OVARIAN EPITHELIAL TUMORS OF B O R D E R L I N E M A L I G N A N C Y (CARCINOMAS OF LOW MALIGNANT POTENTIAL) William R. Hart, M.D.*
Abstract Ovarian epithelial neoplasms that have morphologic features intermediate between those of clearly benign and unquestionably malignant lesions are currently classified as tumors of borderline malignancy (carcinomas of low malignant potential). Patients with stage I lesions of this type have an excellent prognosis following conservative surgery. Survival rates are remarkably good even when extraovarian spread has developed. The clinicopathologic features and histologic criteria for the diagnosis of borderline tumors of serous and mucinous cell types are detailed in this presentation.
T r a d i t i o n a l l y epithelial n e o p l a s m s have been sharply divided into either benign or malignant types, although .the precise diagnostic criteria have vm'ied considerably among pathologists. It is well recognized, however, that about 10 to 20 per cent of primary ovarian epithelial tumors are intermediate in their histologic appearance between the innocuous cystadenoma and the highly aggressive cystadenocarcinoma. ~ The wide variations in reported survival statistics for patients with ovarian carcinoma reflect to a considerable extent the inclusion of such tumors as carcinomas in some series and their exclusion in others. Indeed, atte,npts to categorize rigidly all ovarian neoplasms as either benign or malignant frequently prove frustrating to the pathologist and misleading to the surgeon. Several investigators have directed attention to the
intermediate grade tumors by classifying them as borderline, potentially malignant, semimalignant, or questionably malignant. Others prefer to continue diagnosing thena as carcinomas because of their ability to spread beyond the confines of the ovary, but apply such qualifying designations as "grade 0," "grade 1," "low grade," or "well differentiated." l, _o In 1961 the International Federation of Gynecology and Obstetrics (FIGO) developed a classification wherein all common epithelial tumors of the ovary were subdivided into three groups: benign cystadenomas, cystadenomas with proliferating activity of the epithelial cells and imclear abnormalities but with no infiltrative destructive growth (low potential malignancy), and cystadenocarcinomas. 3 The World Heahh Organization (WHO) also recognized the intermediate grade
--*Associatel'rofessor of l'athology, Universityof Michigau MedicalSchool, Ann Arbor, Michigan.
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tunmrs, and in its recently publislmd classification referred to them synonymously as tulnors of borderline malignancy or carcinomas of low malignant potential. 4 The authors of the WHO classification defined a borderline tumor as "one that has some, but not all of the morphological features of malignancy; those present include in varying combinations: stratification of epithelial cells, apparent detachment of celhllar clusters from their sites of origin, and mitotic activity and nuclear abnormalities intermediate between tlmse of clearly benign and unquestionably malignant tumors of a similar cell type; on the other band, obvious invasion of the adjacent stroma is lacking." They also indicated that the histologic diagnosis must be based exclusively on an examination of the ovarian tumor without consideration of whether spread beyond the ovary has taken place. In view of the official support of these international organizations, it is likely that the borderline tumor will become entrenched in pathology nonaenclature. Unless the borderline tumor is specifically delineated, meaningfifl assessments of prognosis" and efficacy of therapeutic modalities for ovarian "carcinomas" are severely hampered. The value of histopathologic distinction between borderline tnmors and overt carcinomas has been supported by several long term follow-up studies2 "a'~-' These have documented the excellent prognosis of borderline tumors clinically confined to one or both ovaries (stage I) and the indolent behavior of those with extraovarian extension. Of particular importance is the observation that tumors of borderline malignancy tend to occur at an earlier age than do tim usual ovarian carcinomas of corresponding cell types?'r A significantly large proportion are discovered in women between tlm ages of 20 and 40 years3' 5-7 Because of their highly favorable prognosis, modit]cations in therapy are possible for selected young women with borderline tumors. ''~- Several patients have become pregnant and delivered normal infants following conservative surgical management. -~ Both the FIGO and WHO schemes emphasize that invasion of the ovarian stroma Inust be absent before a tumor can
qualify for tile designation of borderline malignancy?'4 Yet assessment of stromal invasion at times is difficult and evaluation of the degree of nuclear abnormalities requires an even more subjective imerpretation by the observer. We believe that tumors with clear-cut malignant nuclear features should be regarded as carcinoma, irrespective of whether stromal invasion is identified. Generally tumors exhibiting unequivocal stromal invasion also show malignant cytologic features but the reverse need not occur. Consequently a "gray zone" in the interpretation, of atypical proliferative-epitimlial ovarian neoplasms is likely to persist even for those who embrace the concept of tumors of borderline malignancy. Ovarian tumors are notorious for the wide variations in the degree of histologic differentiation that can be found in different areas of the same neoplasnt. Since malignant potential is determined by the least differentiated portion, extensive sampling by nmltiple sections is essential for accurate diagnosis. Special attention should be given to markedly papillary areas, nodular thickenings and rouglmned portions of a cyst wall, solid areas, and regions where llemorrhage or necrosis is conspicuous.' As a general guideline, we have advocated taking a block of tissue for each I to 2 cm. of tim tumor's maximal dimension.-" Carehfl documentation o f the overall configuration of the tumor and its relationship to the cortical surface of the ovary sltould be made. This effort is especially valuable in deterlnining therapy, since entirely intracystic, encapsulated lesions are less likely to produce peritoneal ilnplants than are those that involve tim cortical surface. Whenever possible, ovarian epithelial tumors should be classified initially according to their predominant cell type into serous, mucinous, endontetrioid, mesonephroid (clear cell), or Brenner (transitional cell) groups." s, 4 Each group then can be fln'ther subdivided into benign, borderline, or malign.ant categories. To date, borderline tumors have been well studied only in the serous and mucinous groups. A borderline or proliferative form of Brenner tumor has been defined recently, but such lesions are exceptionally nncommon and will not be fllrther dis-
OVARIAN EI'ITHELIAI~ TUMORS OF BORDERLINE MALIGNANCY--HART cussed here. 4 In this presentation tim clinical and pathologic aspects and the histologic diagnostic criteria for serous and mucmous tumors of borderline malignancy are discussed and illustrated. It is acknowledged that some of the espoused criteria reflect a personal bias and universal acceptance of them is not anticipated. Nonetheless they have proved to be usefifl to the attthor and to others.
BORDERLINE
SEROUS TUMORS
Tumors of tim serous cell type are composed of epithelium resembling that of the fallopian tube or the surface epitlmlium of the ovary. They give rise to the most common forms of borderline neoplasm. Borderline serous tumors are characteristically papillary and usually are cystic (Fig. 1). Grossly they may not be distinguislmble from occasional papillary serous cystadenocarcinomas or markedly papillary cystadenomas. Papillary excrescences often invoh'e the cortical surface
Figure 1. Gross appearance of opened serous papillary cystadenoma of borderline malignancy. Mt,ltiple small papillary excrescences i)rotrude into the lumen and a few are on the external surface.
as a resuh of direct neoplastic transformation of the surface epithelinm. Julian and WoodrutT~ found excrescences on the external surface of the involved ovaries in eight (24 per cent) of 34 stage I lesions. Surface growth of this type does not represent invasive extension from the cystic component. Occasionally the entire tumor consists of an exophytic papillary surface lesion unassociated with internal cysts. The least frequent variant is an adenofibromatous or cystadenofibromatous borderline tunlor.
