buds that appeared detached from the papillae were present. The epithelial cells were of two types. The first, of the type typically seen in serous neoplasms, was composed of cuboidal to pseudostratified columnar cells with occasional cilia, delicate cytoplasm, and ovoid nuclei. The second type of cell was cuboidal, columnar or hobnail-shaped with abundant dense eosinophilic cytoplasm and a round hyperchromatic nucleus, which often contained a single large nucleolus (Fig 1). These eosinophilic cells were present in all of the tumors, accounting for less than 10% to more
than 90% of the lining epithelial cells. Eosinophilic lining cells were present within one high power field of the invasive foci in 18 cases, within 2 mm in two cases, and in separate sections in one case. In each case, one of three histologic patterns predominated in the invasive foci. In 17 cases, the stroma of the tumor papillae was infiltrated predominantly by small, scattered foci of individual cells and small irregularly-shaped nests and papillary clusters of cells with dense eosinophilic cytoplasm and a round hyperchromatic nucleus with a single large nucleolus, resembling the eosinophilic cells of the lining epithelium (Figs 1 and 2). A clear zone or cleft was often present between the infiltrating cells and the stroma (Fig 2). No stromal reaction to the tumor cells was present except for a slightly increased number of mature stromal fibroblasts in the three cases with the largest aggregates. The number of foci ranged from one to eight in most cases and over 10 in four cases. The invasive foci were small and scattered and did not form measurable aggregates in 16 cases; in one case, they formed ill-defined aggregates that measured up to 2.5 mm in greatest dimension. Clusters of eosinophilic cells were present in spaces lined by flattened cells resembling lymphatics in four cases (Fig 2). In two cases, although individual eosinophilic cells and small nests of eosinophilic cells were present in the stroma, the histologic appearance was dominated by a second pattern, characterized by confluent nests of eosinophilic cells with a cribriform pattern (Figs 3 and 4). These foci measured 1 and 1.1 mm in diameter, respectively. In the final two cases a third pattern was encountered-a predominance of rounded aggregates of papillae lined by typical serous-type epithelial cells (Figs 5 and 6). These papillae were separated from the stroma by a clear zone or cleft (Fig 6). The aggregates measured 1.1 and 2.5 mm in greatest
FIGURE 1. Individual eosinophilic cells and small irregular nests of eosinophilic cells infiltrate the stroma between the glands of SBT. The non-invasive glands of the SBT are lined by typical columnar serous-type epithelial cells as well as polygonal or hobnail-shaped cells with abundant dense eosinophilic cytoplasm. [Hematoxylin-eosin stain, magnification x 313.)
398
SEROUS BORDERLINE TUMORS WITH MICROINVASION (Bell & Sadly]
FIGURE 2. A small, irregularly shaped nest of eosinophilic cells and an individual eosinophilIC cell are present in the stroma adjacent to several smoothly contoured non-invasive glands of an SBT. The infiltrative cells are surrounded by a cleft or clear zone devoid of lining cells. ,A nest of similar tumor cells is present in a lymphatic space lined by prominent endothelial cells. (Hematoxylin-eosin stain, magnification x 313.)
dimension. Blood vessel or lymphatic invasion or a stromal reaction to the tumor was not identified in these last four cases. The invasive foci in each of the 2 1 cases tiere present in the stroma of the tumor and did not invade the adjacent normal ovarian tissue. Follow-up
Data
Sixteen patients were alive without evidence of disease 1 to 1 1 (mean, 5.2) years postoperatively, including the woman with a documented hepatic metastatic tumor. She was alive and well 47 months after total abdominal hysterectomy, bilateral salpingooophorectomy, and omentectomy and combination chemotherapy. In one patient who had undergone a right salpingo-oophorectomy and left ovarian cystec-
FIGURE 3. Confluent nests of eosinophilic cells with a cribriform pattern are present in the stroma of a papilla of an otherwise typical SBT. (Hematoxylin-eosin stain, magnification x 50.1
tomy for an SBT with microinvasion of the right ovary and an SBT without invasion of the left ovary, a recurrent SBT with small foci of microinvasion developed in the left ovary 32 months postoperatively. She was well 6 months after a second left ovarian cystectomy. Two women were lost to follow-up, including the woman with a para-aortic lymph node metastasis. and two cases are too recent for a meaningful follow-up. Clinical Features of the Patients with Lymphatic Invasion The four women whose tumors contained lymphatic invasion were 19, 28. 30 and 36, years of age. Three of them were pregnant at the tune of opera-
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FIGURE 4. The cells lining the cribriform spaces are polygonal with round-to-oval nuclei and prominent nucleoli. [Higher power of Fig 3, Hematoxylin-eosin stain, magnification x 313.)
