BRIEF REPORTS
Cellular Follicular Cyst of the Ovary: Fluid Cytology Mimicking Malignancy Michael W. Stanley, M.D., Charles A. Horwitz, M.D., and William J. Frable, M.D.
We report three ovarian cysts studied by aspiration cytology. The fluids obtained were highly cellular, with numerous groups of atypical cells featuring a high nuclear-cytoplasmic ratio, nuclear hyperchromasia, and prominent nucleoli. In each case, these features were considered evidence of a low-grade malignant neoplasm. All three patients underwent oophorectomy, which revealed benign follicular cysts. Possible means of resolving the diagnostic dilemma posed by these cellular follicular cysts are discussed. Diagn Cytopathol 1991;7:48-52. Key Words: Carcinoma; Needle aspiration; Low-grade malignant neoplasm
A variety of cystic lesions affect the ovary, including physiologic follicular cysts (FC), simple cysts, cystic endometriosis, and corpus luteum cysts. Serous and mucinous neoplasms of benign, borderline, and malignant nature are usually cystic and constitute the most clinically important group of ovarian masses. Several less common neoplasms may be focally or extensively cystic, including teratomas, granulosa cell tumors, and Brenner tumors. Fluid from this wide range of lesions can be obtained for cytologic evaluation. Cyst aspiration can be performed at the time of laparoscopy or laparotomy, as well as by a transcutaneous approach with radiographic or ultrasonographic guidance. FC are commonly encountered, and, although they are benign by ultrasound criteria (thin walled, unilocular, and lacking solid areas), ’,* they may occasionally be as large as 5-8 cm.3,4Thus they make Received April 25, 1990. Accepted July 30, 1990. From the Departments of Pathology at the Hennepin County Medical Center and the University of Minnesota, Minneapolis, MN; Metropolitan-Mt. Sinai Medical Center, Minneapolis, MN; Virginia Commonwealth University, Health Sciences Division, Medical College of Virginia, Richmond, VA Presented in part at the November 1990 meeting of the American Society of Cytology, Washington, DC. Address reprint requests to Michael W. Stanley, M.D. Hennepin County Medical Center, Department of Pathology (815), 701 Park Avenue South, Minneapolis, MN 55415.
48
Diagnostic Cytopathology, Vol 7, No I
tempting targets for aspiration by physicians seeking to explain a patient’s symptoms or to exclude the presence of malignancy. Most FC aspirates have been illustrated with air-dried, Romanovsky-stained material, and the usual cytologic picture is that of a clear, cell-free fluid.5 In some cases, however, numerous cells have been described.3,6 In one such study of 155 FC aspirations stained by the Romanovsky method, 36 contained small numbers of atrophic cells, 2 were acellular, and 117 (75.5%) contained numerous granulosa cells from the cyst lining. Call-Exner bodies may also be encountered. We report three patients in whom aspiration of small, incidentally discovered ovarian cysts yielded highly cellular, cytologically atypical cells initially felt to represent malignancies. In each case, surgical excision revealed FC. We designated the cytologic pattern to be described as cellular follicular cyst (CFC).
Patient Histories Case
I
This 36-yr-old female had a pelvic mass clinically thought to represent a myomatous uterus. Diagnostic laparoscopy was undertaken because of the patient’s extreme anxiety; her sister had recently expired at age 34 yr with ovarian carcinoma. This evaluation revealed multiple uterine leiomyomas and a 2-cm left ovarian cyst from which 2 ml of clear, yellow fluid was aspirated. Uterine adhesions were attributed to previous Cesarean sections. Following cytologic study of the cyst fluid, total abdominal hysterectomy with bilateral salpingo-oophorectomy, biopsy of adhesions, lymph node sampling, and pelvic washings were performed. There was no evidence of malignancy. Case 2
This 27-yr-old nulliparous female underwent diagnostic laparotomy for evaluation of pelvic pain. Uterine myo0 1991 WILEY-LISS, INC.
FOLLICULAR OVARIAN CYST MIMICKING MALIGNANCY
mectomy and removal of a left ovarian cyst were performed. One milliliter of clear fluid was aspirated from a 1-cm right ovarian cyst. After examination of the cyst fluid, she underwent repeat surgery and right oophorectomy. Pelvic washings, as well as the resected ovary, showed no evidence of malignancy.