Histologically, borderline serous tumors are noninvasive neoplasms characterized by multiple extensively branching papillae with fibrous cores (Fig. 2A). Invaginations of the epithelium are frequent and should not be misinterpreted as stromal invasion. Separate small epithelial cysts may be scattered througimut t h e ovary. The epithelium covering the papillae may be stratified into several layers. Exfoliation of cellular clusters from the papillae is characteristic (Fig. 2B). Detached buds of these cells become suspended in the cyst fluid. Tnmors with an exophytic surface component may shed such cellular clusters into the pelvic cavity, where some implant on tim parietal peritoneuul, oulentum, or serosal s u r f a c e s o f adjacent reprodnctive and intestinal organs. The proliferating epithelial cells have slightly to moderately atypical nuclei, which are enlarged, irregular, and hyperchromatic. Nucleoli, if present, are usually small or inconspicuous. Mitotic figures are relatively few. From a cytologic aspect the cells do not show unmistakable changes of carcinoma. Many of them display cilia, and some assume a rounded shape with abnndant cytoplasm and have been referred to as "mesotlmlial" cells (Fig. 2C). 6 Psammorea bodies sometimes are numerous; they were found in 23 per cent of the 74 borderline serous tumors reported by Aure et al. 8 Bilateral ovarian involveinent has been reported in about 14 to 33 per cent of tim cases of serous cystadenoma of borderline malignancy6"~ and is believed to represent separate independent primary tumor development in most instances. Of greatest concern is the high incidence of extraovarian spread of borderline serous neoplasms. Extension beyond the ovaries
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Figure 2. Forty-nine )'ear old woman with bilateral serous papillary cystadcnomas of borderline malignancy. Excrescences of neoplasm were on external surfaces. Ascitic fluid positive for adenocarcinonm. Extensive implants on pelvic peritoneum and serosa of colon at operation. Postoperative radiation therap)' admi,fistered after palliative bilateral salpingo-oop!lorectom)-. No residual tumor observed at time ot-hysterectomy 10 )'ears later. Patient alive and well without recurrence 13V= )'ears after initial operation. zl, Numerous i~al)illae with complex branching pattern, no invasion of stroma. B, l'apillae covered by proliferating epithelium with multila)'ering of cells and exfoliation of cellular clusters. C, Small papilla covered by atypical columnar cells. Notice detached "lnesothelium"-like cell (arrow) and area of muhilayering of cells. (Ilematoxylin and eosin stain. A, reduced from x 100. B, reduced from x260. C, reduced from x405.)
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has b e e n f o u n d at t h e t i m e o f initial s u r g e r y in 20 to 46 p e r c e n t o f t h e p a t i e n t s in some series?'6 Such spread typically app e a r s as m u l t i p l e s u p e r f i c i a l i m p l a n t a t i o n "metastases" on the peritoneum and serosal surfaces of pelvic organs. These a r e e s p e c i a l l y p r o n e to d e v e l o p w h e n inv o l v e m e n t o f t h e e x t e r n a l Ovarian s u r f a c e
is p r o m i n e n t - A s c i t e s o f t e n r e s u l t s , a n d cytologic examination of peritoneal fluid may reveal papillary clusters of neoplastic cells. P s a m m o m a b o d i e s a r e o f t e n a b u n d a n t in t h e i m p l a n t s . F i b r o u s a d h e s i o n s resulting from peritoneal studding produce repeated bouts of intestinal obstrttction ill s o m e p a t i e n t s . O c c a s i o n a l l y l ) ' m p h
OVARIAN EPITHELIAL TUMORS OF BORDERLINE MALIGNANCY-- HART node metastases developfl" 'j but hematogenous nletastasis is rare, as is extension outside the abdominopelvic cavity. In spite of the great frequency of spread beyond the ovaries, the prognosis is highly favorable, even for patients with disseminated peritoneal implants. Regardless of the extent of the tumor and its clinical stage, corrected five )'ear survival rates of 92 to I00 per cent have been reported in patients with borderline serous tumors, 5-~ and 10 year rates have ranged from about 75 to over 90 per cent?'5'7 Although the patients in most series had received postoperative radiation therapy, adjunctive treatment with chemotherapeutic agents or irradiation was employed rarely in the group of 64 patients reported by Julian and Woodruff. 6 Recurrent lesions within the pelvis or abdomen may develop after long latent intervals of up to 20 or even 50 )'ears. ~ 10 I n such cases the recurrences have shown the same histologic appearance as the primary ovarian tmnors. It is apparent that the cells of borderline serous tumors have a fixed and static degree of differentiation. They maintain their histologic characteristics and slow growth and do not undergo progressive anaplasia or dedifferentiation with the passage of time. Some peritoneal implants presumably fail to proliferate, and rare instances o f s p o n t a n e o u s r e g r e s s i o n have been cited.n" ~z Some examples of peritoneal implants actually may represent muhiple foci of de novo neoplastic transformation of peritoneal mesothelium rather than metastases? s In fact, increasing numbers of cases now are being recognized in which widespread primary papillary neoplasms of pelvic peritoneum simulate metastatic ovarian tunlors. Aure et al., z however, warned that up to 25 per cent of the patients eventually may die from recurrent tnmor if the cases are followed for sufficiently long periods of time. Entirely intracystic tumors probably can be expected to be cured by conservative surgery. Julian and Woodruff6 recorded no deaths due to neoplasm during a five year observation period in patients with nnilateral stage I tumors; 15 patients had been treated by unilateral salpingo-oophorectomy and 10 patients by hysterectomy and bilateral adnexectomy.
