Ovary

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 23, and is a cellular fibroma of the ovary.

The information provided in this case was accurate and correct at the time of publication in 2021.

Any changes in terminology since the time of publication may not be reflected in this case.

The sections show a densely cellular tumor composed of oval to spindled cells arranged in a fascicular pattern. Intervening small areas with stromal hyalinization or stromal edema are also present. The neoplastic cells are uniform in size with even chromatin and scant cytoplasm. There is no evidence of cytologic atypia. Mitotic activity is low, with fewer than four mitoses/10 high-power fields (HPF) identified. The morphologic appearance is that of a cellular fibroma (CF).

Ovarian fibromas are a type of sex cord stromal tumor that are composed predominantly or exclusively of fibroblastic cells. They account for approximately 1% to 5% of ovarian tumors. There are three subtypes of fibromas: 1) fibroma of usual type (FUT; also called conventional fibromas), 2) cellular fibroma (CF), and 3) mitotically active cellular fibroma (MACF). The majority of fibromas (90%) are FUT. Ovarian fibromas can occur at any age but are most commonly identified in middle-aged women (mean age of 48). Fewer than 10% occur in women under 30. Rare cases have been reported in children, in which case they may be associated with an underlying genetic disorder, in particular nevoid basal cell carcinoma syndrome (Gorlin syndrome). Up to 75% of females with nevoid basal cell carcinoma syndrome have ovarian fibromas. The clinical presentation is variable. Small tumors are usually asymptomatic. Larger tumors may torse, causing acute abdominal pain. Tumors larger than 10 cm may be associated with ascites or Meigs syndrome, which is defined as the development of ascites and pleural effusion in the setting of an ovarian fibroma. These patients also may have elevated levels of CA-125 as a reaction to non-specific peritoneal irritation.

Grossly, fibromas are well-circumscribed with a smooth lobulated surface. Up to 20% may be pedunculated. They range in size from 1 to 20 cm. FUT have a whorled, firm, solid white or tan appearance, grossly resembling leiomyomas. Compared to fibromas of the usual type, CFs are more likely to have cystic areas (33% compared to 25%) and to have a softer, fleshier gross appearance. Calcifications are noted in about 10% of cases. Most fibromas are unilateral and solitary, but multiple tumors can be seen in 8% to 10% of cases. Calcified, multinodular, multifocal, and bilateral cases are common features of fibromas arising in patients with nevoid basal cell carcinoma syndrome.

Microscopically, fibromas are composed of short intersecting fascicles of cytologically bland fibroblastic cells. Cellular and conventional fibromas can be differentiated by the cellular density. In conventional fibromas, hyalinized plaques or collagen bands are frequent. In CF there is less intervening collagen and the tumors are more densely cellular, often with a more prominent and more easily recognizable fascicular or storiform pattern. All types of fibromas can have islands of hypocellularity due to edema or stromal hyalinization. In conventional fibromas, mitoses are rare to absent. CF by definition have 3 or fewer mitoses per 10 HPF. Cellular fibromas with 4 or more mitoses per 10 HPF are classified as MACFs. Unusual microscopic features that can be identified include nuclear palisading, suggestive of Verocay bodies; minor sex cord elements such as microscopic nests of granulosa cells; intracytoplasmic hyaline globules; clusters of signet ring-like cells; and rare bizarre cells and foamy histocytes. The sex cord elements should be less than 10% of the tumor.

While CF may show focal reactive nuclei near areas of necrosis or hemorrhage due to torsion, diffuse nuclear atypia is not seen. Reticulin staining shows complete investment of each cell (unlike in adult granulosa cell tumor; see below). Immunohistochemically, fibromas are positive for WT1, SF1, ER, and PR. Variable expression is seen with inhibin and calretinin, smooth muscle actin, S100, and CD34. Fibromas are negative for CD10, desmin, caldesmon, and CD99.

Conventional fibromas are benign and best treated by surgical excision. CF, including the mitotically active ones, can recur if incompletely excised or if there is ovarian surface involvement or intraoperative rupture. Extra-ovarian spread has been noted at surgery in some cases.

Adult granulosa cell tumor (AGCT) is a sex cord stromal tumor composed of granulosa cells with a variable number of fibroblasts and theca cells. The most common growth pattern is diffuse sheets of cells, creating an appearance that can be confused with a CF. Identification of other areas showing an insular, trabecular, or microfollicular pattern can be helpful in diagnosis, so ample sectioning is important. The nuclei are often pale and vesicular. Nuclear grooves are a characteristic feature of AGCT but are not always easily identified. Reticulin stains may be useful, as reticulin fibers surround nests of cells in AGCT, as opposed to each cell in CF. Molecular studies have identified a FOXL2 mutation in 90 to 95% of cases of AGCT, including metastases, making this a useful diagnostic tool in challenging cases. Importantly, the immunohistochemical stain for FOXL2 stains a wide variety of stromal tumors and therefore cannot substitute for genetic analysis.