Case 3 This 4 I-yr-old female underwent diagnostic laparoscopy for evaluation of pelvic pain and menstrual irregularity. A small ovarian cyst was aspirated. Following cytologic study of this fluid, the ovary was surgically excised. No malignancy was found.
Materials and Methods Cyst fluids were processed for cytologic examination using standard techniques, including cytocentrifugation (case l), smears of whole specimen centrifuge pellet (case 2), and membrane filtration (case 3). All slides were fixed in 95% ethanol after which a Papanicolaou stain was applied. Surgically resected tissues were formalin fixed and paraffin embedded. Sections were stained with hematoxylin and eosin.
Results The three specimens were cytologically quite similar with very high cellularity apparent at low magnification (Fig. C-IA). The fluid was bloody only in case 2. Both single cells and cell groups of variable size were noted. The single cells ranged from well preserved to pyknotic and degenerated. In cases not prepared by membrane filtration, fragments of cytoplasm and a proteinaceous precipitate were present, initially suggesting necrosis as might be expected in a malignant neoplasm. Cell groups were usually threedimensional and showed smooth, scalloped, or ragged borders. The latter pattern gave the impression of dyscohesion. Individually, the cells had a high nuclear-cytoplasmic ratio and featured a thin rim of cyanophilic cytoplasm with fine vacuolization (Fig. C-1B). Spherical groups were strikingly similar to the appearance of breast carcinoma in body cavity fluid specimens (Fig. C-2A). Less commonly, three-dimensional branching groups with a smooth border were distinctly papillary (Fig. C-2B). Occasional mitotic figures were seen within cell groups. The nuclei were mostly round, with only slight size variation. Moderate hyperchromasia, distinct chromatin, and the presence of one or more small nucleoli were also noted. Some cells showed mild irregularities of chromatin distribution with small areas of parachromatin clearing. In case 3, rare groups of cells surrounded a clear central lumen, suggesting Call-Exner body formation (Fig. C-3). The histology of the resected ovaries from all three cases showed follicular cysts with no evidence of malig-
nancy. These cysts were lined by several layers of small dark granulosa cells (Fig. C-4) that were hyperchromatic with scanty cytoplasm and frequent small nucleoli (Fig. C-4). Surrounding these were theca cells with variable degrees of luteinization. In one instance (case l), large groups of follicular cells were floating in the cyst lumen (Fig. C-5). Associated with this was a proteinaceous precipitate. Within these groups were single necrotic cells similar to the degenerated cells described cytologically.
Discussion We describe three cases of CFC in which the cytologic findings were sufficiently provocative to eventuate in oophorectomy. In each case, the fluids proved to have originated in benign physiologic cysts of the follicular type. In case 1, the resection specimen showed a highly cellular cyst lumen that might explain the cytologic presentation (Fig. C-5). In the remaining cases, however, no histologic explanation for the extreme fluid cellularity was forthcoming. The atypia was similar in cytologic (Fig. C-1B) and histologic (Fig. C-4) preparations. These alarming nuclear features apparently reflect the metabolic activity of follicle maturation rather than neoplasia. Their significance is that, coupled with high cellularity and numerous large cell groups, they strongly suggest a process of low-grade malignancy. The differential diagnostic considerations that arise from cytologic study of CFC include cystic granulosa cell tumor and low-grade surface epithelial neoplasms (borderline or malignant). Granulosa cell tumor (GCT) is suggested by high fluid cellularity, a monotonous pattern of small cells with a high nuclear-cytoplasmic ratio and Call-Exner bodies. Since GCT and F C represent neoplastic and physiologic proliferations of a single cell type, it is not possible at this time to devise immunohistochemical or functional measurements that could be used to differentiate these entities. It has been suggested that high cyst fluid content of estradiol can be used to differentiate FC from other types of cysts. 1*7,8 Because GCT also produces estrogens, it is unlikely that such measurements would be helpful. In our experience with aspiration of a single case of GCT, the cells were smaller than those of CFC and showed striking nuclear folds and irregularities of contour. Furthermore, the easily identified nucleoli and hyperchromasia typical of CFC were not present (Fig. C-6). Similar findings were noted in four previously reported cases. 9,10 Serous surface epithelial neoplasms are much more common than GCT and thus represent the most serious differential diagnostic consideration. This difficulty extends to benign, borderline, and well-differentiated malignant forms. Our cases demonstrate the difficulty in separating these entities on morphologic grounds. Indeed, high fluid cellularity and the presence of numerous large solid cell groups were strongly suggestive of a sufficiently prolifDiagnostic Cytopatholngy, Vnl 7, No I
