Ovarian Follicular Cysts: A Potential Source of False Positive Diagnoses in Ovarian Cytology Carlos Nuiiez,

M.D.,

and Jose I. Diaz, M.D.

The cytology samples of 22 benign ovarian cysts aspirated during laparoscopy (1 6) or laparotomy (6) were evaluated f o r clinicopathologic correlations. Clinically, most patients were evaluated f o r chronic pelvic pain. The cysts ranged in size from 1 to 5 c m (average 2.4 cm), and were described as having benign appearance. Cytologically, small granulosa cells arranged in clusters or isolated had granular cytoplasm with occasional microvacuoles. The nuclei were round to oval, uniform, and eccentrically placed. They had granular chromatin with chromocenters and one to two micronucleoli. Relative nuclear area averaged 50%. Mitoses were present in all but two cases, ranging from 0 to 38 mitoses per 10 high power fields (average 7.2 mitoses per 10 high power fields). Present in some cases were mesothelial cells and histiocytes. Three cases with follow-up histopathology specimens revealed two follicular cysts and a collapsed cyst withoitt discernible h i n g . The immature appearance of the granulosa cells, the granular chromatin, and the presence of mitoses often suggested cytologically the possibility of a neoplastic process. Recognition of the cytopathology features, knowledge of the clinical history, and the laparoscopic findings may reassure the pathologist about the benign nature of the cysts. Diagn Cytopathol 1992;8:532-537. (c) 19Y2 Wiley-Lis, lnc.

Key Words: Fine-needle aspiration; Laparoscopy; Granulosa cells; Non-neoplastic ovarian cysts; Dysfunctional ovarian cysts

Fine-needle aspiration of ovarian cysts during laparoscopy or ultrasound guidance is increasing as a therapeutic and diagnostic modality in patients with benign-appearing ovarian cysts. Careful selection of the patients from ultrasound findings and visual inspection of the cyst through the laparoscope minimize the risk of aspirating neoplastic The use of these techniques has increased the number of ovarian fine-needle aspiration biopsy specimens submitted to the cytopathology laboratories. A review of the English literature reveals few reports describing the cytopathologic features of non-neoplastic Received November 22, 1991. Accepted February 28, 1992. From the Department of Pathology, The Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Carlos Nuiiez, M.D., Department of Pathology, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195.

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ovarian cysts. 7-’0 Occasional reports have emphasized the fact that some follicular cysts may have cytopathologic features that resemble malignancy. ‘ , I 2 That also has been the experience of one of the authors (CN) with several consultation cases of fine-needle aspiration of non-neoplastic cysts of the ovary, referred to us with a diagnosis of malignancy. The present study was undertaken to describe and characterize the cytopathologic features of follicular cysts in our experience.



Materials and Methods The files of the cytopathology laboratory were searched for all cases of aspiration of ovarian cysts from January 1986 to December 1990. A total of 221 cases were found. Luteal cysts, endometriotic cysts, neoplastic cysts, and cases that had only blood or macrophages were excluded from the study. Twenty-two cysts from 21 patients met the criteria for the diagnosis of follicular cysts as described by Kovacic et a1.7 and are the basis of this study. Sixteen cysts were aspirated during laparoscopy for evaluation of chronic pelvic pain. The other six cysts were aspirated during surgery under direct visualization. The aspirated fluid was sent immediately to the cytopathology laboratory where smears from the centrifuged sediment, cytospins, and cell blocks when indicated were prepared. The direct smears and cytospins were stained by the Papanicolaou method. The cell blocks were fixed in Hollande’s solution, embedded in paraffin, and sections were stained with hematoxylin-eosin (H&E). The following characteristics were evaluated and recorded: background appearance, cellularity, cell arrangement, cell configuration, cytoplasm characteristics, nuclear configuration, chromatin appearance, presence of nucleoli, and mitotic activity .

