Ovarian Adenofibroma

Am J Surg Pathol. 2006 Aug;30(8):929-938. Abstract quote

Cellular fibroblastic tumors of the ovary are currently classified as either cellular fibroma (CF) or fibrosarcoma. The former are characterized by bland nuclei, 3 or fewer mitotic figures per 10 high-power fields (MFs/10 HPFs), and a low malignant potential, whereas fibrosarcomas usually have severe nuclear atypia, >/=4 MFs/10 HPFs, and an aggressive clinical course. The prognosis of cellular fibromatous tumors with >/=4 MFs/10 HPFs and low-grade cytology is not established and it is the purpose of this study to investigate that aspect. It has been our anecdotal experience that otherwise typical CFs with >/=4 MFs/10 HPFs usually have a benign clinical course, suggesting that such tumors should be regarded as "mitotically active cellular fibroma" (MACF) rather than fibrosarcoma.

Seventy-five cellular fibromatous neoplasms were analyzed to determine their clinicopathologic features and the appropriateness of "MACF" as a designation for otherwise typical CFs with >/=4 MFs/10 HPFs. The mean age of patients with CF (n=35, 0 to 3 MFs/10 HPFs) and MACF (n=40, >/=4 MFs/10 HPFs) was 51 and 41 years, respectively. Patients most commonly presented with symptoms related to a pelvic mass. All tumors were unilateral. The mean tumor size of CFs was 8.0 cm and 9.4 cm for MACFs. The majority of the tumors were solid; approximately one-third of them had a cystic component. Ovarian surface adhesions, involvement of the ovarian surface, or both, was present in 6% of CFs and 10% of MACFs. Eleven percent of CFs and 13% of MACFs were associated with extraovarian involvement. All tumors consisted of cellular, intersecting bundles of spindle cells with bland nuclear features. The mean highest mitotic count for MACFs was 6.7 MFs/10 HPFs (range 4 to 19 MFs/10 HPFs). Follow-up of 3 months to 12 years (mean 4.75 y) was available in 18 of the 40 patients with MACFs and was uneventful in all cases.

We conclude that cellular fibromatous neoplasms with bland cytology and elevated mitotic counts are associated with favorable patient outcome and should be diagnosed as MACF rather than fibrosarcoma, which usually have moderate to severe atypia and elevated mitotic rates.

As prior observations have shown that even typical CFs can occasionally recur locally, particularly if they are associated with rupture or adherence, long-term follow-up for patients with CFs and MACFs is appropriate.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

DISEASE ASSOCIATIONS	CHARACTERIZATION
BRCA1 AND BRCA2 MUTATIONS
Unexpected gynecologic neoplasms in patients with proven or suspected BRCA-1 or -2 mutations: implications for gross examination, cytology, and clinical follow-up. Agoff SN, Mendelin JE, Grieco VS, Garcia RL. Department of Cytology, Harborview Medical Center/University of Washington Medical Center, 1959 NE Pacific Street, Seattle, WA 98195-6100, U.S.A.	Am J Surg Pathol 2002 Feb;26(2):171-8 Abstract quote Identification of inheritable mutations associated with the development of malignancy has led to prophylactic surgeries to remove tissues at risk. We report seven unrelated patients with family histories of breast and/or ovarian cancer, five of whom underwent prophylactic salpingo-oophorectomy with hysterectomy. Four had proven BRCA-1 or -2 mutations. Malignant cells were found unexpectedly in the peritoneal washings of two patients, leading to the discovery of early-stage fallopian tube carcinoma. After changing the sampling technique at our institution, two more cases of unexpected fallopian tube carcinoma in situ were discovered. Another patient had a significant family history and underwent hysterectomy for uterine fibroids, leading to the discovery of fallopian tube carcinoma. Another patient with BRCA-1 mutation had unexpected widespread primary peritoneal papillary serous adenocarcinoma. The final patient had a borderline malignant clear cell adenofibroma. These cases underscore the importance of peritoneal cytology and thorough sampling in the management of patients undergoing hysterectomy with a family history of breast/ovarian cancer and/or known BRCA-1/BRCA-2 mutations. As prophylactic surgeries are becoming more common secondary to advances in molecular diagnostics, pathologists need to be aware that surgical specimens from these patients may require more rigorous examination to uncover early neoplastic changes.