49
Fig. C-1’4
Fig. C-1B
Fig. C-2A
Fig. C-3
Fig. C-4
Fig. C-5
Fig. C-6
Fig. C-2B
Figs. C - 1 4 - 6 . Fig. C-1. (A) Case 3. This membrane filter preparation of ovarian cyst fluid shows extremely high cellularity, featuring both single cells and large, three-dimensional cell groups. Ragged group borders suggest dyscohesion (Papanicolaou stain, X 125). (B) Case 1. Cellular details include scant, cyanophilic cytoplasm with fine vacuolization. Nuclei are round and hyperchromatic with distinct chromatin and small nucleoli (Papanicolaou stain, X 1,250). Fig. C-2. (A) Case 2. This spherical group of follicular cyst lining cells is tightly cohesive with a smooth group border. Individual cell nuclei can be appreciated at the edge of the group (Papanicolaou stain, X 1,250). (B) Case 2. Occasional branching, three-dimensional groups with smooth borders had a distinctly papillary appearance (Papanicolaou stain, x 600). Fig. C-3. Case 3. Occasional cell groups with a central lumen suggested Call-Exner bodies. These structures are normally found in the wall of maturing follicles, but their presence in a cellular ovarian cyst fluid might suggest a granulosa cell tumor. This type of neoplasm frequently has a cystic component (Papanicalaou stain, X 1,250). Fig. C-4. Case 2. The lining of this follicular cyst consists of several layers of small uniform granulosa cells that are similar to those seen in the cyst fluids (H&E, X600). Fig. C-5. Case 1. This follicular cyst shows large groups of granulosa cells floating in its lumen. This finding is very unusual in the authors’ experience, but might help to explain some examples of highly cellular fluids from such cysts (H&E, X 125). Fig. C-6. This aspiration specimen from a proven example of granulosa cell tumor shows cells that are smaller than those of the follicular cysts. Furthermore, these cells have more irregular nuclear contours with prominent nuclear grooves and demonstrate only occasional nucleoli (Papanicolaou stain, X 1,250).
FOLLICULAR OVARIAN CYST MIMICKING MALIGNANCY
erative lesion to warrant suspicion of a borderline or malignant process. Perhaps biochemical or immunohistochemical distinction would be possible, Pinto et al. found that fluid levels of the ovarian carcinoma-associated antigen CA125 were very low in F C but elevated in both benign and malignant epithelial neoplasms. Further work confirming this observation could be useful in evaluation of difficult cases with the cytologic features of CFC. Application of this method would require that fluid remaining after centrifugation or filtration be stored prospectively in a frozen state suitable for analysis of protein antigens. Unpublished observations by one of the authors (M.W.S.) indicate that the granulosa cells lining FC are immunohistochemically negative for cytokeratins (monoclonal antibodies AE-1 and AE-3 were applied to paraffin-embedded tissue sections without predigestion). Welldifferentiated surface epithelial neoplasms generally express cytokeratins. Therefore, positive staining might exclude a diagnosis of CFC. Further work with both CAI 25 analysis and cytokeratin immunostaining is needed. Selvaggi l 2 recently described two cases that occurred 6 and 8 mo postpartum and were cytologically similar to CFC. She designated these lesions as follicular cysts with cellular atypia. Both patients were alive and well 1 and 2 yr after cyst aspiration. Neither was subjected to oophorectomy. Rodin et al. l 3 described four cytologically benign cysts occurring in pregnancy and the postpartum period that were treated by ultrasonographically guided aspiration. Three of the four resolved sonographically. The fourth persisted, and resection revealed a benign serous cystadenoma. The cases reported by Selvaggi may be similar to those described in histologic terms by Clement and Scully4 as “large solitary luteinized follicular cysts of pregnancy and puerperium.” These lesions were up to 26 cm in diameter