Results Clinical Features The patients ranged from 15 to 50 yr old (average 37.6 years). All 16 patients whose cysts were aspirated during c

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OVARIAN FOLLICULAR CYSTS: FALSE POSITIVE DIAGNOSES

laparoscopy had a history of chronic pelvic pain. Six patients underwent aspiration of ovarian cysts found incidentally during exploratory laparotomies. The cysts ranged in size from 1 to 5 cm in diameter (average 2.4 cm). All cysts had a benign laparoscopic appearance; they were small, unilocular, smooth, and translucent without wall thickening. The aspirated fluid was clear, straw colored, or hemorrhagic, and ranged from 0.5 to 25 ml (average 5.5 ml). Two patients underwent subsequent oophorectomies. All other patients were followed clinically.

Cytopathology and Histopathology Most cysts had moderate to abundant cellularity in either a clear or hemorrhagic background. The granulosa cells were arranged isolated, in clusters of variable size with smooth outlines, or occasionally in large irregular clusters (Figs. 1-5). Cell size was equal to or smaller than histiocytes. Most cells had a polygonal configuration with granular, eosinophilic cytoplasm (Fig. 1). Microvacuoles were present in some cases. The nuclei were round to oval, and usually single, although binuclea-

Fig. 1. Group of granulosa cells with round, uniform nuclei and granular cytoplasm. The chromatin is coarsely granular. Micronucleoli are present in some nuclei. One mitosis is present at the center of the group (Papanicolaou, ~ 4 0 8 ) .

tion was occasionally observed. Nuclear membranes were smooth without indentations or “grooves.” The chromatin was predominantly coarsely granular with chromocenters. One or two micronucleoli were often observed (Fig. 1). The relative nuclear area averaged 50% (25%-70%). Mitotic figures were identified in all but two cysts (Fig. l), ranging from 0 to 38 mitoses per 10 high power fields (average 7.2 mitoses per 10 high power fields). Some cases, in addition to the granulosa cells, had histiocytes, cells from the ovarian surface epithelium, or both (Fig. 2). Histologic follow-up was available in three cases. One patient had a hysterectomy and bilateral salpingo-oophorectomy 1 m o after laparoscopy for persistent severe pelvic pain. A collapsed cyst with a hemorrhagic wall and a luteinized theca externa was found in the right ovary at the same location as the aspirated cyst (Fig. 3). A second patient who had a previous vaginal hysterectomy underwent an exploratory laparotomy for evaluation of a 10-cm cystic right adnexal mass. During laparotomy 10 ml of fluid was aspirated from an incidental left ovarian cyst with benign gross appearance. Both ovaries were removed.

Fig. 2. A large, folded sheet of ovarian surface epithelial cells is seen next to a group of granulosa cells. Surface epithelial cells resemble mesothelial cells (Papanicolaou, X 204).

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Fig. 3. (A) Hemorrhagic follicular cyst. Groups of granulosa cells are identified in a background of red blood cells (Papanicolaou, X 377). (B) Subsequent oophorectomy revealed a collapsed cyst with a hemorrhagic wall and a Iuteinized theca externa (H&E, x 60).

Histopathology revealed a follicular cyst of the left ovary and a benign serous cystadenoma of the right ovary (Fig. 4). A third patient had a laparoscopic biopsy of the wall of a 4.6-cm cyst that showed histologically a follicular cyst. (Fig. 5).

Discussion Because of the increased use of fine-needle aspiration biopsy as a therapeutic and diagnostic modality in selected patients with ovarian cysts pathologists must become familiar with the cytomorphology of non-neoplastic ovarian cysts. Conservative evaluation and treatment of non-neoplastic ovarian cysts is important in this population of women, most of whom are in their reproductive years, when conservation of fertility and ovarian function is desirable. Despite the benign appearance of the cysts by ultrasound or laparoscopy, cytologic examination of the aspirated fluid helps to confirm the non-neoplastic nature of the cysts. Most ovarian cysts evaluated by fine-needle aspiration biopsy are follicular cysts, corpus luteum cysts, and en534

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Fig. 4. (A) Intraoperatory cyst aspirate shows irregular groups of granulosa cells (Papanicolaou, X 302). (B) Oophorectomy disclosed a follicular cyst with a well-preserved granulosa cell lining (H&E. X 151).

