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Fibrosarcoma

Fibrosarcoma (fibroblastic sarcoma) is a malignant tumor derived from fibrous connective tissue and characterized by immature proliferating fibroblasts or undifferentiated anaplastic spindle cells. more...

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Pathology

The tumor may present different degrees of differentiation: low grade (differentiated), intermediate malignancy and high malignancy (anaplastic). Depending on this differentiation, tumor cells may resemble mature fibroblasts (spindle-shaped), secreting collagen, with rare mitoses. These cells are arranged in short fascicles which split and merge, giving the appearance of "fish bone". Poorly differentiated tumors consist in more atypical cells, pleomorphic, giant cells, multinucleated, numerous atypical mitoses and reduced collagen production. Presence of immature blood vessels (sarcomatous vessels lacking endothelial cells) favors the bloodstream metastasizing.

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Fibrosarcoma of the ovary arising in a fibrothecomatous tumor with minor sex cord elements: A case report and review of the literature
From Archives of Pathology & Laboratory Medicine, 1/1/03 by Lee, Hwei-Yee

* We report the case of a 69-year-old woman who presented with postmenopausal bleeding. Endometrial curettings showed complex atypical hyperplasia with focal welldifferentiated adenocarcinoma. A computed tomographic scan of the abdomen revealed a right ovarian mass. Histologically, the right ovarian tumor was a fibrothecoma with minor sex cord elements showing focal fibrosarcomatous change. Fibrosarcoma of the ovary is a rare tumor that is considered to arise de novo or secondary to benign fibromatous tumors. Fibrothecoma of the ovary with minor sex cord elements is also a rare entity. To the best of our knowledge, this is the first reported case of a fibrosarcoma arising in a fibrothecoma with minor sex cord elements.

(Arch Pathol Lab Med. 2003;127:81-84)

Fibrosarcoma is a rare entity in the ovary.1 A review of the literature yielded isolated reports of unilateral primary fibrosarcoma of the ovary2-4 and a rare case of bilateral ovarian fibrosarcoma following hysterectomy.5 Fibrosarcoma has also been reported in association with the basal cell nevus syndrome6 and Maffucci syndrome.7 Dudzinski et al8 described a malignant luteinized thecoma in a 13-year-old girl. Fibrosarcoma may arise de novo or as a result of malignant change in a benign fibromatous or fibrothecomatous tumor of the ovary.1 The presence of minor sex cord elements in a fibrothecoma, defined as sex cord elements occupying less than 10% of the average cross-sectional area of the tumor, is also rare.9 We describe a case of fibrosarcoma arising in a fibrothecomatous tumor containing minor sex cord elements. We found evidence of hormone production with diffuse complex atypical hyperplasia and focal well-differentiated endometrioid carcinoma of the endometrium presenting as postmenopausal bleeding. To our knowledge, the presence of minor sex cord elements in a fibrothecomatous tumor showing malignant change has not been described in the English literature to date.

REPORT OF A CASE

A 69-year-old Chinese woman presented with postmenopausal bleeding. Endometrial curettage showed complex atypical hyperplasia and focal adenocarcinoma. A computed tomographic scan of the abdomen revealed a solid mass in the right adnexa measuring 11.6 x 9.5 x 9 cm, with focal cystic change. The intraoperative findings included a large right ovarian mass, which was focally adherent to the peritoneum of the ovarian fossa, as well as minimal ascites. The contralateral ovary was grossly normal. A total hysterectomy and bilateral salpingo-oophorectomy were performed.

MATERIALS AND METHODS

The surgical specimen was fixed in formalin, and sections for histologic examination were routinely processed in paraffin wax and stained with hematoxylin-eosin. Reticulin stains were performed on selected blocks of the ovarian tumor. A formal mitotic count was carried out on all the representative sections of the ovarian tumor by recording the number of mitotic figures in 50 consecutive high-power fields (HPF) and calculating the average per 10 HPF. Immunohistochemical stains were performed with a standard streptavidin-biotin-peroxidase method (Dako Corporation, Carpinteria, Calif). Selected sections of the tumor were stained with monoclonal antibodies to inhibin (1:40, Oxford, Oxfordshire, United Kingdom) and MIB-1 (1:200, Immunotech, Marseille, France). Immunohistochemistry was performed using appropriate positive and negative controls.