and showed bizarre cells in the cyst linings. The authors ascribed development of such lesions to excessive gonadotropin stimulation. They also warn of the possible confusion of large FC with GCT. The cystic lesions described by Selvaggi, Rodin et al., and Clement and Scully bear certain similarities to those in this report but are set apart by their occurrence during or near the time of pregnancy. Diagnostic needle aspiration of ovarian masses has been used extensively in several European centers 3,6,14 but has not been widely accepted in North America. Without examining the data that underly these contrasting points of view, Table I summarizes some of the published reasons given by several authors for their unwillingness to embrace this method. To this chorus we add our description of the difficulties encountered with the cases in this report. Furthermore, we add our support to that of Dr. Koss for the suggested indications for ovarian aspiration 8,15718
Table I. Published Objections to Diagnosis of Ovarian Masses by Needle Aspiration Objections
References
1. Aspiration may “transform a potentially curable tumor into an incurable one” by tumor spillage. This makes aspiration a high-risk procedure with little justification 2. It is difficult to distinguish borderline tumors from malignant neoplasms by cytology alone 3. Ovarian tumors are histologically very diverse and cannot always be reliably classified in cytologic preparations 4. Proper treatment requires precise knowledge of tumor type and stage, which can only be obtained surgically 5. Aspiration is often a redundant and unnecessary procedure, because excision is usually required for proper management 6. 1.6% incidence of postaspiration pelvic infections following transvaginal or transrectal aspiration (n = 191 ualoable ovarian masses)
16,17,19
17 15
17
16,17
8
advanced by Geier and Strecker. * These are limited to the following: “( 1) recurrence of a previously diagnosed and treated ovarian cancer, (2) rare cases of poor physical condition of patients that does not allow laparotomy and (3) in benign cysts, the possible derivation of some additional information by measurement of the unconjugated estradiol- 17.” As noted previously, the third indication may be of limited utility. When clinical judgment deems ovarian cyst aspiration appropriate, additional information might improve the accuracy of cytologic interpretation. Such features as a thick cyst wall, surface irregularities, and failure of complete collapse following aspiration would point toward a malignancy. Thus accurate clinical correlation is essential.
Acknowledgments Case 3 was contributed by Dr. Rosalyn I. Andrews, Lexington Memorial Hospital, Lexington, North Carolina.
References 1. Buckley CM. Is needle aspiration of ovarian cysts adequate for diagnosis? J Obstet Gynecol 1989;96:1021-23. 2. Hall DA, McCarthy KA. The significance of the postmenopausal simple adnexal cyst. J Ultrasound Med 1986;5:507-9. 3. KovaEiE J, Rainer S, LeviEnik. Aspiration cytology of normal structures and non-neoplastic cysts of the ovary. In: Blaustein A, ed. Pathology of the female genital tract. 2nd ed. New York: SpringerVerlag, 1982:71 6 2 4 . 4. Clement PB, Scully RE. Large solitary luteinized follicle cyst of pregnancy and puerperium: A clinicopathological analysis of eight cases. Am J Surg Pathol 1980;4:431-8. 5 . Zajicek J. The aspiration biopsy smear. In: Koss LG, ed. Diagnostic cytology and its histopathologic basis. 3rd ed. Philadelphia: JB Lippincott Co., 1979:1085-6. 6. KovaEiE J, Raines S, LeviEnik, Cizelj T. Cytology of benign ovarian lesions in connection with laparoscopy. In: Zajicek J, ed. Aspiration Diagnostic Cytopathology, Vol 7, No I
51
STANLEY ET AL.
7.
8.
9. 10.
11.
12.
52
biopsy cytology, Part 2: cytology of Infradiaphragmatic organs. Basel: Karger, 1979:58-61. DeCrespigny L CH, Robinson HP, Davoren RAM, Fortune D: The “simple” ovarian cyst: Aspirate or operate. J Obstet Gynecol 1989; 96:1035-9. Geier GR, Strecker JR: Aspiration cytology and E, content in ovarian tumors. Acta Cytol 1981;25:400-6. Ehya H, Lang WR. Cytology of granulosa cell tumor of the ovary. Am J Clin Pathol 1986;85:402-5. Fidles WJ. Recurrent granulosa cell tumor: Aspiration cytology findings. Acta Cytol 1982;26:688-90. Pinto MM, Bernstein LH, Brogan DA: Measurement of CA-125, carcinoembryonic antigen and alpha fetoprotein in ovarian cyst fluids: Diagnostic adjunct to cytology. Acta Cytol 1988;32:747. Selvaggi SM. Cytologic features of luteinized follicle cysts with cellular atypia from postpartum patients. Acta Cytol 1989;33:711-2.