BORDERLINE
MUCINOUS
TUMORS
Mucin0us ttunors of borderline malignancy are somewhat less common than the serous varieties. Of the 20 per cent of mncinous neoplasms that are not clearl)" benign, about 40 per cent belong in the borderline category and the remainder are unequivocal carcinomas? It is likely that the good prognosis attributed to mucinous carcinomas in some reported series retlects inclusion of a high proportion of tumors of borderline malignancy. In borderline as well as benign mncinous tumors, the epithelial element contains cells resembling those of endocervical or gastrointestinal tract mucosa. Practically all are cystic and three-fourths are muhiloculated c)'sts. 2 Grossly they cannot be reliably distinguished fi'om benign cystadenomas or cystadenocarcinomas. An increase in thickness of the cyst walls or intrac)'stic papillations are sometimes observed. Growth on the external ovarian surface is rarely seen, in contrast to its fi'equency in cases of borderline serous neoplasms. Most examples are large; in a series of 97 cases the median diameter was 17 c m . -~
Extensive sampling is especially critical with mucinous lesions, since the most atypical degree of epithelial proliferation may be localized to a small portion of the tumor. Microscopically, mncinous c)'stadenomas of borderline malignancy have a variety of complicated glandular patterns (Fig. 3). Their overall appearance is frequently reminiscent of hyperplastic and adenomatous polyps of the colon or of proliferating types of appendiceal mucocele. Assessment of stromal invasion is more difficult in mucinous than in serous tumors, since the former have multiple cysts and are often parvilocular. Small secondar)' cysts and outpouchings from larger glands may appear to be isolated within ovarian stroma and be misinterpreted as evidence of invasion (Fig. 4). Broad fibrous papillary processes are uncommon in mucinons cystadenomas of borderline malignancy, but short delicate papillae are frequently found. The cells lining the cysts and covering the papillations are stratified into two to three layers and display a loss of normal polarity (Figs. 5, 6).
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Figure 3. Mucinous cystadenoma of borderline malignancy consists of cysts lined by nun-terous delicate short papillary infoldings. The patient was alive and well without recurrence 3.9 )'ears after hysterectomy and bilateral sallfingo-oophorcctomy. (Hematoxylin and cosin stain. Reduced from xl40.)
E x f o l i a t e d c l u s t e r s o f cells m a y b e m i x e d with m u c i n o n s d e b r i s , T h e cells l m v e e n l a r g e d n u c l e i w i t h m i l d to m o d e r a t e degrees of atypism. The amount of intrac e l h f l a r m u c i n m a y b e r e d u c e d in t h e a t y p i c a l cells. M i t o t i c f i g u r e s a r e o f t e n m o r e p l e n t i f i f l t h a n in b o r d e r l i n e s e r o u s tumors. A d i a g n o s i s o f m u c i n o u s c a r c i n o m a is
warranted, of c o u r s e , w l l e n e v e r s t r o m a l i n v a s i o n is p r e s e n t . U n e q i v o c a l i n v a s i o n can be diagnosed confidently when irregul a r nests o r s o l i d c o r d s o f cells a r e h a p b a z a r d l ) ' s c a t t e r e d in t h e o v a r i a n s t r o m a (Fig. 7). T h e s e p a t t e r n s a r e u n l i k e t h e orderly arrangement of small branching g l a n d s t h a t h a v e s m o o t h c o n t o u r s a n d well f o r m e d l u m e n s . I n v a s i o n also m a y t a k e
Figure 4. Mucinous c)stadenoma of borderline malignancy. Several small glands with smooth contours and all orderly arrangement appear isolated in tile ovarian stroma as a result of secondary gland formation. The patient was alive and well without recurrence 3.3 )ears after hysterectomy and bilateral sallfingo-oophorectomy. (Iiematoxylin and eosin stain. Reduced from xl00. Reprinted by permission fiom Hart, W. R., and Norris, tt.J.: Borderline and maligtmm mucinous tumors of the ovary. Histologic criteria and clinical behavior. Cancer, 31:1031, 1973.)
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Figure 5. Higher magnification of tumor illustratcd in Figure 4 shows mucinous cells with atypical hypcrchromatic nuclei and disturbed polarity lining a c)st, (ttematoxylin and eosin stain. Reduced from • Reprinted by permission from Hart, W. R., and Norris, H.J.: Borderline and malignant mucinous tumors of the ovary, tlistologic criteria and clinical behavior. Cancer, 31:1031, 1973.)
Figure 6. Mucinous cystadenoma of borderline malignatlcy illustrated in Figure 3. Short intraluminal finger-like projections covered by mucinous cells with enlarged atypical nuclei rest on delicate connective tissue SUpl~orts. (ttematoxylin and eosin slain. Reduced from • Reprinted by permission from Hart, W. R., and Norris, H.J.: Borderline and malignant mucinous tumors oftheovary. Histologiccriteria and clinical behavior. Cancer, 31 : 1031, 1973.)
the f o r m o f large sheets o f glands with a back to back a r r a n g e m e n t a n d no intervening stroma, ht the absence o f tmeqtfivocal infiltrative growth, a m u c i n o u s t u m o r sltould also be r e g a r d e d as carcin o m a w h e n t h e r e is a m a r k e d o v e r g r o w t h o f atypical epithelial cells or w h e n severely anaplastic nuclear features are observed. C r i b r i f o r m i n t r a g l a n d u l a r proliferations and finger-like projections o f solid cellular masses without connective tissue s u p p o r t s are indicative o f carcinoma. As a general rule, we have i n t e r p r e t e d as c a r c i n o m a those t u m o r s in which stratification o f atypical epithelial cells lms exceeded' t h r e e layers in thickness (Fig. 8). 2 Such t u m o r s often also show severe nuclear anaplasia or are a c c o m p a n i e d by stromal invasion. Only a b o u t 10 p e r cent o r less o f borderline m n c i n o u s c y s t a d e n o m a s are bilateral. 2 In o u r e x p e r i e n c e they are usuall)" not a c c o m p a n i e d by evidence o f extraovariau s p r e a d at the time o f the
initial o p e r a t i o n . H o w e v e r , in the series r e p o r t e d b)" A u r e et al. 5 a b o u t 15 p e r cent h a d e x t e n d e d b e y o n d the ovaries b)" tile time tile diagnosis was established. Diffuse peritoneal seeding, as occurs with b o r d e r line serous t u m o r s , is distinctly rare. S o m e o f the b o r d e r l i n e m u c i n o u s t u m o r s , however, have been associated with pseudom y x o n t a peritonei, an enigmatic condition often attributed to p r i o r r u p t u r e o f m u cinous t u m o r s a n d spillage o f their contents. Yet peritoneal p s e u d o m y x o m a is not a f i e q u e n t complication o f r u p t u r e d ovarian tumors. N o n e o f the 11 patients r e p o r t e d b)' H a r t a n d Norris 2 with t u m o r s o f b o r d e r l i n e m a l i g n a n c y tlmt lind r u p t u r e d d u r i n g or p r i o r to o p e r a t i o n subsequently had p s e u d o m y x o m a a f t e r followu p intervals o f t h r e e to 19 }'ears, n o r did any o f the five patients witlt stage I m u cinons carcinomas that lind r u p t u r e d in tile s a m e series. Since p s e u d o m y x o m a peritonei is f r e q u e n t l y a c c o m p a n i e d by a
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Figure 7. lnvasive mucinous cystadenocarcinoma. Irregular nest and cords of anaplastic cells haphazardly infiltrate the ovarian stroma adjacent to small cysts. This destructive growth pattern is unlike the orderly arrangement of small, well formed glands found in borderliqe mucinous tumors. (Hematoxylin and eosin stain. Reduced from x200.)