dometriotic cysts. The peculiar cytologic appearance of follicular cysts may present diagnostic problems, namely they may be interpreted as malignancies, resulting in unnecessary oophorectomy. Our cytopathologic findings in follicular cysts are similar to those reported. '-I0 Cell samples have abundant isolated cells or cell aggregates. The cells are small with granular or occasionally vacuolated cytoplasm and have a large relative nuclear area. The nuclei are round to oval with granular chromatin and inconspicuous nucleoli. Mitoses are almost invariably present. We could not document in our cases the presence of nuclear grooves as described by Selvaggi. lo However, nuclear grooves are not a feature of follicular granulosa cells. l 3 The abundant cellularity, immature appearance of the cells, granularity of the chromatin, and presence of mitotic figures impart a rather alarming aspect to the aspirates. Thus, unless the pathologist is familiar with the clinicopathologic appearance of follicular cysts, a mistaken diagnosis of malignancy may be rendered. " , I 2 That has been the experience with several cases of follicular cysts referred to us with different malignant diagnoses including malignant tumor

OVARIAN FOLLICULAR CYSTS: FALSE POSITIVE DIAGNOSES

Fig. 5. (A) This cyst aspirate had many tight aggregates of granulosa cells (Papanicolaou, x 302). (B) A laparoscopic biosy of the cyst wall shows a follicular cyst with a well-preserved granulosa cell lining (H&E, x 302).

of undetermined type, granulosa cell tumor, carcinoid tumor, and serous malignant tumor. All these are valid differential diagnoses and potential pitfalls in the diagnosis of follicular cyst. Because the cellular components of follicular cysts are granulosa cells, these cysts have to be distinguished from granulosa cell tumors, particularly the cystic juvenile type. The few cytomorphologic reports about granulosa cell tumors describe a uniform population of small cells with scanty cytoplasm and occasional rosette-like structures suggestive of Call-Exner bodies. The nuclei have pronounced indentations or grooves, fine chromatin, and small nucleoli. Although this cytomorphology resembles that of a follicular cyst, the indented irregular nuclei with fine chromatin, and rosette-like formations argue against the diagnosis of follicular cyst. Carcinoid tumors of the ovary appear most commonly as a solid nodule in the wall of a cystic teratoma or mucinous cystadenoma. l 8 Cytologically, carcinoids feature uniform small cells with finely granular cytoplasm and round to oval nuclei with coarse chromatin that may simulate granulosa cells. 15,16,19 However, carcinoids are ar-

gyrophilic and may express immunoreactivity for enolase, chromogranin, or neuronal peptides. Serous neoplasms are characterized by abundant papillary clusters of epithelial cells with moderate amounts of cytoplasm and markedly atypical nuclei. Psammoma bodies and necrotic debris may be present in the background. 20*21 All these neoplasms have ultrasonographic and laparoscopic appearances different from follicular cysts; i.e., they are usually large, multilocular, and may have excrescences, capsular irregularities, or both, or may be solid. These features are contraindications for aspiration of ovarian cyst. Therefore, when evaluating fluid aspirated from ovarian cysts it is imperative to know the laparoscopic or ultrasonographic appearance of the cyst. Other ancillary tests, such as the determination of estradiol 2,22 and CA125 23 in the aspirated fluid, may help to distinguish between neoplastic and non-neoplastic cysts. In our experience, a large number of aspirations from ovarian cysts that appear benign by laparoscopy can be classified only as “consistent with cyst,” as a result of the paucity of cellular elements. In these cases, occasional macrophages and rare degenerated cells are the only cellular elements present. Many of these cysts probably represent atretic follicles or old follicular cysts with an attenuated granulosa cell lining. However, others may be corpus luteum cysts, endometriotic cysts, or surface inclusion cysts. The corpus luteum cyst can be recognized cytologically by the presence of large polyhedral cells with abundant vacuolated cytoplasm and eccentrically placed nuclei. Aspirations of endometriotic cysts often yield hemorrhagic fluid with many hemosiderin-laden macrophages and broken down red blood cells. However, endometrial cells must be present for a diagnosis of endometriosis. Some authors have expressed reservations about the use of fine-needle aspiration biopsies in evaluating ovarian cysts. I 2 However, if the aspiration is performed according the to strict laparoscopic or ultrasonographic criteria, risks of aspirating a neoplastic cyst appear to be small. Moreover, it is important for the pathologist to know the clinical findings and the cytomorphology of follicular cysts to avoid false positive diagnoses. If these premises are followed, fine-needle aspiration biopsy may be safely used in the evaluation of ovarian cysts.