Fibrosarcoma is a malignant fibroblastic tumor of the ovary. It most commonly occurs in postmenopausal women who present with symptoms due to an abdominal mass. Fibrosarcomas are usually unilateral and large. On gross examination, the tumors are solid and often have areas of hemorrhage and necrosis. Extra-ovarian spread may be present. Microscopically, the tumors resemble CFs, as they are hypercellular and are composed of spindled cells arranged in sweeping fascicles. Fibrosarcomas are differentiated from CF by their moderate to marked cytologic atypia and high mitotic rate, including atypical mitoses. However, the cytologic atypia is a crucial component of the diagnosis, as a cytologically bland cellular fibroblastic tumor with at least 4 mitoses per 10 HPF is better classified as a MACF.

Sclerosing stromal tumors are benign, typically unilateral tumors affecting young women with an average age of 27 years. Patients present with symptoms related to an abdominal mass. Hormonal symptoms are uncommon. The tumors are composed of intermixed spindled and round cells with a pseudolobular appearance due to the presence of alternating cellular and hypocellular foci. Hemangiopericytoma-like, dilated, thin-walled vessels are present. Lutein cells with signet-ring-like appearance can be seen. Fibromas lack the distinct vasculature and pseudolobulation of sclerosing stromal tumors.

Thecomas are stromal tumors composed of polygonal to fusiform cells with poorly defined cell borders and abundant cytoplasm that may be vacuolated, resembling theca cells. Hyaline plaques are common. Like fibromas, they are usually unilateral and can occur in a similar age group to fibromas. However, in contrast to fibromas, patients with thecomas often have symptoms related to excess estrogen due to the tumor, and about 60% will present with uterine bleeding. Immunohistochemically, most thecomas are diffusely positive for inhibin and calretinin.

1. Which of the following features would be most useful in separating a mitotically active cellular fibroma from a fibrosarcoma?
   
   
   1. Extraovarian spread
   2. FOXL2 mutation
   3. Hormonal manifestations
   4. Marked diffuse cytologic atypia
   5. More than 5 mitoses per HPF
2. Which of the following tumors can present with hormonal manifestations and demonstrates a nested staining pattern with reticulin?
   
   
   1. Adult granulosa cell tumor
   2. Cellular fibroma
   3. Fibrosarcoma
   4. Sclerosing stromal tumor
   5. Thecoma
3. Which of the following features are characteristic of fibromas arising in a patient with nevoid basal cell carcinoma syndrome?
   
   
   1. Bilaterality, marked cytologic atypia, necrosis.
   2. Calcification, bilaterality, multinodularity
   3. Microfollicles, reticulin surrounding cell groups, grooved nuclei
   4. Unilaterality, hormonal manifestations, uterine bleeding
   5. Unilaterality, thin-walled vessels, calcification

1. Irving JA. Cellular fibromatous neoplasms of the ovary. Surg Pathol Clin. 2009;2(4):731-753.
2. Irving JA, McCluggage WG. Ovarian spindle cell lesions: a review with emphasis on recent developments and differential diagnosis. Adv Anat Pathol. 2007;14(5):305-319.
   
3. McCluggage WG, Singh N, Kommoss S, Huntsman DG, Gilks CB. Ovarian cellular fibromas lack FOXL2 mutations: a useful diagnostic adjunct in the distinction from diffuse adult granulosa cell tumor. Am J Surg Pathol. 2013;37(9):1450-1455.
4. McCluggage WG, Kiyokawa t, Staats PN, Young RH. Sex cord-stromal tumors-pure stromal tumors. In Kurman RJ, Carcangiu ML, Herrington CS, Young RH, eds. WHO classification of tumors of the female reproductive system. IARC Press, 2014;44-51.
5. Young RH. Ovarian sex cord-stromal tumors: Reflections on a 40-year experience with a fascinating group of tumors, including comments of the seminal observations of Robert E Scully, MD. Arch Pathol Lab Med. 2018;142(12):1459-1484.
6. Young RH. Ovarian sex cord-stromal tumors and their mimics. Pathology. 2018;50(1):5-15.
7. Zhao C, Vinh TN, McManus K, Dabbs D, Barner R, Vang R. Identification of the most sensitive and robust immunohistochemical markers in different categories of ovarian sex cord-stromal tumors. Am J Surg Pathol. 2009;33(3):354-366.

1. Marked diffuse cytologic atypia (d)
2. Adult granulosa cell tumor (a)
   
3. Calcification, bilaterality, multinodularity (b)