BREAST CANCER AND THYROID DISEASE
The association of benign and malignant ovarian adenofibromas with breast cancer and thyroid disorders. Silva EG, Tornos C, Malpica A, Deavers MT, Tortolero-Luna G, Gershenson DM. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.	Int J Surg Pathol 2002 Jan;10(1):33-9 Abstract quote An unexpected association with breast cancer and thyroid disorders was found during a review of 91 cases of benign and malignant ovarian adenofibromas. Sixty-three tumors were benign, 11 had areas of borderline neoplasms, and 17 had a component of carcinoma. Such tumors were divided into glandular/cystic (61 cases) and papillary (30 cases) according to their gross and microscopic appearance. Among the 61 patients with glandular/cystic adenofibromas, 13 (21%) had breast cancer and 19 (31%) also had thyroid disorders. Among the 30 patients with papillary adenofibromas there were no cases of breast cancer and only 2 patients had thyroid disorders. The average age of the patients with ovarian adenofibroma and breast cancer or thyroid disorders was higher (66 years) than that of patients without breast cancer or thyroid disorders (55 years). More patients with breast cancer and thyroid disorders had bilateral adenofibromas than patients without breast cancer or thyroid disorders. We also reviewed the medical records of 100 patients with ovarian cancer without adenofibroma component, 100 patients with breast cancer, and 100 patients with ovarian and breast cancer. Six percent of patients with ovarian cancer had breast cancer and 16% of each one of these groups had thyroid disorders. This unexpected association found between glandular/cystic adenofibromas, breast cancer, and thyroid disorders might be explained by defects common to these organs. Disorders of some of these organs have been linked by common genetic changes and it is known that these organs are under the influence of similar hormones. Mutations of PTEN have been found in breast and thyroid cancer. The thyroid and ovaries are controlled by glycoprotein hormones of the pituitary gland, which have common alpha subunits.

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
Sonographic features of ovarian cystadenofibromas: spectrum of findings. Alcazar JL, Errasti T, Minguez JA, Galan MJ, Garcia-Manero M, Ceamanos C. Department of Obstetrics and Gynecology, Clinica Universitaria de Navarra, School of Medicine, University of Navarra, Pamplona, Spain.	J Ultrasound Med 2001 Aug;20(8):915-9 Abstract quote OBJECTIVE: To describe the sonographic characteristics of ovarian cystadenofibromas. METHODS: We conducted a retrospective study of 23 ovarian tumors histopathologically confirmed as ovarian cystadenofibromas that were preoperatively evaluated by transvaginal color Doppler sonography. RESULTS: In all cases the mass was predominantly cystic. Septations appeared in 30.4% of the tumors. Papillary projections or solid nodules appeared in 56.5% of the cases. The most frequent appearance was a unilocular complex cystic mass. In 47.8% of the tumors, vascularization was detected, having a typical pattern of peripheral vascularization with scattered vessels of high blood flow impedance. CONCLUSIONS: We have described the sonographic spectrum of findings of ovarian cystadenofibromas. The most frequent appearance was a unilocular cystic mass with gross papillary projections or solid nodules. In almost half of the tumors, vascularization could be detected.