mucocele of the appendix or a carcinoma o f t h e c o l o n , it is e x t r e m e l y difficult to determine the cause of the pseudomyxoma in m a n ) ' i n s t a n c e s . 2 Mucinous cystadenomas of borderline m a l i g n a n c y Imve a m o r e f a v o r a b l e p r o g nosis t i t a n d o s e r o u s t u m o r s o f s i m i l a r type, probably because surface involvernent and widespread peritoneal implanta-
t i o n a r e so i n f r e q u e n t . I n a l o n g t e r m followup study of stage I tumors, Hart and Norris z reported corrected actuarial s u r v i v a l r a t e s o f 98 p e r c e n t at five y e a r s a n d 96 p e r c e n t at 10 y e a r s . O v e r h a l f t h e p a t i e n t s lind b e e n t r e a t e d solely b y t m i lateral salpingo-oophorectomy. In contrast, m u c i n o u s c a r c i n o m a s o f a s i m i l a r clinical s t a g e w e r e a s s o c i a t e d with s u r v i v a l s
Figure 8. Stage I mutinous c)stadenocarcinoma without unequivocal stromal invasion. The epitheliunl exceeds three cell layers ill thickness and intraglandular cellular bridges are not supported b)" connective tissue cores. The patient died of metastatic carcinoma i.6 )'ears after hysterectomy and bilateral salpingo-ool~horectomy. (Hematoxylin and cosin stain. Reduced from •
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O V A R I A N E P I T H E L I A L T U M O R S O F B O R D E R L I N E MALIGNANCY--HAR-r o f o n l y 66 p e r c e n t at five )'ears a n d 59 p e r c e n t at 10 )'ears in t h e s a m e series, z I r r e s p e c t i v e o f t h e clinical s t a g e , A u r e et al. 5 f o u n d a 20 ) ' e a r s u r v i v a l r a t e o f a b o u t 85 p e r cent; e x c e p t f o r a s m a l l n u m b e r o f y o u n g p a t i e n t s , all h a d r e c e i v e d s o m e form of postoperative radiation therapy.
2.
3.
SUMMARY I n c u r r e n t classifications p r i m a r y e p i thelial o v a r i a n t u m o r s a r e d i v i d e d a c c o r d i n g to lfistologic c r i t e r i a i n t o t h r e e g r o u p s : benign, borderline, and malignant. The t u m o r s o f b o r d e r l i n e m a l i g n a n c y (carcin o m a s o f low m a l i g n a n t p o t e n t i a l ) h a v e a c o n s i d e r a b l y m o r e f a v o r a b l e clinical b e h a v i o r t h a n d o t h e h i g h e r g r a d e s o f carcin o m a . Sufficient e x p e r i e n c e with b o r d e r l i n e t u m o r s o f t h e s e r o u s a n d mt~cinous cell t y p e s h a s a c c r u e d to p r o v i d e r e a s o n able histopathologic criteria for accurate diagnosis. Extensive sampling and microscopic examination of the primary ovarian n e o p l a s m is essential. T h e p r e s e n c e o r absence of involvement of the external surface of the ovary should be documented, because knowledge of the overall c o n f i g u r a t i o n o f t h e t u m o r is e x t r e m e l ) ' v a h m b l e in d e t e r m i n i n g t h e r a p y . S p r e a d b e y o n d t h e o v a r i e s , w h i c h o c c u r s o f t e n in t h e s e r o u s cell g r o u p , is o f i m p o r t a n c e in t r e a t m e n t b u t d o e s n o t a l t e r t h e lfistologic diagnosis of borderline malignancy. Although there are some semantic, philos o p h i e , a n d c o n c e p t u a l p r o b l e m s with usage of the designation "borderline malignancy," adoption of the terminology p r o p o s e d in W H O c l a s s i f i c a t i o n s e e m s worthwhile, especially for purposes of r e p o r t i n g t h e r a p e u t i c results.
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8. 9.
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REFERENCES 13. 1. Morrow, C. P., and Hart, W. R.: The ovaries. In Romney, S., et al. (Editors): Gynecology and
Obstetrics: The Health Care of Women. New York, McGraw-tlill Book Company, 1975, Ch. 49, p. 1056. Hart, W. R., and Norris, H. J." Borderline and malignant muciuous tumors of the ovary. Histologic criteria and clinical behavior. Cancer, 31 : 1031, 1973. Santesson, L., and Kottmeier, H. l..: General classification of ovarian tumot, rs. In Gentil, F., and Junquerira, A. C. (Editors): Ovarian Cancer. U.I.C.C. Monograph Series. New York, Springer-Verlag, 1968, Vol. 11, p. 1. Serov, S. F., Scully, R. E., and Sobin, L. H.: International Histological Classification of Tumours. No. 9. Histological Typing of Ovarian Turnouts. Geneva, World Heahh Organization, 1973. Aure, J. C., HCeg, K., and Kolstad, 1'.: Clinical and histologic studies of ovarian carcinoma. Long-term folk)w-up of 990 cases. Obstet. Gynecol.,37:l, 1971. Julian, C. G., and Woodruff, J. D.: The biologic belmvior of low-grade papillary serous carcinoma of the ovary. Obstet. Gynecol., 40:860, 1972. l'urola. E.: Serous papillary ovarian tu,nours. A study of 233 cases with special reference to the histological type of tumour and its influehce on prognosis. Acta Obstet. Gynecol. Scand., 42:7, 1963. Aure, J. C., tt0eg, K., and Kolstad, P.: l'sammorea bodies in serous carcinoma of the ovary. Am. J. Obstet. Gynecol., 109:i 13, 1971. Malloy, J. J., Dockerty, M. B., Welch, J. S., and Hunt, tt. B.: Papillary ovarian tumors. I. Benign tumors and serous and mucinous cystadenocarcinomas. Am. J. Obstet. Gynecol., 93:867, 1965. Woodruff, J. D., and Jtdian, C. G.: tlistologic grading and morphologic changes of sig,fificance in the treatment of semi-malignaut and malignant ovarian tumors. In Proceedings of the Sixth National Cancer Conference. Philadelt~hia, J. B. I.ippincott Co., 1968. p. 347. Gaudrauh, G. L.: Papillary carcinoma of the ovary. Report of a case with prolonged dormancy and spontaneous regression of metastases. New Eng. J. Med., 264:398, 1961. Ta)'lor, H. C., Jr., and Alsop, W. E.: Spontaneous regression of peritoneal implantations fi'om ovarian papillary cystadenonm. Am. J. Cancer, 16:1305, 1932. Burmeister, R. E., Fechner, R. E., and Franklin, R. R.: Endosalpingiosis of the peritoneum. Obstet. Gynecol.,34:310, 1969.