References CH.Is needle aspiration of ovarian cysts adequate for diagnosis? Br J Obstet Gynaecol 1989;96:1021-1023.

1. Buckley

2. DeCrespigny LC,Robinson HP,Davoren RAM, Fortune D. The “simple” ovarian cyst: Aspirate or operate? Br J Obstet Gyiiaecol 1989;96:1035-1039. 3. Rodin A, Coltart TM, Chapman MG. Needle aspiration of simple Diugnoctic Cyfopu[hoiogy,Voi 8, No 8

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NUNEZ AND DIAZ ovarian cysts in pregnancy. Case reports. Br J Obstet Gynaecol 1989;96:994996. 4 Kleppinger RK. Ovarian cyst fenestration via laparoscopy. J Rrprod Med 1978;21:16-19. 5 Larsen JF, Pendersen OD, Gregersen E. Ovarian cyst fenestration via the laparoscope. A laparoscopic method for treatment of nonneoplastic ovarian cysts. Acta Obstet Gynecol Scand 1986;65:539542. 6 Hasson HM. Laparoscopic management of ovarian cysts. J Reprod Med 1990;35:863-867, 7 Kovacic J, Rainer S, Levicnik A, Cizeli T. Cytology of benign ovarian lesion in connection with laparoscopy. In: Zajicek J, ed. Aspiration biopsy cytology. Part 11: Cytology of infradiaphragmatic organs. Basel: Karger, 1979:57-79. 8 Kovacic J, Rainer S, Levicnik A. Aspiration cytology of normal structures and non-neoplastic cysts of the ovary. In: Blaustein A, ed. Pathology of the female genital tract. Yew York: Springer-Verlag, 1982:716-740. 9 Ramzy I, Delaney M, Rose P. Fine-needle aspiration of ovarian masses. 11. Correlative cytologic and histologic study of non-neoplastic cysts and noncelomic epithelial neoplasms. Acta Cytol 1979; 23: 185-1 93. 10 Selvaggi SM. Cytology of non-neoplastic cysts of the ovary. Diagn Cytopathol 1990;6:77-85. I 1 Selvaggi SM. Fine-needle aspiration cytology of ovarian follicle cysts with cellular atypia from reproductive-age patients. Diagn Cytopatho1 1991;7:189-192. 12 Stanley MW, Horwitz CA, Frable WJ. Cellular follicular cysts ofthe ovary: Fluid cytology mimicking malignancy. Diagn Cytopathol 1991;7:48-52. 13 Clement PB. Histology of the ovary. Am J Surg Pathol 1987;11:277303.