LABORATORY MARKERS
Significant increases in serum CA125 and CA19-9 following torsion from an adenofibroma of the ovary: a case report. Fujiwara K, Moriya T, Mikami Y, Hiratsuka J, Sawada S, Imajo Y, Kohno I. Department of Obstetrics and Gynecology, Kawasaki Medical School, Kurashiki.	Jpn J Clin Oncol 1994 Apr;24(2):116-9 Abstract quote Significant increases in the serum levels of cancer antigen 125 (CA125) and carbohydrate antigen 19-9 (CA19-9) were observed over one month prior to the removal of an ovarian adenofibroma. The serum levels of CA125 and CA19-9 decreased rapidly after surgery. The surface of the tumor at surgery showed marked inflammation, probably induced by the necrosis produced by torsion. Pathologically, most of the tumor was necrotic, and histoimmunochemical staining of the viable cells was weak for CA125 but intense for CA19-9. Clinicopathological observations of the case suggested that CA125 and CA19-9 might be stimulated in the cells by inflammation or that originally existing CA125 and CA19-9 were released from the tumor cells following the cell necrosis.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIANTS
HYPERREACTIO LUTEINALIS
Bilateral serous cystadenofibromas clinically simulating hyperreactio luteinalis following controlled ovarian hyperstimulation and in vitro fertilization. Ditkoff EC, Tucker T, Levine RU, Lindheim SR, Sauer MV, Longacre T. Department of Obstetrics and Gynecology, Columbia-Presbyterian Medical Center, Columbia University, New York, New York 10032, USA.	J Assist Reprod Genet 1997 Apr;14(4):230-3 Abstract quote We report a case of bilateral serous cystadenofibromas clinically simulating hyperreactio luteinalis during a normal pregnancy resulting from controlled ovarian stimulation and in vitro fertilization. Incomplete regression at 2-year follow-up prompted surgical intervention. This case demonstrates that the clinical and sonographic features that have been associated with hyperreactio luteinalis are not specific for this condition and emphasizes the need for close clinical follow-up in all presumptive cases for which a histologic diagnosis has not been established.
PARAOVARIAN
Multicentric ovarian and extraovarian cystadenofibroma. Hafiz MA, Toker C.	Obstet Gynecol 1986 Sep;68(3 Suppl):94S-98S Abstract quote A case of multicentric ovarian and diffuse pelvic cystadenofibroma is described. Despite multicentricity, the histologic findings are completely benign. Electron microscopy was performed and possible mesothelial origin is discussed.
Paraovarian cystadenomas and cystadenofibromas: sonographic characteristics in 14 cases. Korbin CD, Brown DL, Welch WR. Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.	Radiology 1998 Aug;208(2):459-62 Abstract quote PURPOSE: To describe the sonographic features of paraovarian cystadenomas. MATERIALS AND METHODS: We searched the computerized pathology and radiology databases for cases of histopathologically proved paraovarian cystadenomas from January 1993 through December 1996 in which preoperative sonography had also been performed. Fourteen paraovarian cystadenomas or cystadenofibromas were identified in 14 patients aged 20-57 years. Sonographic and pathologic findings were correlated. RESULTS: Three of the masses appeared as simple cysts sonographically. Of the remaining 11 masses, nine had solid nodular areas within the cyst; three had septations; and four had a thick wall, an irregular wall, or both at sonography. At sonography, four masses were thought to arise outside the ovary, four were erroneously thought to arise in the ovary, and the location was uncertain in six. CONCLUSION: Paraovarian cystadenomas are cystic masses that usually contain one or more small solid nodules and occasionally contain septations.

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
Cystadenofibromas of the ovary with epithelial atypia. Kao GF, Norris HJ.	Am J Surg Pathol 1978 Dec;2(4):357-63 Abstract quote Epithelial atypia is rarely encountered in ovarian cystadenofibromas. Ten examples are reported with cytological features identical to serous tumors with low malignant potential. In two neoplasms the epithelium resembled an atypical endometrial hyperplasia, and one of these had squamous metaplasia. These two neoplasms probably qualify as endometrioid tumors of low malignant potential. None of the 10 patients had recurrence following excision of their neoplasm, and no similar patients have been encountered with neoplasms in more advanced stages. Even though aggressive behavior has not yet been established, the histologic features suggest a low degree of malignant potential and long-term follow-up of patients is warranted. Cystadenofibromas iwth epithelial atypia probably have less malignant potential than serous tumors of low malignant potential possessing the same epithelial characteristics because cystadenofibromas with atypia have less epithelial surface area and the epithelium is enveloped by connective tissue more than it is in serous tumors of low malignant potential.