The MIB-1 labeling index was established using the method described by Tsuji et al,10 in which a count of the MIB-1-labeled nuclei was made in the most evenly and distinctly labeled areas of the tumor. The MIB-1 labeling index was then expressed as a percentage of MIB-1-positive cells based on the count of 1000 tumor cells.

PATHOLOGIC FINDINGS

Grossly, the right ovary measured 13 x 8.5 X 6 cm. The external surface was smooth, except for a capsular defect measuring 4 cm, which was created during surgical removal of the tumor from its focal adherence to the peritoneum. Sectioning revealed a predominantly solid, firm, yellow-grey mass containing an area of cystic degeneration measuring 6 cm filled with bloody fluid and blood clots. The left ovary and the fallopian tubes showed no gross pathology. Sectioning the uterus revealed an irregular endometrial cavity with multifocal polypoid thickenings of the endometrium of up to 1 cm. No gross evidence of myometrial invasion was present. The myometrium was distorted by multiple fibroids, the largest measuring 6.6 cm.

Histologically, the right ovarian tumor was composed of uniform spindle cells arranged in sheets and intersecting fascicles. The stroma showed loose areas as well as more fibrous areas containing intercellular collagen. In some areas, thick hyaline fibrous plaques could be observed. Focally, the spindle cells showed abundant vacuolated cytoplasm, characteristic of thecal differentiation. The nuclei were bland and slim with pointed ends and indistinct nucleoli. The mitotic count in these areas averaged less than 3 per 10 HPF.

Interspersed among the fascicles of bland spindle cells were small, well-demarcated, relatively closely packed aggregates of cells showing oval to angular nuclei with prominent nuclear grooves and scanty cytoplasm (Figures 1 and 2, A). The cell islands were further demarcated from the surrounding stroma by reticulin condensation around groups of cells. The characteristic morphology and positive immunohistochemical staining with inhibin identify these as islands of granulosa cells (Figure 2, B).

Also present were cohesive groups of polyhedral cells with abundant clear cytoplasm and uniform round nuclei, characteristic of steroid-type cells (Figure 3, A). No crystalloids of Reinke were identified. Reticulin condensation was also seen around these cell islands, and they were likewise positive for inhibin (Figure 3, B). The granulosa and steroid cell islands occupied less than 5% to 10% of the surface area of any tumor section, and the largest island measured 2 mm. The overall interpretation was that of a fibrothecomatous tumor with a minor sex cord component.

Focally within the tumor, however, there were also hypercellular areas of spindle cell proliferation in which the cells were arranged in tight, parallel, intersecting fascicles creating a diffuse herringbone appearance (Figure 4). There was mild to moderate nuclear atypia with enlarged, hyperchromatic, and oblong pleomorphic nuclei showing increased vesiculation and more prominent nucleoli (Figure 5). The mitotic count in these areas varied from 6 to 8 per 10 HPF. These features, particularly the increased mitotic activity, are diagnostic of fibrosarcoma. No sex cord islands were seen in these sarcomatous areas.

The MIB-1 labeling index in the fibrothecomatous areas was less than 1%, in contrast to the fibrosarcomatous areas, in which it was up to 10% focally (Figure 6).

The uterus showed a multifocal endometrial adenocarcinoma, endometrioid type, FIGO grade 1, arising in a background of diffuse complex atypical hyperplasia. Focal invasion involving less than 5% of the myometrial thickness was present. The tumor extended into the upper endocervical canal to involve the endocervical glands. No invasion of the cervical stroma was present. The myometrium showed multiple benign leiomyomas.

