Clinicopathological Characteristics of Mitotically-active Cellular Fibroma of the Ovary: A Single-institutional Experience

Discussion

Many ovarian tumors composed primarily of fibroblastic cells are fibromas of conventional type and generally do not pose a diagnostic challenge. Most contain spindle- to ovoid-shaped cells as the principal cell type, with variable amounts of extracellular collagenous matrix. A small subset of fibromatous tumors, however, exhibit increased cellularity and mitotic activity, and the presence of either or both features leads to classification as CF or MACF. We investigated the clinicopathological characteristics of ovarian MACF through a retrospective review of our 10-year institutional experience. Age and clinical presentation of patients with MACF were similar to those of previously published cases. In our series, the patient age ranged from 20–71 years, with mean and median age of 46 and 47 years, respectively. The mean age of patients with MACF reported in a previous large study was 41 years (4). Most patients diagnosed as having MACF presented with symptoms associated with an abdominal or pelvic mass, which was the usual presentation of patients reported in the literature. We observed that more than half of the cases presented as mixed solid and cystic lesions in imaging studies, indicating the nature of frequent cystic change in these tumors. There were disagreements between different imaging modalities and radio-pathological interpretations. The radiological impressions of two CFs were discordant between MRI and PET. Furthermore, all CFs evaluated by MRI were interpreted as malignancy and two MACFs were interpreted as borderline epithelial tumor. Our observations suggest limitations of imaging studies in predicting the diagnosis of ovarian CFs and MACFs, and indicate that surgical excision and subsequent histopathological examination are required to make an accurate diagnosis.

Grossly, MACF had a softer, fleshier cut surface than conventional fibroma, which is typically hard, chalky, and white or yellow-to-white, with a vaguely whorled cut surface that resembles uterine leiomyoma. In contrast, all CFs had grossly fibrotic-firm appearances. We assume that the difference in gross appearance of MACF is due to differences in the proportion of collagenous stroma. In CF the collagen fibers were easily recognized at low-power magnification, and an appreciable number of collagen fibers were dissecting and separating tumor cells into bundles. As a result of the relatively large amount of collagen fibers, there was obvious and pronounced fascicular growth of tumor cell bundles. MACFs tended to have subtler evidence of fasciculation due to fewer collagen fibers. They were distinctively more cellular than CFs and allowed little space between the tumor cells. The collagen fibers were not easily identified in conventional hematoxylin and eosin staining but their presence could be confirmed through reticulin staining. This feature might easily deceive a pathologist into misdiagnosing MACF, especially as AGCT. In this situation, reticulin staining is fundamental for differentiating the two entities as it confirms fibroblastic collagen production in MACFs by demonstrating collagen fibers surrounding individual cells.

Histologically, MACF exhibited dense cellularity, sometimes with translation to small hypocellular areas that were accompanied by extensive hyaline degeneration or edema (1, 4, 5). The fascicular arrangement of tumor cells and collagenous stroma that is characteristic of conventional fibroma was subtle in MACFs. The nuclei were oval to spindle-shaped, with relatively smooth nuclear contours and a small nucleolus. All MACFs had mild cytologic atypia. Most importantly, all MACF cases displayed significantly increased mitotic activity. The number of mitotic figures observed ranged from 8-10 per 10 HPFs, without atypical forms. Consistent with previous data, our cases of cellular fibromatous tumors with four or more mitotic figures per 10 HPFs but no diffuse moderate-to-severe cytological atypia warranted designation as MACF. Attention to these histopathological features facilitates the correct diagnosis and avoids potential overdiagnosis as the rare and clinically aggressive fibrosarcoma.