VARIANTS
ADENOSARCOMA
Adenosarcoma of the ovary. A light- and electron-microscopic study with review of the literature. Czernobilsky B, Gillespie JJ, Roth LM.	Diagn Gynecol Obstet 1982 Spring;4(1):25-36 Abstract quote This is a light- and electron-microscopic study of a large ovarian adenosarcoma in a 50-year-old woman as well as a review of the literature. The tumor showed a variety of mullerian type epithelia and a spectrum of stromal patterns including nonspecific fibroblastic, and endometrial type stroma. The latter ranged from normal-appearing to low-grade sarcoma. This study emphasizes the relationship of ovarian adenosarcoma to cystadenofibroma, on the one hand, and to malignant mixed mullerian (mesodermal) tumor, on the other. It appears that the mitotic count which is used as the primary means for the classification of smooth muscle and stromal tumors of the uterus, has less value in the assessment and prognostication of ovarian adenosarcomas.
Mesodermal (mullerian) adenosarcoma of the ovary: a clinicopathologic analysis of 40 cases and a review of the literature. Eichhorn JH, Young RH, Clement PB, Scully RE.	Am J Surg Pathol 2002 Oct;26(10):1243-58 Abstract quote Forty cases of mesodermal adenosarcoma of the ovary occurred in women 30-84 years of age (mean 54 years). Abdominal discomfort and distension were the usual complaints. All the patients were treated with an oophorectomy, which was accompanied by a hysterectomy in 85%, a contralateral oophorectomy in 65%, and nonsurgical therapy in 28%. Tumor rupture occurred at or before the operation in 67% of the cases. Twenty-six tumors were stage I, 11 stage II, and 3 stage III. The tumors were unilateral in 97.5% of the cases and 5.5-50 cm (mean 14 cm) in greatest dimension; most of the tumors were predominantly solid but contained numerous small cysts. Microscopic examination revealed sarcomatous overgrowth in 12 tumors. Sex cord-like elements were present in six tumors (including four with sarcomatous overgrowth) and heterologous elements in five (including two with sarcomatous overgrowth). The highest mitotic index of the sarcomatous component was 1-25 (mean 6) mitotic figures per 10 high power fields. Only 6 of 26 women (23%) who were followed postoperatively for >/=5 years were free of tumor. In the other 20 patients recurrent tumor appeared at 0.4-6.6 years (mean 2.6 years) after operation as pure sarcoma (low grade or high grade) or adenosarcoma (with or without sarcomatous overgrowth). Eight women had additional recurrences, and four women had blood-borne metastases. One patient was alive at 15.7 years after the excision of pulmonary metastases. The 5-, 10-, and 15-year survival rates were 64%, 46%, and 30%, respectively. Age <53 years, tumor rupture, a high grade, and the presence of high-grade sarcomatous overgrowth appeared to be associated with recurrence or extraovarian spread. Ovarian adenosarcomas have a worse prognosis than uterine adenosarcomas, presumably because of the greater ease of peritoneal spread. Many of the tumors caused problems in differential diagnosis.
CLEAR CELL
Ovarian clear cell adenofibromatous tumors. Benign, of low malignant potential, and associated with invasive clear cell carcinoma. Roth LM, Langley FA, Fox H, Wheeler JE, Czernobilsky B.	Cancer 1984 Mar 1;53(5):1156-63 Abstract quote The authors have studied 17 cases of ovarian clear cell tumors having an adenofibromatous pattern and classified them on a histologic basis into three categories: benign, of low malignant potential, and associated with invasive clear cell carcinoma. Clear cell adenofibroma is characterized by orderly tubules and glands lined by uniform epithelium with little or no nuclear atypia set in an abundant stroma with an interlacing pattern resembling ovarian stroma. Clear cell adenofibromatous tumors of low malignant potential had a similar stroma, but exhibited moderate to marked degrees of epithelial proliferation and atypia. In the third category there were cases of invasive clear cell carcinoma in which a distinct portion of the tumor met the criteria for clear cell adenofibroma, or clear cell adenofibromatous tumor of low malignant potential. Cases of invasive clear cell carcinoma exhibiting a desmoplastic reaction or a diffuse fibrous stroma, but lacking typical adenofibromatous areas, were not included in this study. The benign and low malignant potential tumors showed no clinical evidence of aggressive behavior, whereas those associated with invasive clear cell carcinoma often did. Although there have been no recurrences in our small group of patients with tumors of low malignant potential, the histologic similarity of the epithelium in these tumors to that seen in invasive carcinomas justifies such a categorization. Further studies of larger series using the proposed classification should yield more information concerning the biologic behavior of these types of clear cell adenofibromatous tumors.