COMMENT

Primary fibrosarcomas of the ovary are rare and may arise de novo or as a result of malignant change in a preexisting ovarian fibroma.1 Criteria for the diagnosis of fibrosarcoma of the ovary were established by Prat and Scully in 1981.(11) They studied 17 cellular fibrothecomatous lesions of the ovary and identified mitotic count as the most important feature for distinguishing between benign and malignant lesions. When they separated the tumors into 2 groups-cellular fibromatous lesions with mitotic counts up to 3 per 10 HPF (11 cases) and those with counts exceeding 3 per 10 HPF (6 cases)-a significant difference in survival was observed. The degree of cytologic atypia was a less reliable prognostic indicator. Although in their study the lesions selected were pure fibromas showing no evidence of thecomatous differentiation, in a later review, Young and Scully12 suggested that, in the absence of established criteria for malignancy, the same criteria could be applied to fibrothecomatous lesions. Despite the apparent reliability of mitotic counts in differentiating fibrosarcomas from cellular fibrothecomas, a few examples exist in which cellular fibrothecomatous lesions demonstrating low mitotic activity show an unexpected aggressive behavior. In 1998, McCluggage et al13 reported a case of metastatic fibrothecomatous tumor of the ovary in which the mitotic count in the primary tumor was only 1 to 2 per 10 HPF, while the mitotic activity in the secondary foci was much higher, in the range of 12 to 15 per average 10 HPF Assuming that no sampling error was made, this case illustrates that formal mitotic counts are not an absolute indicator of malignant behavior in this group of tumors. A second example can be drawn from the original series by Prat and Scully,11 in which a tumor classified as a cellular fibroma recurred due to incomplete excision and subsequently proved to be fatal.

In a 1997 study, Tsuji et al10 established that the MIB-1 (Ki-67) labeling index in atypical fibromatous lesions of the ovary was also reflective of the potential aggressiveness of the tumor. In their study, the MIB-1 labeling index for cellular fibromas ranged from 0.5 to 4.0 with a median of 2.3, while that for fibrosarcomas ranged from 3.0 to 10.8 with a median of 6.6. The staining pattern in our tumor was in keeping with the results of the study by Tsuji et al,10 with a MIB-1 labeling index of 1.8 in the benign fibromatous areas and up to 9.4 in the fibrosarcomatous areas. Tsuji et al found that the MIB-1 labeling index was related to the mitotic count, and their results may support a formal mitotic count as a diagnostic tool, especially in cases with a count of 3 to 4 mitoses per 10 HPE They also found that the proliferative index by DNA flow cytometry was higher in fibrosarcomas, and a gain of trisomy 8 cells detected with a fluorescence in situ hybridization technique was present in the cases of fibrosarcoma, but not in the cellular fibromas.

We applied the criteria laid down by Prat and Scully11 in distinguishing the fibrosarcomatous and fibromatous areas. Although no sharp transition was found between the 2 areas in the gross specimen, the presence of the 2 histologically distinct patterns with corresponding differences in mitotic activity strongly suggests that the tumor was a fibrosarcoma arising in a cellular fibrothecomatous tumor. The MIB-1 labeling indices were consistent with the assessment of mitotic counts in the different tumor areas.

Minor sex cord elements in benign fibromatous lesions have been well described in the literature.9,13 Their importance lies in the diagnostic dilemmas that they can pose, as they have on various occasions been mistaken to be Brenner tumors, adenofibromas, or metastatic carcinoids. Sex cord elements can be distinguished by their strong immunoreactivity to inhibin. In 1983, Young and Scully9 reported 7 cases of fibromatous tumors of the ovary with minor sex cord elements resembling granulosa cells, Sertoli cells, undifferentiated sex cord cells, or steroid cells. A "minor" component of sex cord elements was defined as sex cord elements occupying no more than 10% of the area of the tumor on any slide. In that study, none of the tumors were malignant. In a separate study of 50 luteinized thecomas and stromal Leydig cell tumors in 1982, Zhang et al14 reported 2 of the 50 tumors to contain sex cord elements consistent with granulosa cells. In addition, 4 of the 50 tumors were found to be histologically malignant. However, it was not stated whether the tumors showing malignant change were the same ones containing the sex cord elements. To the best of our knowledge, this case represents the first report of a cellular fibrothecomatous tumor with minor benign sex cord elements and focal fibrosarcomatous stroma.