Diagnostic Cyiopaihology, Vol 7,No 1
13. Rodin A, Coltart TM, Chapman MG: Needle aspiration of simple ovarian cysts in pregnancy: Case reports. J Obstet Gynecol 1989;96: 994-6. 14. Kjellgren 0, Angstrom T, Bergman F, Wiklund D-E: Fine needle aspiration biopsy in diagnosis and classification of ovarian carcinoma. Cancer 1971;28:967-76. 15. Ganjei P, Nadji M: Aspiration cytology of ovarian neoplasms: A review. Acta Cytol 1984;28:329-32. 16. Koss LG, Woyke S, Olszewski W. Aspiration biopsy: cytologic interpretation and histologic bases. New York: Igaku-Shoin, 1984:416. 17. Hajdu SI, Melamed MR: Limitations of aspiration cytology in the diagnosis of primary neoplasms. Acta Cytol 1984;28:33745. 18. Diernaes E, Rasmussen J, Soerensen T, Hasch E: Ovarian cysts: Management by puncture? Lancet 1987;2:1084. 19. Christopherson WM: Cytologic detection and diagnosis of cancer: Its contributions and limitations. Cancer 1983;51:1201-8.
Cellular Follicular Cyst of the Ovary: Fluid Cytology Mimicking Malignancy Michael W. Stanley, M.D., Charles A. Horwitz, M.D., and William J. Frable, M.D.
We report three ovarian cysts studied by aspiration cytology. The fluids obtained were highly cellular, with numerous groups of atypical cells featuring a high nuclear-cytoplasmic ratio, nuclear hyperchromasia, and prominent nucleoli. In each case, these features were considered evidence of a low-grade malignant neoplasm. All three patients underwent oophorectomy, which revealed benign follicular cysts. Possible means of resolving the diagnostic dilemma posed by these cellular follicular cysts are discussed. Diagn Cytopathol 1991;7:48-52. Key Words: Carcinoma; Needle aspiration; Low-grade malignant neoplasm
A variety of cystic lesions affect the ovary, including physiologic follicular cysts (FC), simple cysts, cystic endometriosis, and corpus luteum cysts. Serous and mucinous neoplasms of benign, borderline, and malignant nature are usually cystic and constitute the most clinically important group of ovarian masses. Several less common neoplasms may be focally or extensively cystic, including teratomas, granulosa cell tumors, and Brenner tumors. Fluid from this wide range of lesions can be obtained for cytologic evaluation. Cyst aspiration can be performed at the time of laparoscopy or laparotomy, as well as by a transcutaneous approach with radiographic or ultrasonographic guidance. FC are commonly encountered, and, although they are benign by ultrasound criteria (thin walled, unilocular, and lacking solid areas), ’,* they may occasionally be as large as 5-8 cm.3,4Thus they make Received April 25, 1990. Accepted July 30, 1990. From the Departments of Pathology at the Hennepin County Medical Center and the University of Minnesota, Minneapolis, MN; Metropolitan-Mt. Sinai Medical Center, Minneapolis, MN; Virginia Commonwealth University, Health Sciences Division, Medical College of Virginia, Richmond, VA Presented in part at the November 1990 meeting of the American Society of Cytology, Washington, DC. Address reprint requests to Michael W. Stanley, M.D. Hennepin County Medical Center, Department of Pathology (815), 701 Park Avenue South, Minneapolis, MN 55415.
48
Diagnostic Cytopathology, Vol 7, No I
tempting targets for aspiration by physicians seeking to explain a patient’s symptoms or to exclude the presence of malignancy. Most FC aspirates have been illustrated with air-dried, Romanovsky-stained material, and the usual cytologic picture is that of a clear, cell-free fluid.5 In some cases, however, numerous cells have been described.3,6 In one such study of 155 FC aspirations stained by the Romanovsky method, 36 contained small numbers of atrophic cells, 2 were acellular, and 117 (75.5%) contained numerous granulosa cells from the cyst lining. Call-Exner bodies may also be encountered. We report three patients in whom aspiration of small, incidentally discovered ovarian cysts yielded highly cellular, cytologically atypical cells initially felt to represent malignancies. In each case, surgical excision revealed FC. We designated the cytologic pattern to be described as cellular follicular cyst (CFC).