ENDOMETRIOID ADENOCARCINOMA
Ovarian endometrioid adenocarcinoma coexistent with benign and borderline endometrioid adenofibroma: a case report. Ushijima K, Nishida T, Muraoka Y, Sugiyama T, Okura N, Shinagawa A, Imaishi K, Yakushiji M. Department of Obstetrics and Gynecology, Kurume University School of Medicine, Japan.	J Obstet Gynaecol Res 1998 Apr;24(2):161-6 Abstract quote A well-differentiated endometrioid adenocarcinoma coexistent with benign and borderline-malignant endometrioid adenofibroma was found in the ovary of a 64-year-old woman. She had vaginal bleeding caused by simple hyperplasia of the endometrium due to high levels of sex steroid hormones. A FIGO stage Ia solid ovarian tumor was identified. It was composed of irregularly shaped endometriotic glands with benign and borderline malignant cytologic features embedded in abundant fibromatous stroma. Well-differentiated malignant epithelium was adjacent to these areas, but fibromatous stroma was not predominant. She was treated by surgery and three cycles of chemotherapy. This paper describes this unusual tumor and reviews the literature.
MUCINOUS ADENOFIBROMA
Mucinous adenofibromas of the ovary. A report of 10 cases. Bell DA. Department of Pathology, Harvard Medical School, Boston, Massachusetts.	Am J Surg Pathol 1991 Mar;15(3):227-32 Abstract quote Mucinous epithelium is the most uncommon type identified in ovarian adenofibromas. Because of the rarity of mucinous adenofibromas and the presence of cytologic atypia in some, these neoplasms may be mistaken for low-grade metastatic adenocarcinoma. The clinicopathologic features of 10 mucinous adenofibromas are reviewed. They occurred in women 24 to 76 (mean, 51) years of age, were unilateral, and ranged in diameter from 1 to 25 cm. Seven tumors were classified as benign, containing glands lined by a single layer of mucin-containing columnar cells. Three tumors that contained crowded glands lined by mucin-containing cells with mild to moderate nuclear atypia, nuclear stratification of up to three cells in thickness, and focal tufting were classified as benign with epithelial atypia. Most women had a hysterectomy and bilateral salpingo-oophorectomy. Follow-up information was available on six women, who were alive and well from 6 to 126 (mean 41) months after diagnosis. The identification of mucinous glands in typical fibromatous stroma should allow the distinction of these benign neoplasms from metastatic carcinomas
Mucinous adenofibroma of the ovary: case report of the endocrinologic findings. Tohya T, Mizutani H, Katabuchi H, Miyazaki K, Okamura H. Department of Obstetrics and Gynecology, Kumamoto University School of Medicine, Japan.	Gynecol Oncol 1994 Aug;54(2):218-21 Abstract quote Endocrine and clinicopathologic findings in a 77-year-old woman with ovarian mucinous adenofibroma of borderline malignancy are reported. The preoperative levels of testosterone, androstenedione, estrone, and estradiol in her peripheral blood were 91 ng/ml, 3.78 ng/ml, 82 pg/ml, and 35 pg/ml, respectively, abnormally high. Those of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were < 0.5 mIU/ml and 12.1 mIU/ml, respectively. Total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. Pathologic diagnosis of the right ovarian tumor was mucinous adenofibroma of borderline malignancy with hyperthecosis. Postoperatively, the levels of sex steroids and gonadotropin returned to the normal range of a postmenopausal woman. The patient remains well 2 years and 6 months after the operation.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
CELLULAR FIBROMA