Department of l'athology University of Michigan Medical School 1335 East Catherine Street Ann Arbor, Michigan 48109
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Abstract Ovarian epithelial neoplasms that have morphologic features intermediate between those of clearly benign and unquestionably malignant lesions are currently classified as tumors of borderline malignancy (carcinomas of low malignant potential). Patients with stage I lesions of this type have an excellent prognosis following conservative surgery. Survival rates are remarkably good even when extraovarian spread has developed. The clinicopathologic features and histologic criteria for the diagnosis of borderline tumors of serous and mucinous cell types are detailed in this presentation.
T r a d i t i o n a l l y epithelial n e o p l a s m s have been sharply divided into either benign or malignant types, although .the precise diagnostic criteria have vm'ied considerably among pathologists. It is well recognized, however, that about 10 to 20 per cent of primary ovarian epithelial tumors are intermediate in their histologic appearance between the innocuous cystadenoma and the highly aggressive cystadenocarcinoma. ~ The wide variations in reported survival statistics for patients with ovarian carcinoma reflect to a considerable extent the inclusion of such tumors as carcinomas in some series and their exclusion in others. Indeed, atte,npts to categorize rigidly all ovarian neoplasms as either benign or malignant frequently prove frustrating to the pathologist and misleading to the surgeon. Several investigators have directed attention to the
intermediate grade tumors by classifying them as borderline, potentially malignant, semimalignant, or questionably malignant. Others prefer to continue diagnosing thena as carcinomas because of their ability to spread beyond the confines of the ovary, but apply such qualifying designations as "grade 0," "grade 1," "low grade," or "well differentiated." l, _o In 1961 the International Federation of Gynecology and Obstetrics (FIGO) developed a classification wherein all common epithelial tumors of the ovary were subdivided into three groups: benign cystadenomas, cystadenomas with proliferating activity of the epithelial cells and imclear abnormalities but with no infiltrative destructive growth (low potential malignancy), and cystadenocarcinomas. 3 The World Heahh Organization (WHO) also recognized the intermediate grade
--*Associatel'rofessor of l'athology, Universityof Michigau MedicalSchool, Ann Arbor, Michigan.
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tunmrs, and in its recently publislmd classification referred to them synonymously as tulnors of borderline malignancy or carcinomas of low malignant potential. 4 The authors of the WHO classification defined a borderline tumor as "one that has some, but not all of the morphological features of malignancy; those present include in varying combinations: stratification of epithelial cells, apparent detachment of celhllar clusters from their sites of origin, and mitotic activity and nuclear abnormalities intermediate between tlmse of clearly benign and unquestionably malignant tumors of a similar cell type; on the other band, obvious invasion of the adjacent stroma is lacking." They also indicated that the histologic diagnosis must be based exclusively on an examination of the ovarian tumor without consideration of whether spread beyond the ovary has taken place. In view of the official support of these international organizations, it is likely that the borderline tumor will become entrenched in pathology nonaenclature. Unless the borderline tumor is specifically delineated, meaningfifl assessments of prognosis" and efficacy of therapeutic modalities for ovarian "carcinomas" are severely hampered. The value of histopathologic distinction between borderline tnmors and overt carcinomas has been supported by several long term follow-up studies2 "a'~-' These have documented the excellent prognosis of borderline tumors clinically confined to one or both ovaries (stage I) and the indolent behavior of those with extraovarian extension. Of particular importance is the observation that tumors of borderline malignancy tend to occur at an earlier age than do tim usual ovarian carcinomas of corresponding cell types?'r A significantly large proportion are discovered in women between tlm ages of 20 and 40 years3' 5-7 Because of their highly favorable prognosis, modit]cations in therapy are possible for selected young women with borderline tumors. ''~- Several patients have become pregnant and delivered normal infants following conservative surgical management. -~ Both the FIGO and WHO schemes emphasize that invasion of the ovarian stroma Inust be absent before a tumor can
qualify for tile designation of borderline malignancy?'4 Yet assessment of stromal invasion at times is difficult and evaluation of the degree of nuclear abnormalities requires an even more subjective imerpretation by the observer. We believe that tumors with clear-cut malignant nuclear features should be regarded as carcinoma, irrespective of whether stromal invasion is identified. Generally tumors exhibiting unequivocal stromal invasion also show malignant cytologic features but the reverse need not occur. Consequently a "gray zone" in the interpretation, of atypical proliferative-epitimlial ovarian neoplasms is likely to persist even for those who embrace the concept of tumors of borderline malignancy. Ovarian tumors are notorious for the wide variations in the degree of histologic differentiation that can be found in different areas of the same neoplasnt. Since malignant potential is determined by the least differentiated portion, extensive sampling by nmltiple sections is essential for accurate diagnosis. Special attention should be given to markedly papillary areas, nodular thickenings and rouglmned portions of a cyst wall, solid areas, and regions where llemorrhage or necrosis is conspicuous.' As a general guideline, we have advocated taking a block of tissue for each I to 2 cm. of tim tumor's maximal dimension.-" Carehfl documentation o f the overall configuration of the tumor and its relationship to the cortical surface of the ovary sltould be made. This effort is especially valuable in deterlnining therapy, since entirely intracystic, encapsulated lesions are less likely to produce peritoneal ilnplants than are those that involve tim cortical surface. Whenever possible, ovarian epithelial tumors should be classified initially according to their predominant cell type into serous, mucinous, endontetrioid, mesonephroid (clear cell), or Brenner (transitional cell) groups." s, 4 Each group then can be fln'ther subdivided into benign, borderline, or malign.ant categories. To date, borderline tumors have been well studied only in the serous and mucinous groups. A borderline or proliferative form of Brenner tumor has been defined recently, but such lesions are exceptionally nncommon and will not be fllrther dis-
OVARIAN EI'ITHELIAI~ TUMORS OF BORDERLINE MALIGNANCY--HART cussed here. 4 In this presentation tim clinical and pathologic aspects and the histologic diagnostic criteria for serous and mucmous tumors of borderline malignancy are discussed and illustrated. It is acknowledged that some of the espoused criteria reflect a personal bias and universal acceptance of them is not anticipated. Nonetheless they have proved to be usefifl to the attthor and to others.
BORDERLINE
SEROUS TUMORS
Tumors of tim serous cell type are composed of epithelium resembling that of the fallopian tube or the surface epitlmlium of the ovary. They give rise to the most common forms of borderline neoplasm. Borderline serous tumors are characteristically papillary and usually are cystic (Fig. 1). Grossly they may not be distinguislmble from occasional papillary serous cystadenocarcinomas or markedly papillary cystadenomas. Papillary excrescences often invoh'e the cortical surface
Figure 1. Gross appearance of opened serous papillary cystadenoma of borderline malignancy. Mt,ltiple small papillary excrescences i)rotrude into the lumen and a few are on the external surface.
as a resuh of direct neoplastic transformation of the surface epithelinm. Julian and WoodrutT~ found excrescences on the external surface of the involved ovaries in eight (24 per cent) of 34 stage I lesions. Surface growth of this type does not represent invasive extension from the cystic component. Occasionally the entire tumor consists of an exophytic papillary surface lesion unassociated with internal cysts. The least frequent variant is an adenofibromatous or cystadenofibromatous borderline tunlor.