tion. Three of the tumors were confined to one ovary, and one woman had tumor in a para-aortic lymph node. All four women were treated with unilateral salpingo-oophorectomy. None received postoperative therapy. Two of them were alive and well at 11 and 42 months postoperatively, and two were lost to follow-up (including the patient with lymph node metastases). Assessment of Frequency Review of 36 consecutive unselected cases of SBTs from the files of the Massachusetts General Hospital revealed four (11%) with microinvasion. Three, seven and more than 10 foci of infiltrating eosinophilic cells were present in three of the tumors.
One tumor contained a 2.5 mm rounded posed of infiltrative papillae.
nodule
com-
DISCUSSION The most important feature that distinguishes SBTs from serous carcinomas is the presence of “destructive” stromal invasion in the latter.‘.’ In most serous carcinomas, the invasion is easily identified by the extensive presence of irregular, ill-defined nests of markedly atypical cells infiltrating a loose and edematous, myxoid, or desmoplastic stroma. In contrast, the epithelium lining the papillae of serous borderline tumors usually exhibits a sharp epithelialstromal junction, and when the epithelium dips into
FIGURE 5. A rounded aggregate of infiltrative popillae is present in the stroma of an SBT. (Hematoxylineosin stain, magnification x 79.)
SEROUS BORDERLINE rUMORS WITH MICROINVASION [Bell & Scully]
FIGURE 6. The infiltrative papillae are surrounded by a cleft or clear zone, (Hematoxylin-eosin stain, magnification x 125.)
the stronna, it does so as regularly distributed, smoothly contoured, sharply defined glands without a stromal reaction. A small number of tumors in the serous category fall between these two extremes, having the general appearance of a serous borderline tumor, but containing small foci of stromal invasion that do not elicit a discernible stromal reaction. We term these latter tumors SBTs with stromal microinvasion if the foci of invasion do not exceed 0.3 cm in greatest dimension. The lclassification and significance of small areas of stromal microinvasion in otherwise typical SBTs has been discussed only rarely in the literature.“,q Katzenstein and her coworkers” described several histologic patterns they interpreted as destructive stroma1 invasion which, they concluded, justified a diagnosis of well-differentiated serous cystadenocarcinoma. These patterns included infiltration of the stroma bv (1) glands with poorly-defined borders in an edematous stroma, (2) cell clusters and individual cells in a pale, loose stroma, (3) confluent backto-back glands and solid sheets of tumor cells, (4) small irregular tongues of cells extending from the base of glands accompanied by chronic inflammation and creating a pattern similar to that of microinvasive squamous carcinoma of the cervix, and (5) haphazardly distributed single cells and cell clusters often separated from the stroma by a clear zone or cleft. A sixth pattern of stromal involvement characterized by “unattached single epithelial cells scattered within the stromal stalks of the papillae, and at times even appearing to break off from glands” was not interpreted as indicating invasion.” Tavassoli, in her review of 18 patients with tumors of this type, 4 defined serous tumors of low malignant potential with microinvasion as tumors with all the clharacteristics of SBTs, except for the presence of foci of early invasion that did not evoke a These foci were composed of isostromal response.