Cellular Fibromas of the Ovary: A Study of 75 Cases Including 40 Mitotically Active Tumors Emphasizing Their Distinction From Fibrosarcoma Irving JA, Alkushi A, Young RH, Clement PB. *Department of Pathology, Vancouver General Hospital and the University of British Columbia, Vancouver, BC, Canada daggerDepartment of Pathology and Laboratory Medicine, King Fahad National Guard Hospital, Riyadh, Saudi Arabia double daggerJames Homer Wright Pathology Laboratories of the Massachusetts General Hospital and Department of Pathology, Harvard Medical School, Boston, MA.	Am J Surg Pathol. 2006 Aug;30(8):929-938. Abstract quote Cellular fibroblastic tumors of the ovary are currently classified as either cellular fibroma (CF) or fibrosarcoma. The former are characterized by bland nuclei, 3 or fewer mitotic figures per 10 high-power fields (MFs/10 HPFs), and a low malignant potential, whereas fibrosarcomas usually have severe nuclear atypia, >/=4 MFs/10 HPFs, and an aggressive clinical course. The prognosis of cellular fibromatous tumors with >/=4 MFs/10 HPFs and low-grade cytology is not established and it is the purpose of this study to investigate that aspect. It has been our anecdotal experience that otherwise typical CFs with >/=4 MFs/10 HPFs usually have a benign clinical course, suggesting that such tumors should be regarded as "mitotically active cellular fibroma" (MACF) rather than fibrosarcoma. Seventy-five cellular fibromatous neoplasms were analyzed to determine their clinicopathologic features and the appropriateness of "MACF" as a designation for otherwise typical CFs with >/=4 MFs/10 HPFs. The mean age of patients with CF (n=35, 0 to 3 MFs/10 HPFs) and MACF (n=40, >/=4 MFs/10 HPFs) was 51 and 41 years, respectively. Patients most commonly presented with symptoms related to a pelvic mass. All tumors were unilateral. The mean tumor size of CFs was 8.0 cm and 9.4 cm for MACFs. The majority of the tumors were solid; approximately one-third of them had a cystic component. Ovarian surface adhesions, involvement of the ovarian surface, or both, was present in 6% of CFs and 10% of MACFs. Eleven percent of CFs and 13% of MACFs were associated with extraovarian involvement. All tumors consisted of cellular, intersecting bundles of spindle cells with bland nuclear features. The mean highest mitotic count for MACFs was 6.7 MFs/10 HPFs (range 4 to 19 MFs/10 HPFs). Follow-up of 3 months to 12 years (mean 4.75 y) was available in 18 of the 40 patients with MACFs and was uneventful in all cases. We conclude that cellular fibromatous neoplasms with bland cytology and elevated mitotic counts are associated with favorable patient outcome and should be diagnosed as MACF rather than fibrosarcoma, which usually have moderate to severe atypia and elevated mitotic rates. As prior observations have shown that even typical CFs can occasionally recur locally, particularly if they are associated with rupture or adherence, long-term follow-up for patients with CFs and MACFs is appropriate.
ENDOMETRIOID ADENOFIBROMAS
Ovarian endometrioid adenofibromatous and cystadenofibromatous tumors: benign, proliferating, and malignant. Roth LM, Czernobilsky B, Langley FA.	Cancer 1981 Oct 15;48(8):1838-45 Abstract quote Ovarian endometrioid tumors with an adenofibromatous pattern have been described but the entire spectrum of these tumors has not been analyzed. A series of ten cases was studied and divided into two benign, four proliferating, and four malignant tumors on the basis of their morphologic characteristics. The most useful criterion for distinguishing proliferating from benign adenofibromatous tumors is increased epithelial proliferation, associated with glandular complexity and crowding in the former. Proliferating tumors may represent one form of the endometrioid tumor of borderline malignancy. The presence of a confluent growth pattern with invasion of the stroma distinguishes malignant from proliferating tumors. The various tumors in this group frequently show squamous metaplasia and are often associated with endometriosis. Because of the relatively small series, the biologic behavior of these histologic variants cannot be evaluated at this time.