Histologically, borderline serous tumors are noninvasive neoplasms characterized by multiple extensively branching papillae with fibrous cores (Fig. 2A). Invaginations of the epithelium are frequent and should not be misinterpreted as stromal invasion. Separate small epithelial cysts may be scattered througimut t h e ovary. The epithelium covering the papillae may be stratified into several layers. Exfoliation of cellular clusters from the papillae is characteristic (Fig. 2B). Detached buds of these cells become suspended in the cyst fluid. Tnmors with an exophytic surface component may shed such cellular clusters into the pelvic cavity, where some implant on tim parietal peritoneuul, oulentum, or serosal s u r f a c e s o f adjacent reprodnctive and intestinal organs. The proliferating epithelial cells have slightly to moderately atypical nuclei, which are enlarged, irregular, and hyperchromatic. Nucleoli, if present, are usually small or inconspicuous. Mitotic figures are relatively few. From a cytologic aspect the cells do not show unmistakable changes of carcinoma. Many of them display cilia, and some assume a rounded shape with abnndant cytoplasm and have been referred to as "mesotlmlial" cells (Fig. 2C). 6 Psammorea bodies sometimes are numerous; they were found in 23 per cent of the 74 borderline serous tumors reported by Aure et al. 8 Bilateral ovarian involveinent has been reported in about 14 to 33 per cent of tim cases of serous cystadenoma of borderline malignancy6"~ and is believed to represent separate independent primary tumor development in most instances. Of greatest concern is the high incidence of extraovarian spread of borderline serous neoplasms. Extension beyond the ovaries
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Figure 2. Forty-nine )'ear old woman with bilateral serous papillary cystadcnomas of borderline malignancy. Excrescences of neoplasm were on external surfaces. Ascitic fluid positive for adenocarcinonm. Extensive implants on pelvic peritoneum and serosa of colon at operation. Postoperative radiation therap)' admi,fistered after palliative bilateral salpingo-oop!lorectom)-. No residual tumor observed at time ot-hysterectomy 10 )'ears later. Patient alive and well without recurrence 13V= )'ears after initial operation. zl, Numerous i~al)illae with complex branching pattern, no invasion of stroma. B, l'apillae covered by proliferating epithelium with multila)'ering of cells and exfoliation of cellular clusters. C, Small papilla covered by atypical columnar cells. Notice detached "lnesothelium"-like cell (arrow) and area of muhilayering of cells. (Ilematoxylin and eosin stain. A, reduced from x 100. B, reduced from x260. C, reduced from x405.)
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has b e e n f o u n d at t h e t i m e o f initial s u r g e r y in 20 to 46 p e r c e n t o f t h e p a t i e n t s in some series?'6 Such spread typically app e a r s as m u l t i p l e s u p e r f i c i a l i m p l a n t a t i o n "metastases" on the peritoneum and serosal surfaces of pelvic organs. These a r e e s p e c i a l l y p r o n e to d e v e l o p w h e n inv o l v e m e n t o f t h e e x t e r n a l Ovarian s u r f a c e
is p r o m i n e n t - A s c i t e s o f t e n r e s u l t s , a n d cytologic examination of peritoneal fluid may reveal papillary clusters of neoplastic cells. P s a m m o m a b o d i e s a r e o f t e n a b u n d a n t in t h e i m p l a n t s . F i b r o u s a d h e s i o n s resulting from peritoneal studding produce repeated bouts of intestinal obstrttction ill s o m e p a t i e n t s . O c c a s i o n a l l y l ) ' m p h
OVARIAN EPITHELIAL TUMORS OF BORDERLINE MALIGNANCY-- HART node metastases developfl" 'j but hematogenous nletastasis is rare, as is extension outside the abdominopelvic cavity. In spite of the great frequency of spread beyond the ovaries, the prognosis is highly favorable, even for patients with disseminated peritoneal implants. Regardless of the extent of the tumor and its clinical stage, corrected five )'ear survival rates of 92 to I00 per cent have been reported in patients with borderline serous tumors, 5-~ and 10 year rates have ranged from about 75 to over 90 per cent?'5'7 Although the patients in most series had received postoperative radiation therapy, adjunctive treatment with chemotherapeutic agents or irradiation was employed rarely in the group of 64 patients reported by Julian and Woodruff. 6 Recurrent lesions within the pelvis or abdomen may develop after long latent intervals of up to 20 or even 50 )'ears. ~ 10 I n such cases the recurrences have shown the same histologic appearance as the primary ovarian tmnors. It is apparent that the cells of borderline serous tumors have a fixed and static degree of differentiation. They maintain their histologic characteristics and slow growth and do not undergo progressive anaplasia or dedifferentiation with the passage of time. Some peritoneal implants presumably fail to proliferate, and rare instances o f s p o n t a n e o u s r e g r e s s i o n have been cited.n" ~z Some examples of peritoneal implants actually may represent muhiple foci of de novo neoplastic transformation of peritoneal mesothelium rather than metastases? s In fact, increasing numbers of cases now are being recognized in which widespread primary papillary neoplasms of pelvic peritoneum simulate metastatic ovarian tunlors. Aure et al., z however, warned that up to 25 per cent of the patients eventually may die from recurrent tnmor if the cases are followed for sufficiently long periods of time. Entirely intracystic tumors probably can be expected to be cured by conservative surgery. Julian and Woodruff6 recorded no deaths due to neoplasm during a five year observation period in patients with nnilateral stage I tumors; 15 patients had been treated by unilateral salpingo-oophorectomy and 10 patients by hysterectomy and bilateral adnexectomy.