lated cells and cell clusters with abundant eosinophilic or pink cytoplasm. Typical serous cells invaded the stroma in one tumor as a single papillary cluster. Since these foci were small and scattered, a maximum size dimension allowable in this category was not determined. In our study, we defined SBTs with stromal microinvasion as tumors with foci of invasion, each measuring less than 3 mm in greatest dimension, that were unassociated with a significant stromal reaction. Review of our cases revealed that one of three patterns of invasion predominated in each case. The most common pattern of scattered foci of infiltration of the stroma by eosinophilic cells, present in 17 of our cases, was similar to that seen in the cases described by Tavassoli.q Although isolated single eosinophilic cells were present in most of our cases of this !ype, nests of eosinophilic cells were present as well m all of our cases and in those described by Tavassoli.4 For this reason. these tumors would be classified as welldifferentiated serous cystadenocarcinomas according to the criteria of Katzenstein and her coworkers.g The clinical features of the tumors wit.11 this pattern of infiltration in our study and in that of Tavassoli4 were remarkably similar. The 18 women described by Tavassoli ranged from 22 to 80 years of age with a median age of 34.5 years; the median age of our 17 patients in this category was 38.5 years. Five women in Tavassoli’s study and six in ours had tumors that were discovered during pregnancy. Twelve of the 18 patients in Tavassoli’s series had stage I tumors, whereas 16 of 17 of the patients in the present series had tumor confined to one or both ovaries. One patient in each study had metastatic tumor in lymph nodes in the form of eosinophilic cells resembling those of the microinvasive foci seen in the ovarian tumor. All of the patients in this category in the present study for whom followup data were available were alive and well: one of 17 patients in Tavassoli’s 401
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course of action are emphasized by the patient in our study who underwent a right salpingo-oophorectomy and left ovarian cystectomy for a right-sided SBT with microinvasion and a left-sided SBT without invasion. She had a recurrent serous borderline tumor with microinvasion foci in her conserved left ovarian tissue 34 months postoperatively. Because of the indolent but real malignant potential of these tumors, the standard therapy in older women would be bilateral salpingo-oophorectomy and hysterectomy. The excellent survival rate of patients with microinvasive serous borderline tumors with surgical therapy alone also indicates that postoperative radiation or chemotherapy is unlikely to be of value. The major problem of clinical importance in the histologic diagnosis of SBTs with microinvasion is distinguishing them from serous carcinomas. The individual cells, nests and papillae of stromal microinvasion are often of the eosinophilic cell type, do not elicit a significant stromal response, and according to our definition, are less than 0.3 cm in greatest dimension. In contrast, serous carcinoma is typically characterized by irregular, ill-defined nests of markedly atypical cells with a solid or complex bridging pattern that usually elicit an edematous, myxoid, or desmoplastic stromal response. The eosinophilic cells in microinvasive foci may be mistaken for stromal decidual transformation, especially when a woman is pregnant. In general, stromal decidual cells may be identified by their smooth amphophilic cytoplasm, and delicate, vesicular, uniform nuclei. Finally, microinvasive foci may be difficult to detect in an SBT, especially at low power. In the examination of SBTs, special attention should be paid to the presence of epithelial elements within the connective tissue cores of the papillae. If they are not in the form of regularly distributed glands with or without intraglandular papillae, these elements should be carefully studied to exclude microinvasion. A helpful feature in this regard is identification of clear zones or clefts that are usually present between the infiltrating tumor cells and the stroma, and are not generally seen surrounding noninvasive branching glands of SBTs. Also, the infiltrative nests have irregular contours, unlike the smoothly contoured epithelial budding typically seen in SBTs. That these foci are not uncommon and are easily overlooked, even on careful examination, is documented by the discovery of four examples of stromal microinvasion on review of 36 consecutive serous borderline tumors at our hospital. The presence of eosinophilic cells lining the papillae and glands within a high-power field of the microinvasive foci in many of our cases, and the apparent direct connection of the overlying eosinophilic epithelium with cytologically similar invasive foci, suggest that this type of epithelium may have a higher propensity for invasion than the more typical serous lining cells usually seen in SBTs. A recently performed study from our institution (Cajigas H, LimTan SK, Scully RE. Unpublished observations, 1989) has shown an association of extensive eosinophilic cell change of the epithelium of ovarian SBTs with preg-