In terms of pathological examination, caution should be applied regarding malignant tumors showing overlapping histopathological features with MACFs. Importantly, in our 10-year single-institutional experience there was no case diagnosed as ovarian fibrosarcoma. Clinicians should be aware of the overlapping features of frequent mitoses between fibrosarcoma and MACF to prevent overdiagnosis of an ovarian cellular fibromatous tumor as fibrosarcoma. At the initial discovery of fibrosarcoma by Prat and Scully (1), it was suggested that a mitotic index of more than 4 per 10 HPFs is sufficient for the diagnosis of fibrosarcoma. However, subsequent observations amended the diagnostic criteria for fibrosarcomas to additionally require nuclear pleomorphism and severe cytologic atypia rather than only a high mitotic index (4). In regard to the higher prevalence of MACF compared to fibrosarcoma demonstrated in this study, the majority of particularly cellular fibromatous tumors with frequent mitoses of the ovary may be MACFs rather than fibrosarcomas. In fact, fibrosarcoma is exceptionally rare. Grossly, these tumors are typically large and overtly malignant with extensive coagulative necrosis and hemorrhage (1, 5). In contrast to CF and MACF, on microscopic examination they show diffuse moderate-to-severe cytological atypia and brisk mitotic activity with a typical mitotic count of up to 25 per 10 HPFs (1, 5, 13). Fibrosarcomas have often spread beyond the ovary at presentation and have been fatal in more than half of reported cases, with death usually occurring within less than 2 years from diagnosis (1, 5, 13, 14). Occasional tumors can show areas of fibrosarcoma in a background of MACF, thus thorough histological sampling is essential in all cellular fibromatous tumors.

AGCT should also be distinguished from MACF. Ovarian AGCT, an aggressive sex cord-stromal tumor, is more common than MACF. AGCT that exhibits a prominent fibromatous stromal component may resemble MACF. The fibroblastic origin should be confirmed using reticulin staining, which highlights individually wrapped tumor cells by collagen fibers (15). In contrast, reticulin staining in AGCT demonstrates aggregation of tumor cell groups, clusters, or nests by collagen fibers. In tumors with a diffuse growth pattern, an extensive search may be required to show insular, follicular, or other typical patterns of adult granulosa cell tumor. Attention to the pale, vesicular nuclear characteristics of AGCT and the presence of nuclear grooves can be helpful. However, the latter finding is not required for diagnosis, and is by no means exclusive to AGCT. Leiomyosarcomas involving the ovary, whether primary or metastatic, should be readily distinguished from CF and MACF by their high-degree of nuclear pleomorphism and atypical mitotic figures. Metastatic gastrointestinal stromal tumor (GIST) has important prognostic and therapeutic implications and may enter into differential diagnoses of a cellular fibromatous tumor. Histologically, metastatic GIST to the ovary may show pure spindled cell morphology, with mitotic activity in the range of that seen in MACFs. Furthermore, skeinoid fibers, brightly eosinophilic globules and plaques frequently present in the stroma of GISTs of small bowel origin, may be mistaken for the wavy collagen fibers and hyaline plaques seen in fibromas and thecomas (4, 16). Skeinoid fibers are densely staining and have irregular hard edges, in contrast to hyaline plaques, which have more fibrillary, wavy collagen fibers coalescing into larger aggregates. Although skeinoid fibers are believed to be nonspecific, in the context of a spindled-cell neoplasm of the ovary their presence should raise the index of suspicion for metastatic GIST.

In summary, we describe the clinicopathological characteristics of ovarian CF and MACF. This study highlights the potential danger of misdiagnosing ovarian cellular fibromatous tumors as malignant aggressive tumors such as fibrosarcoma and AGCT. Increases in both cellularity and mitotic activity raise the index of suspicion of malignancy, but the absence of diffuse moderate-to-severe cytological atypia or atypical mitotic figures does not support the diagnosis of fibrosarcoma. Our data support the notion that increased cellularity, mild cytological atypia, and frequent mitotic figures are suggestive of MACF. Surgical excision seems to be a curative treatment for ovarian MACF, although given its rarity, further investigation using a large patient cohort is necessary to establish its biological nature and clinical outcome.