BORDERLINE
MUCINOUS
TUMORS
Mucin0us ttunors of borderline malignancy are somewhat less common than the serous varieties. Of the 20 per cent of mncinous neoplasms that are not clearl)" benign, about 40 per cent belong in the borderline category and the remainder are unequivocal carcinomas? It is likely that the good prognosis attributed to mucinous carcinomas in some reported series retlects inclusion of a high proportion of tumors of borderline malignancy. In borderline as well as benign mncinous tumors, the epithelial element contains cells resembling those of endocervical or gastrointestinal tract mucosa. Practically all are cystic and three-fourths are muhiloculated c)'sts. 2 Grossly they cannot be reliably distinguished fi'om benign cystadenomas or cystadenocarcinomas. An increase in thickness of the cyst walls or intrac)'stic papillations are sometimes observed. Growth on the external ovarian surface is rarely seen, in contrast to its fi'equency in cases of borderline serous neoplasms. Most examples are large; in a series of 97 cases the median diameter was 17 c m . -~
Extensive sampling is especially critical with mucinous lesions, since the most atypical degree of epithelial proliferation may be localized to a small portion of the tumor. Microscopically, mncinous c)'stadenomas of borderline malignancy have a variety of complicated glandular patterns (Fig. 3). Their overall appearance is frequently reminiscent of hyperplastic and adenomatous polyps of the colon or of proliferating types of appendiceal mucocele. Assessment of stromal invasion is more difficult in mucinous than in serous tumors, since the former have multiple cysts and are often parvilocular. Small secondar)' cysts and outpouchings from larger glands may appear to be isolated within ovarian stroma and be misinterpreted as evidence of invasion (Fig. 4). Broad fibrous papillary processes are uncommon in mucinons cystadenomas of borderline malignancy, but short delicate papillae are frequently found. The cells lining the cysts and covering the papillations are stratified into two to three layers and display a loss of normal polarity (Figs. 5, 6).
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Figure 3. Mucinous cystadenoma of borderline malignancy consists of cysts lined by nun-terous delicate short papillary infoldings. The patient was alive and well without recurrence 3.9 )'ears after hysterectomy and bilateral sallfingo-oophorcctomy. (Hematoxylin and cosin stain. Reduced from xl40.)
E x f o l i a t e d c l u s t e r s o f cells m a y b e m i x e d with m u c i n o n s d e b r i s , T h e cells l m v e e n l a r g e d n u c l e i w i t h m i l d to m o d e r a t e degrees of atypism. The amount of intrac e l h f l a r m u c i n m a y b e r e d u c e d in t h e a t y p i c a l cells. M i t o t i c f i g u r e s a r e o f t e n m o r e p l e n t i f i f l t h a n in b o r d e r l i n e s e r o u s tumors. A d i a g n o s i s o f m u c i n o u s c a r c i n o m a is
warranted, of c o u r s e , w l l e n e v e r s t r o m a l i n v a s i o n is p r e s e n t . U n e q i v o c a l i n v a s i o n can be diagnosed confidently when irregul a r nests o r s o l i d c o r d s o f cells a r e h a p b a z a r d l ) ' s c a t t e r e d in t h e o v a r i a n s t r o m a (Fig. 7). T h e s e p a t t e r n s a r e u n l i k e t h e orderly arrangement of small branching g l a n d s t h a t h a v e s m o o t h c o n t o u r s a n d well f o r m e d l u m e n s . I n v a s i o n also m a y t a k e
Figure 4. Mucinous c)stadenoma of borderline malignancy. Several small glands with smooth contours and all orderly arrangement appear isolated in tile ovarian stroma as a result of secondary gland formation. The patient was alive and well without recurrence 3.3 )ears after hysterectomy and bilateral sallfingo-oophorectomy. (Iiematoxylin and eosin stain. Reduced from xl00. Reprinted by permission fiom Hart, W. R., and Norris, tt.J.: Borderline and maligtmm mucinous tumors of the ovary. Histologic criteria and clinical behavior. Cancer, 31:1031, 1973.)
546
OVARIAN E P I T H E L I A L TUMORS OF BORDERLINE MALIGNANCY--HART
Figure 5. Higher magnification of tumor illustratcd in Figure 4 shows mucinous cells with atypical hypcrchromatic nuclei and disturbed polarity lining a c)st, (ttematoxylin and eosin stain. Reduced from • Reprinted by permission from Hart, W. R., and Norris, H.J.: Borderline and malignant mucinous tumors of the ovary, tlistologic criteria and clinical behavior. Cancer, 31:1031, 1973.)
Figure 6. Mucinous cystadenoma of borderline malignatlcy illustrated in Figure 3. Short intraluminal finger-like projections covered by mucinous cells with enlarged atypical nuclei rest on delicate connective tissue SUpl~orts. (ttematoxylin and eosin slain. Reduced from • Reprinted by permission from Hart, W. R., and Norris, H.J.: Borderline and malignant mucinous tumors oftheovary. Histologiccriteria and clinical behavior. Cancer, 31 : 1031, 1973.)
the f o r m o f large sheets o f glands with a back to back a r r a n g e m e n t a n d no intervening stroma, ht the absence o f tmeqtfivocal infiltrative growth, a m u c i n o u s t u m o r sltould also be r e g a r d e d as carcin o m a w h e n t h e r e is a m a r k e d o v e r g r o w t h o f atypical epithelial cells or w h e n severely anaplastic nuclear features are observed. C r i b r i f o r m i n t r a g l a n d u l a r proliferations and finger-like projections o f solid cellular masses without connective tissue s u p p o r t s are indicative o f carcinoma. As a general rule, we have i n t e r p r e t e d as c a r c i n o m a those t u m o r s in which stratification o f atypical epithelial cells lms exceeded' t h r e e layers in thickness (Fig. 8). 2 Such t u m o r s often also show severe nuclear anaplasia or are a c c o m p a n i e d by stromal invasion. Only a b o u t 10 p e r cent o r less o f borderline m n c i n o u s c y s t a d e n o m a s are bilateral. 2 In o u r e x p e r i e n c e they are usuall)" not a c c o m p a n i e d by evidence o f extraovariau s p r e a d at the time o f the
initial o p e r a t i o n . H o w e v e r , in the series r e p o r t e d b)" A u r e et al. 5 a b o u t 15 p e r cent h a d e x t e n d e d b e y o n d the ovaries b)" tile time tile diagnosis was established. Diffuse peritoneal seeding, as occurs with b o r d e r line serous t u m o r s , is distinctly rare. S o m e o f the b o r d e r l i n e m u c i n o u s t u m o r s , however, have been associated with pseudom y x o n t a peritonei, an enigmatic condition often attributed to p r i o r r u p t u r e o f m u cinous t u m o r s a n d spillage o f their contents. Yet peritoneal p s e u d o m y x o m a is not a f i e q u e n t complication o f r u p t u r e d ovarian tumors. N o n e o f the 11 patients r e p o r t e d b)' H a r t a n d Norris 2 with t u m o r s o f b o r d e r l i n e m a l i g n a n c y tlmt lind r u p t u r e d d u r i n g or p r i o r to o p e r a t i o n subsequently had p s e u d o m y x o m a a f t e r followu p intervals o f t h r e e to 19 }'ears, n o r did any o f the five patients witlt stage I m u cinons carcinomas that lind r u p t u r e d in tile s a m e series. Since p s e u d o m y x o m a peritonei is f r e q u e n t l y a c c o m p a n i e d by a
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Figure 7. lnvasive mucinous cystadenocarcinoma. Irregular nest and cords of anaplastic cells haphazardly infiltrate the ovarian stroma adjacent to small cysts. This destructive growth pattern is unlike the orderly arrangement of small, well formed glands found in borderliqe mucinous tumors. (Hematoxylin and eosin stain. Reduced from x200.)