Patient Histories Case
I
This 36-yr-old female had a pelvic mass clinically thought to represent a myomatous uterus. Diagnostic laparoscopy was undertaken because of the patient’s extreme anxiety; her sister had recently expired at age 34 yr with ovarian carcinoma. This evaluation revealed multiple uterine leiomyomas and a 2-cm left ovarian cyst from which 2 ml of clear, yellow fluid was aspirated. Uterine adhesions were attributed to previous Cesarean sections. Following cytologic study of the cyst fluid, total abdominal hysterectomy with bilateral salpingo-oophorectomy, biopsy of adhesions, lymph node sampling, and pelvic washings were performed. There was no evidence of malignancy. Case 2
This 27-yr-old nulliparous female underwent diagnostic laparotomy for evaluation of pelvic pain. Uterine myo0 1991 WILEY-LISS, INC.
FOLLICULAR OVARIAN CYST MIMICKING MALIGNANCY
mectomy and removal of a left ovarian cyst were performed. One milliliter of clear fluid was aspirated from a 1-cm right ovarian cyst. After examination of the cyst fluid, she underwent repeat surgery and right oophorectomy. Pelvic washings, as well as the resected ovary, showed no evidence of malignancy.
Case 3 This 4 I-yr-old female underwent diagnostic laparoscopy for evaluation of pelvic pain and menstrual irregularity. A small ovarian cyst was aspirated. Following cytologic study of this fluid, the ovary was surgically excised. No malignancy was found.
Materials and Methods Cyst fluids were processed for cytologic examination using standard techniques, including cytocentrifugation (case l), smears of whole specimen centrifuge pellet (case 2), and membrane filtration (case 3). All slides were fixed in 95% ethanol after which a Papanicolaou stain was applied. Surgically resected tissues were formalin fixed and paraffin embedded. Sections were stained with hematoxylin and eosin.
Results The three specimens were cytologically quite similar with very high cellularity apparent at low magnification (Fig. C-IA). The fluid was bloody only in case 2. Both single cells and cell groups of variable size were noted. The single cells ranged from well preserved to pyknotic and degenerated. In cases not prepared by membrane filtration, fragments of cytoplasm and a proteinaceous precipitate were present, initially suggesting necrosis as might be expected in a malignant neoplasm. Cell groups were usually threedimensional and showed smooth, scalloped, or ragged borders. The latter pattern gave the impression of dyscohesion. Individually, the cells had a high nuclear-cytoplasmic ratio and featured a thin rim of cyanophilic cytoplasm with fine vacuolization (Fig. C-1B). Spherical groups were strikingly similar to the appearance of breast carcinoma in body cavity fluid specimens (Fig. C-2A). Less commonly, three-dimensional branching groups with a smooth border were distinctly papillary (Fig. C-2B). Occasional mitotic figures were seen within cell groups. The nuclei were mostly round, with only slight size variation. Moderate hyperchromasia, distinct chromatin, and the presence of one or more small nucleoli were also noted. Some cells showed mild irregularities of chromatin distribution with small areas of parachromatin clearing. In case 3, rare groups of cells surrounded a clear central lumen, suggesting Call-Exner body formation (Fig. C-3). The histology of the resected ovaries from all three cases showed follicular cysts with no evidence of malig-
nancy. These cysts were lined by several layers of small dark granulosa cells (Fig. C-4) that were hyperchromatic with scanty cytoplasm and frequent small nucleoli (Fig. C-4). Surrounding these were theca cells with variable degrees of luteinization. In one instance (case l), large groups of follicular cells were floating in the cyst lumen (Fig. C-5). Associated with this was a proteinaceous precipitate. Within these groups were single necrotic cells similar to the degenerated cells described cytologically.