In the study by Young and Scully,9 2 of the 7 cases of fibromas with minor sex cord elements showed evidence of hormone overproduction with the presence of well-differentiated adenocarcinoma in the endometrium. Also, in the study by Zhang et al,14 23 of the fibrothecomatous tumors showed the coexistence of cystic hyperplasia, atypical hyperplasia, or adenocarcinoma of the endometrium. These findings were attributed to production of estrogenic hormone by the tumors. Similarly in our case, the findings of atypical complex hyperplasia and multifocal endometrioid carcinoma in a postmenopausal woman may be the result of a hyperestrogenic state due to hormone production by the ovarian tumor.

In conclusion, a case of fibrosarcoma arising in a fibrothecoma with minor sex cord elements is described. The criteria used for the diagnosis of fibrosarcoma were increased mitotic counts in association with hypercellularity and mild to moderate nuclear atypia. The benign fibrothecomatous areas showed minor sex cord elements with granulosa cell and steroid cell morphology. The presence of endometrial hyperplasia and cancer suggests hormone production by the ovarian tumor.

References

1. Talerman A. Non-specific tumors of the ovary, including mesenchymal tumors and malignant lymphoma. In: Kurman RJ, ed. Blaustein's Pathology of the Female Genital Tract. 4th ed. New York, NY: Springer Verlag; 1993:916-1917.

2. Stellato G, Di Bonito M, Tramontana S. Primary fibrosarcoma of the ovary. Acta Obstet Gynecol Scand. 1995;74:649-652.

3. Ikegami A, Ono I, Harada T, et al. A case of fibrosarcoma of the ovary [in Japanese]. Nippon Sanka Fujinka Gakkai Zasshi. 1996;48:1177-1179.

4. Miles PA, Kiley KC, Mena H. Giant fibrosarcoma of the ovary. Intl Gynecol Pathol. 1985;4:83-87.

5. Ghosh AK. Bilateral fibrosarcoma of the ovary following hysterectomy. Am J Obstet GynecoL 1972;112:1136-1138.

6. Kraemer BB, Silva EG, Sneige N. Fibrosarcoma of the ovary: a new component in the nevoid basal-cell carcinoma syndrome. Am J Surg Pathol. 1984;8: 231-236.

7. Christman JE, Ballon SC. Ovarian fibrosarcoma associated with Maffucci's syndrome. Gynecol Oncol. 1990;37:290-291.

8. Dudzinski M, Cohen M, Ducatman B. Ovarian malignant luteinized thecoma: an unusual tumor in an adolescent. Gynecol Oncol. 1989;35:104-109. 9. Young RH, Scully RE. Ovarian stromal tumors with minor sex cord elements: a report of seven cases. IntJ Gynecol Pathol. 1983;2:227-234.

10. Tsuji T, Kawauchi S, Utsunomiya T, Nagata Y, Tsuneyoshi M. Fibrosarcoma versus cellular fibroma of the ovary: a comparative study of their proliferative activity and chromosome aberrations using MIB-1 immunostaining, DNA flow cytometry and fluorescence in situ hybridization. Am J Surg PathoL 1997;21:5259.

11. Prat J, Scully RE. Cellular fibromas and fibrosarcomas of the ovary: a comparative clinicopathological analysis of 17 cases. Cancer. 1981;47:2663-2670.

12. Young RH, Scully RE. Ovarian sex cord-stromal tumors: problems in differential diagnosis. Pathol Annu. 1988;23(part 1):237-296.

13. McCluggage WG, Sloan JM, Boyle DD, Toner PG. Malignant fibrothecomatous tumor of the ovary: diagnostic value of anti-inhibin immunostaining. J Clin Pathol. 1998;51:868-871.

14. Zhang J, Young RH, Arseneau J, Scully RE. Ovarian stromal tumors containing lutein or Leydig cells (leuteinized thecomas and stromal Leydig cell tumors): a clinicopathological analysis of fifty cases. Int] Gynecol Pathol. 1982;1: 270-285.

Hwei-Yee Lee, MB, BS; Qasim Ahmed, MD

Accepted for publication January 29, 2002.

From the Department of Pathology, Singapore General Hospital, Singapore.

Reprints: Hwei-Yee Lee, MB,BS, Department of Pathology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore (e-mail: hwei_yee@hotmail.com).

Copyright College of American Pathologists Jan 2003
Provided by ProQuest Information and Learning Company. All rights Reserved

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