mucocele of the appendix or a carcinoma o f t h e c o l o n , it is e x t r e m e l y difficult to determine the cause of the pseudomyxoma in m a n ) ' i n s t a n c e s . 2 Mucinous cystadenomas of borderline m a l i g n a n c y Imve a m o r e f a v o r a b l e p r o g nosis t i t a n d o s e r o u s t u m o r s o f s i m i l a r type, probably because surface involvernent and widespread peritoneal implanta-
t i o n a r e so i n f r e q u e n t . I n a l o n g t e r m followup study of stage I tumors, Hart and Norris z reported corrected actuarial s u r v i v a l r a t e s o f 98 p e r c e n t at five y e a r s a n d 96 p e r c e n t at 10 y e a r s . O v e r h a l f t h e p a t i e n t s lind b e e n t r e a t e d solely b y t m i lateral salpingo-oophorectomy. In contrast, m u c i n o u s c a r c i n o m a s o f a s i m i l a r clinical s t a g e w e r e a s s o c i a t e d with s u r v i v a l s
Figure 8. Stage I mutinous c)stadenocarcinoma without unequivocal stromal invasion. The epitheliunl exceeds three cell layers ill thickness and intraglandular cellular bridges are not supported b)" connective tissue cores. The patient died of metastatic carcinoma i.6 )'ears after hysterectomy and bilateral salpingo-ool~horectomy. (Hematoxylin and cosin stain. Reduced from •
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O V A R I A N E P I T H E L I A L T U M O R S O F B O R D E R L I N E MALIGNANCY--HAR-r o f o n l y 66 p e r c e n t at five )'ears a n d 59 p e r c e n t at 10 )'ears in t h e s a m e series, z I r r e s p e c t i v e o f t h e clinical s t a g e , A u r e et al. 5 f o u n d a 20 ) ' e a r s u r v i v a l r a t e o f a b o u t 85 p e r cent; e x c e p t f o r a s m a l l n u m b e r o f y o u n g p a t i e n t s , all h a d r e c e i v e d s o m e form of postoperative radiation therapy.
2.
3.
SUMMARY I n c u r r e n t classifications p r i m a r y e p i thelial o v a r i a n t u m o r s a r e d i v i d e d a c c o r d i n g to lfistologic c r i t e r i a i n t o t h r e e g r o u p s : benign, borderline, and malignant. The t u m o r s o f b o r d e r l i n e m a l i g n a n c y (carcin o m a s o f low m a l i g n a n t p o t e n t i a l ) h a v e a c o n s i d e r a b l y m o r e f a v o r a b l e clinical b e h a v i o r t h a n d o t h e h i g h e r g r a d e s o f carcin o m a . Sufficient e x p e r i e n c e with b o r d e r l i n e t u m o r s o f t h e s e r o u s a n d mt~cinous cell t y p e s h a s a c c r u e d to p r o v i d e r e a s o n able histopathologic criteria for accurate diagnosis. Extensive sampling and microscopic examination of the primary ovarian n e o p l a s m is essential. T h e p r e s e n c e o r absence of involvement of the external surface of the ovary should be documented, because knowledge of the overall c o n f i g u r a t i o n o f t h e t u m o r is e x t r e m e l ) ' v a h m b l e in d e t e r m i n i n g t h e r a p y . S p r e a d b e y o n d t h e o v a r i e s , w h i c h o c c u r s o f t e n in t h e s e r o u s cell g r o u p , is o f i m p o r t a n c e in t r e a t m e n t b u t d o e s n o t a l t e r t h e lfistologic diagnosis of borderline malignancy. Although there are some semantic, philos o p h i e , a n d c o n c e p t u a l p r o b l e m s with usage of the designation "borderline malignancy," adoption of the terminology p r o p o s e d in W H O c l a s s i f i c a t i o n s e e m s worthwhile, especially for purposes of r e p o r t i n g t h e r a p e u t i c results.
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REFERENCES 13. 1. Morrow, C. P., and Hart, W. R.: The ovaries. In Romney, S., et al. (Editors): Gynecology and
Obstetrics: The Health Care of Women. New York, McGraw-tlill Book Company, 1975, Ch. 49, p. 1056. Hart, W. R., and Norris, H. J." Borderline and malignant muciuous tumors of the ovary. Histologic criteria and clinical behavior. Cancer, 31 : 1031, 1973. Santesson, L., and Kottmeier, H. l..: General classification of ovarian tumot, rs. In Gentil, F., and Junquerira, A. C. (Editors): Ovarian Cancer. U.I.C.C. Monograph Series. New York, Springer-Verlag, 1968, Vol. 11, p. 1. Serov, S. F., Scully, R. E., and Sobin, L. H.: International Histological Classification of Tumours. No. 9. Histological Typing of Ovarian Turnouts. Geneva, World Heahh Organization, 1973. Aure, J. C., HCeg, K., and Kolstad, 1'.: Clinical and histologic studies of ovarian carcinoma. Long-term folk)w-up of 990 cases. Obstet. Gynecol.,37:l, 1971. Julian, C. G., and Woodruff, J. D.: The biologic belmvior of low-grade papillary serous carcinoma of the ovary. Obstet. Gynecol., 40:860, 1972. l'urola. E.: Serous papillary ovarian tu,nours. A study of 233 cases with special reference to the histological type of tumour and its influehce on prognosis. Acta Obstet. Gynecol. Scand., 42:7, 1963. Aure, J. C., tt0eg, K., and Kolstad, P.: l'sammorea bodies in serous carcinoma of the ovary. Am. J. Obstet. Gynecol., 109:i 13, 1971. Malloy, J. J., Dockerty, M. B., Welch, J. S., and Hunt, tt. B.: Papillary ovarian tumors. I. Benign tumors and serous and mucinous cystadenocarcinomas. Am. J. Obstet. Gynecol., 93:867, 1965. Woodruff, J. D., and Jtdian, C. G.: tlistologic grading and morphologic changes of sig,fificance in the treatment of semi-malignaut and malignant ovarian tumors. In Proceedings of the Sixth National Cancer Conference. Philadelt~hia, J. B. I.ippincott Co., 1968. p. 347. Gaudrauh, G. L.: Papillary carcinoma of the ovary. Report of a case with prolonged dormancy and spontaneous regression of metastases. New Eng. J. Med., 264:398, 1961. Ta)'lor, H. C., Jr., and Alsop, W. E.: Spontaneous regression of peritoneal implantations fi'om ovarian papillary cystadenonm. Am. J. Cancer, 16:1305, 1932. Burmeister, R. E., Fechner, R. E., and Franklin, R. R.: Endosalpingiosis of the peritoneum. Obstet. Gynecol.,34:310, 1969.
Department of l'athology University of Michigan Medical School 1335 East Catherine Street Ann Arbor, Michigan 48109
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