Discussion We describe three cases of CFC in which the cytologic findings were sufficiently provocative to eventuate in oophorectomy. In each case, the fluids proved to have originated in benign physiologic cysts of the follicular type. In case 1, the resection specimen showed a highly cellular cyst lumen that might explain the cytologic presentation (Fig. C-5). In the remaining cases, however, no histologic explanation for the extreme fluid cellularity was forthcoming. The atypia was similar in cytologic (Fig. C-1B) and histologic (Fig. C-4) preparations. These alarming nuclear features apparently reflect the metabolic activity of follicle maturation rather than neoplasia. Their significance is that, coupled with high cellularity and numerous large cell groups, they strongly suggest a process of low-grade malignancy. The differential diagnostic considerations that arise from cytologic study of CFC include cystic granulosa cell tumor and low-grade surface epithelial neoplasms (borderline or malignant). Granulosa cell tumor (GCT) is suggested by high fluid cellularity, a monotonous pattern of small cells with a high nuclear-cytoplasmic ratio and Call-Exner bodies. Since GCT and F C represent neoplastic and physiologic proliferations of a single cell type, it is not possible at this time to devise immunohistochemical or functional measurements that could be used to differentiate these entities. It has been suggested that high cyst fluid content of estradiol can be used to differentiate FC from other types of cysts. 1*7,8 Because GCT also produces estrogens, it is unlikely that such measurements would be helpful. In our experience with aspiration of a single case of GCT, the cells were smaller than those of CFC and showed striking nuclear folds and irregularities of contour. Furthermore, the easily identified nucleoli and hyperchromasia typical of CFC were not present (Fig. C-6). Similar findings were noted in four previously reported cases. 9,10 Serous surface epithelial neoplasms are much more common than GCT and thus represent the most serious differential diagnostic consideration. This difficulty extends to benign, borderline, and well-differentiated malignant forms. Our cases demonstrate the difficulty in separating these entities on morphologic grounds. Indeed, high fluid cellularity and the presence of numerous large solid cell groups were strongly suggestive of a sufficiently prolifDiagnostic Cytopatholngy, Vnl 7, No I
49
Fig. C-1’4
Fig. C-1B
Fig. C-2A
Fig. C-3
Fig. C-4
Fig. C-5
Fig. C-6
Fig. C-2B
Figs. C - 1 4 - 6 . Fig. C-1. (A) Case 3. This membrane filter preparation of ovarian cyst fluid shows extremely high cellularity, featuring both single cells and large, three-dimensional cell groups. Ragged group borders suggest dyscohesion (Papanicolaou stain, X 125). (B) Case 1. Cellular details include scant, cyanophilic cytoplasm with fine vacuolization. Nuclei are round and hyperchromatic with distinct chromatin and small nucleoli (Papanicolaou stain, X 1,250). Fig. C-2. (A) Case 2. This spherical group of follicular cyst lining cells is tightly cohesive with a smooth group border. Individual cell nuclei can be appreciated at the edge of the group (Papanicolaou stain, X 1,250). (B) Case 2. Occasional branching, three-dimensional groups with smooth borders had a distinctly papillary appearance (Papanicolaou stain, x 600). Fig. C-3. Case 3. Occasional cell groups with a central lumen suggested Call-Exner bodies. These structures are normally found in the wall of maturing follicles, but their presence in a cellular ovarian cyst fluid might suggest a granulosa cell tumor. This type of neoplasm frequently has a cystic component (Papanicalaou stain, X 1,250). Fig. C-4. Case 2. The lining of this follicular cyst consists of several layers of small uniform granulosa cells that are similar to those seen in the cyst fluids (H&E, X600). Fig. C-5. Case 1. This follicular cyst shows large groups of granulosa cells floating in its lumen. This finding is very unusual in the authors’ experience, but might help to explain some examples of highly cellular fluids from such cysts (H&E, X 125). Fig. C-6. This aspiration specimen from a proven example of granulosa cell tumor shows cells that are smaller than those of the follicular cysts. Furthermore, these cells have more irregular nuclear contours with prominent nuclear grooves and demonstrate only occasional nucleoli (Papanicolaou stain, X 1,250).