14 Fidler WJ. Recurrent granulosa-cell tumor. Aspiration cytology findings. Acta Cytol 1982;26:688-690. 15 Ehya H, Lang WR. Cytology of granulosa cell tumor of the ovary. Am J Clin Pathol 1986;85:402405. 16 Bender JA, Zaleski S. Fine-needle aspiration cytology features of hepatic metastasis of granulosa cell tumor of the ovary. Differential diagnosis. Acta Cytol 1988;32:527-532. 17 Stamp GWM, Krausz T. Fine needle aspiration cytology of a recurrent juvenile granulosa cell tumor. Acta Cytol 1988;32:533539. 18 Rusell P, Bannatyne P.Surgical pathology of the ovaries. New York: Churchill Livingstone, 1989:44-49. 19 Lozowski W, Hajdu SI, Melamed MR. Cytomorphology of carcinoid tumors. Acta Cytol 1979;23:360-365. 20 Ramzy I, Delaney M. Fine-needle aspiration of ovarian masses. 1. Correlative cytology and histologic study of celomic epithelial neoplasms. Acta Cytol 1979;23:97-104. 21 Kjellgren 0, Angstrom T. Aspiration biopsy cytology of ovarian tumors. In: Blaustein A, ed. Pathology of the female genital tract. New York: Springer-Verlag, 1982:741-75 1. 22 Geier G R , Strecker JR: Aspiration cytology and E, content in ovarian tumors. Acta Cytol 198 1 ; 2 5 : 4 W 0 6 . 23 Pinto MM, Bernstein LH, Brogan DA, Parikh F, Lavy G. Measurement of CA125, carcinoembryonic antigen, and alpha-fetoprotein in ovarian cyst fluid: Diagnostic adjunct to cytology. Diagn Cytopathol 1990;6:160-1 63.

Editorial Comments Literature on the aspiration cytology of ovarian follicle cysts has surged over the past five years. With the increase

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in the number of women seeking medical assistance for infertility problems, and with the rise in the number of women who delay pregnancy, techniques to ensure preservation of ovarian function are desirable. As a result of increased usage of the laparoscope, ovarian lesions are more accessible and cysts more easily aspirated. A few of the earliest reports in the English literature on ovarian follicle cyst cytology date to 1979.6,7 Kovacic and coworkers6 discussed their experience with aspirated material from 155 ovarian follicle cysts obtained at laparoscopy. Smear preparations were fixed by air-drying and stained according to May-Grunwald-Giemsa. Cellular smear preparations were found in 117 cases (75.5%) and contained numerous granulosa cells occurring singly and in small groups. The cells had central, round nuclei with coarsely granular chromatin and inconspicuous nucleoli. The cell cytoplasm was finely vacuolated, and occasional mitotic figures were present. In 36 cases (23.3%) the aspirates, predominately from regressing follicle cysts, contained fewer granulosa cells, and in 2 cases (1.2%), the aspirates were acellular. Utilizing the Papanicolaou staining method, Ramzy and coworkers’ described similar cytologic findings on aspirated material from 11 follicle cysts. Relatively little else was published on this subject until the late 1 9 8 0 ~ ’ -Reports ~. describing the cytology of ovarian follicle cysts emphasized a potential diagnostic pitfall; namely, malignancy. This is evident particularly when the specimens are cell rich, show cellular atypia and contain mitotic figures. Cysts with these features have been termed “cellular follicular cysts” by Stanley and associates and “follicle cysts with cellular atypia” by Selvaggi. 3,5 Smear preparations contained luteinized granulosa cells arranged singly, in clusters, and in glandular and papillary configurations. The cells had an increased nuclear/cytoplasmic ratio and contained nuclei with granular chromatin, prominent chromocenters and large nucleoli, some irregular in shape. The cell cytoplasm was foamy, and the cell borders were often indistinct. The current article by Nufiez and Diaz addresses the issue of mitotic figures in detail. Ninety-one percent of the cytologic specimens contained mitotic figures with an average of 7.2 mitoses/lO hpf examined. Although other reports have noted their presence in aspirated follicle cyst contents, this is the first study to quantify their numbers. This article attests to the proliferative ability of granulosa cells from benign ovarian follicle cysts. In general, ovarian follicle cysts can be divided into two basic types; follicle cysts composed of nonluteinized granulosa cells and follicle cysts composed of luteinized granulosa cells. I The cases presented by Nufiez and Diaz and those of others have described and depicted the cytologic features of luteinized granulosa cells. Although *s3f5