study died of tumor. These findings are also comparable to those of the seven cases with “noninvasive” stromal involvement by single eosinophilic cells (category 6) of Katzenstein and her coworkers.” The median age of those patients was 27.5 years; four of their tumors were stage I, two were stage II and one was stage III. All seven women were without evidence of disease from 4 to 21 years postoperatively. Although it is probable that some of the 13 patients classified as having well-differentiated serous cystadenocarcinomas by Katzenstein and coworkers had small foci of stromal invasion by nests of eosinophilic cells, comparison of the clinicopathologic features of their cases with ours is not possible because the pattern of invasion and the size of the invasive foci in those cases were not described in detail. The second and third patterns of microinvasion noted in this study, those of infiltration of the stroma dominated by aggregates of papillae or small confluent foci of tumor cells with a cribriform pattern, were seen in older women, aged 26, 67, 74 and 83 years. Three of these tumors were stage I and one was stage IV because of parenchymal liver involvement. All four women were without evidence of disease at 47, 60,97 and 130 months postoperatively. Both of these patterns would have been considered well-differentiated serous carcinomas by Katzenstein and coworkers.” Although 58% of the patients with serous carcinomas in Katzenstein and coworkers’3 study died of tumor, these figures are not comparable to our results because the well-differentiated serous carcinoma group in the Katzensteir? study was heterogenous, containing cases ranging from those with minimal microinvasion to overt serous carcinomas containing solid sheets of tumor or irregularly contoured nests of malignant cells that elicited a marked stromal reaction (categories 1, 2, and 3 as described previously). These types of stromal invasion were not discussed by Tavassoli.-’ Four of the 21 patients’ tumors showed lymphatic invasion, as assessed on hematoxylin and eosin-stained sections. Although the clinical significance of this finding is unclear due to the small number of cases, one of the four patients had metastatic tumor in a para-aortic lymph node, suggesting that lymphatic invasion in these tumors may be associated with spread beyond the ovary. Lymphatic invasion was not identified on immunoperoxidase stains for factor VIII in any of Tavassoli’s 18 cases.A The disease-free survival of all 16 of 17 patients with followup in the present study, 17 of 18 patients and in all 7 patients with in Tavassoli’s study,’ “noninvasive” stromal infiltration in the study of Katzenstein et al,” suggests that SBTs with stromal microinvasion are associated with an excellent prognosis, similar to that of SBTs without invasive foci. Furthermore, many of the women who were diseasefree were treated with limited surgical procedures, indicating that conservation of the contralateral ovary and uterus may be an acceptable procedure in young women with this type of tumor if preservation of reproductive potential is desired. The risks of this 402
SEROUS BORDERLINE TUMORS WITH MICROINVASION (Bell & Scully)
nancy, compatible with the large number of pregnant patients in this series and that of Tavassoli4 That 28% of the women with microinvasive SBTs in these series were pregnant, compared with 4% in the group of unselected women with SBTs without microinvasion from our hospital, raises the possibility that pregnant women are at greater risk of having stromal microinvasion in their SBTs than other women. Larger studies of SBTs in pregnant and nonpregnant patients are necessary to confirm this observation.
Cooley Dickinson Hospital, Northampton, MA; Sherry Parker, Tumor Registrar, Midland Memorial Hospital, and R. H. Hardy, MD, Midland, TX. The authors also thank Judith M. Shnider for excellent research and secretarial assistance.
REFERENCES 1. Serov SF, Scully RE, Sobin LH: Histological typing of ovarian tumours. in: International Histological Classification of Tumours, no. 9. Geneva, Switzerland, World Health Organization, 1973. pp. 37-38 2. Taylor HC: Malignant and semi-malignam (urnor? of the ovarv. Surg Gynec-ol Obstet 48:204-230. 1929 3. Katzenstein A-L A. Mazur MT. Morgan TE, et al: Proliferative serous tumors of the ovary. Histologic features and prognosis. Am J Surg Path01 2:339-355, 1978 4. Tavassoli FA: Serous tumor of low malignant potential with early stromal invasion (serous LMP with microinvasion). Mod Pathol 1:407-414. 1988 5. Russell P: The pathological assessment of ovarian neoolasm. III. The mahenant ‘eoithehal’ tumours. Patholocrv 11:493u j32. 1979 6. Oncology Committee of the Internal Federation of Gynecology and Obstetrics: Changes in definitions of clinical staging for carcinoma of the cervix and ovary: International Federation of Gynecologv and Obstetrics. Am J Obstet Gcnecol 156:263-264, 1987 7. Scully RE: Tumors of the ovxy and maldeveloped gonads, in: Atlas of Tumor Pathology, 2nd Serves. Fascicle 16.Washington, DC. Armed Forces Institute of Patholog). 1979, pp I 17.127
Acknou~l~~&~c~~: The authors thank the following individuals for generously contributing cases, clinical data and followup information: N. Nikrui, MD. C. Granai, MD. A. Fuller, MD, M. Etkin, MD, J. Dineen, MD, and H. Safaii, MD, Boston. MA; Y. S. Fu, MD, Los Angeles, CA; Nancy Reas. Tumor Registrar, University of California, Los Angeles Medical Center. Los Angeles, CA; J. T. Wharton, MD, Houston, TX; Tumor Registrar, Columbia Hospital, Milwaukee, WI; S. Carinelli, MD, Milan, Italy; B. Pritzker, MD, Vallejo, CA; E. Davis, MD, and C. R. Minick, MD, New York, NY: M. de Sousa Paino, MD, Araraguara, Brazil; B. Westphall, MD, Anderson, CA; Northern Laboratories. Redding, C4; 1). R. Duffell, MD, and the Tumor Registrar, Northwest Community Hospital, Arlington Heights, IL; A. Fabbri, MD, Wakefield, MA: V. Lynch, MD, Hamden, CT; M. Carcangiu. MD, New Haven, CT; I. F. Hitti. MD, Forest Hills, NY: G. R. Marrocco, MD, and the Tumor Registrar,
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