FOLLICULAR OVARIAN CYST MIMICKING MALIGNANCY
erative lesion to warrant suspicion of a borderline or malignant process. Perhaps biochemical or immunohistochemical distinction would be possible, Pinto et al. found that fluid levels of the ovarian carcinoma-associated antigen CA125 were very low in F C but elevated in both benign and malignant epithelial neoplasms. Further work confirming this observation could be useful in evaluation of difficult cases with the cytologic features of CFC. Application of this method would require that fluid remaining after centrifugation or filtration be stored prospectively in a frozen state suitable for analysis of protein antigens. Unpublished observations by one of the authors (M.W.S.) indicate that the granulosa cells lining FC are immunohistochemically negative for cytokeratins (monoclonal antibodies AE-1 and AE-3 were applied to paraffin-embedded tissue sections without predigestion). Welldifferentiated surface epithelial neoplasms generally express cytokeratins. Therefore, positive staining might exclude a diagnosis of CFC. Further work with both CAI 25 analysis and cytokeratin immunostaining is needed. Selvaggi l 2 recently described two cases that occurred 6 and 8 mo postpartum and were cytologically similar to CFC. She designated these lesions as follicular cysts with cellular atypia. Both patients were alive and well 1 and 2 yr after cyst aspiration. Neither was subjected to oophorectomy. Rodin et al. l 3 described four cytologically benign cysts occurring in pregnancy and the postpartum period that were treated by ultrasonographically guided aspiration. Three of the four resolved sonographically. The fourth persisted, and resection revealed a benign serous cystadenoma. The cases reported by Selvaggi may be similar to those described in histologic terms by Clement and Scully4 as “large solitary luteinized follicular cysts of pregnancy and puerperium.” These lesions were up to 26 cm in diameter and showed bizarre cells in the cyst linings. The authors ascribed development of such lesions to excessive gonadotropin stimulation. They also warn of the possible confusion of large FC with GCT. The cystic lesions described by Selvaggi, Rodin et al., and Clement and Scully bear certain similarities to those in this report but are set apart by their occurrence during or near the time of pregnancy. Diagnostic needle aspiration of ovarian masses has been used extensively in several European centers 3,6,14 but has not been widely accepted in North America. Without examining the data that underly these contrasting points of view, Table I summarizes some of the published reasons given by several authors for their unwillingness to embrace this method. To this chorus we add our description of the difficulties encountered with the cases in this report. Furthermore, we add our support to that of Dr. Koss for the suggested indications for ovarian aspiration 8,15718
Table I. Published Objections to Diagnosis of Ovarian Masses by Needle Aspiration Objections
References
1. Aspiration may “transform a potentially curable tumor into an incurable one” by tumor spillage. This makes aspiration a high-risk procedure with little justification 2. It is difficult to distinguish borderline tumors from malignant neoplasms by cytology alone 3. Ovarian tumors are histologically very diverse and cannot always be reliably classified in cytologic preparations 4. Proper treatment requires precise knowledge of tumor type and stage, which can only be obtained surgically 5. Aspiration is often a redundant and unnecessary procedure, because excision is usually required for proper management 6. 1.6% incidence of postaspiration pelvic infections following transvaginal or transrectal aspiration (n = 191 ualoable ovarian masses)
16,17,19
17 15
17
16,17
8
advanced by Geier and Strecker. * These are limited to the following: “( 1) recurrence of a previously diagnosed and treated ovarian cancer, (2) rare cases of poor physical condition of patients that does not allow laparotomy and (3) in benign cysts, the possible derivation of some additional information by measurement of the unconjugated estradiol- 17.” As noted previously, the third indication may be of limited utility. When clinical judgment deems ovarian cyst aspiration appropriate, additional information might improve the accuracy of cytologic interpretation. Such features as a thick cyst wall, surface irregularities, and failure of complete collapse following aspiration would point toward a malignancy. Thus accurate clinical correlation is essential.
Acknowledgments Case 3 was contributed by Dr. Rosalyn I. Andrews, Lexington Memorial Hospital, Lexington, North Carolina.
References 1. Buckley CM. Is needle aspiration of ovarian cysts adequate for diagnosis? J Obstet Gynecol 1989;96:1021-23. 2. Hall DA, McCarthy KA. The significance of the postmenopausal simple adnexal cyst. J Ultrasound Med 1986;5:507-9. 3. KovaEiE J, Rainer S, LeviEnik. Aspiration cytology of normal structures and non-neoplastic cysts of the ovary. In: Blaustein A, ed. Pathology of the female genital tract. 2nd ed. New York: SpringerVerlag, 1982:71 6 2 4 . 4. Clement PB, Scully RE. Large solitary luteinized follicle cyst of pregnancy and puerperium: A clinicopathological analysis of eight cases. Am J Surg Pathol 1980;4:431-8. 5 . Zajicek J. The aspiration biopsy smear. In: Koss LG, ed. Diagnostic cytology and its histopathologic basis. 3rd ed. Philadelphia: JB Lippincott Co., 1979:1085-6. 6. KovaEiE J, Raines S, LeviEnik, Cizelj T. Cytology of benign ovarian lesions in connection with laparoscopy. In: Zajicek J, ed. Aspiration Diagnostic Cytopathology, Vol 7, No I
51
STANLEY ET AL.
7.
8.
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