~

3

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OVARIAN FOLLICULAR CYSTS: FALSE POSITIVE DIAGNOSES

nuclear grooves are absent in luteinized granulosa cells, they have been noted in nonluteinized granulosa cells. The differential diagnoses of follicle cysts of the ovary on aspiration cytology have been reported to include granulosa cell tumors, ‘-3,6 serous tumors, particularly serous cystadenomas 2,4,6 and carcinoid tumors, proposed by Nuiiez and Diaz. In contrast to follicle cysts, cellular aspirates of granulosa cell tumors have been reported to contain Call-Exner bodies. * The granulosa cells have a prominent indentation of the nuclear membrane and contain nuclei with finely granular, evenly dispersed chromatin. Although few diagnostic difficulties should exist in differentiating borderline and invasive serous cystadenocarcinomas from follicle cysts on cytology, differentiation from serous cystadenomas may be difficult. Serous cystadenomas9 are composed of sheets and/or papillary groups of epithelial cells with round to oval nuclei containing finely granular chromatin and inconspicuous nucleoli. The cell cytoplasm is often ample and dense. In my experience, ciliated epithelial cells have been noted. Additional information may be provided by cyst fluid analysis of CA125, CEA, and AFP levels. l o Carcinoid tumors pose an interesting diagnostic dilemma. Usually solid lesions, carcinoid tumors of the ovary most commonly occur in association with benign cystic teratomas or mucinous cystadenomas. Nuiiez and Diaz have described the similar cytologic features of carcinoid and granulosa cells. Immunocytochemistry would aid in differentiating the two cell types. The current era of modern technology has enabled radiologists to obtain material for cytologic analysis from remote body sites. The ovary has fast become one of these organs. With women seeking medical assistance for pelvic

disease and infertility problems, fine-needle aspiration of ovarian follicle cysts will become a mainstay in the future. Suzanne Selvaggi, M.D. Department of Pathology University of Michigan Ann Arbor, Michigan

References 1. Selvaggi SM. Cytology of non-neoplastic cysts of the ovary. Diagn Cytopathol 1990;6:77-85. 2. Stanlev MW. Horwitz CA. Frable WJ. Cellular follicular cv’its of the ovary: fluid cytology mimicking malignancy. Diagn Cytopathol 1991;7:48-52. 3. Selvaggi SM. Fine-needle aspiration cytology of ovarian follicle cysts with cellular atypia from reproductive-age patients. Diagn Cytopatho1 I99 l;7: 189-192. 4. Greenebaum E, Mayer JR, Stangel JJ, Hughes P. Aspiration cytology in ovarian cysts in in vitro fertilization patients. Acta Cytol 1992;36:11-18. 5. Selvaggi, SM. Aspiration cytology of the ovarian follicle cyst. Check Sample Series, ASCP. Cytopathology I. No. C92-4, 1992. 6. Kovacic J, Rainer S, Levicnik A, Cizelj T. Cytology of benign ovarian lesions in connection with laparoscopy. I n : ZajicekJ, ed. Aspirdtion biopsy cytology, 11. Cytology of infradiaphragmatic organs. Basel: Karger, 1979:57-79. 7. Ramzy I, Delaney M, Rose P. Fine needle aspiration of ovarian masses 11. Correlative cytologic and histologic study of non-neoplastic cysts and noncelomic epithelial neoplasms. Acta Cytol 1979;23: 185-193. 8. Ehya H, Lang WR. Cytology of granulosa cell tumor of the ovary. Am J Clin Pathol 1986;85:402405. 9. Ramzy I, Delaney M. Fine needle aspiratton of ovarian masses I . Correlative cytology and histologic study of celomic epithelial neoplasms. Acta Cytol 1979;23:95-104. 10. Pinto MM, Bernstein LH, Brogan DA, Parikh F, Lavy G. Measurement of CA125, carcinoembryonic antigen, and alpha-fetoprotein in ovarian cyst fluid: diagnostic adjunct to cytology. Diagn Cytopathol 1990;6:160-163.

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Ovarian follicular cysts: a potential source of false positive diagnoses in ovarian cytology.

The cytology samples of 22 benign ovarian cysts aspirated during laparoscopy (16) or laparotomy (6) were evaluated for clinicopathologic correlations...
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