—  SHORT COURSE #21  —

Mesenchymal Neoplasms of the Female Genital Tract

Case 8 - Cellular Mitotically Active Fibroma

Teri Longacre, Esther Oliva and Robert Soslow


Introduction
Fibromas belong to the category of pure stromal tumors of the ovary (Table 1). Considered to originate from specialized ovarian stromal cells they are the most common subtype and account for approximately 4% of all ovarian tumors. Among fibromas, cellular/mitotically active fibromas represent a very small (<10%) subset, but these are the ones that most often pose diagnostic challenges.

Clinical Features
Fibromas may occur at any age but they are more commonly found in middle-aged women. They are rare before the second decade, except for in patients with the Gorlin Syndrome (nevoid basal cell carcinoma syndrome), an autosomal dominant disorder, characterized by congenital malformations and predisposition to basal cell carcinomas, ovarian fibromas, medulloblastomas and other tumors. The main presenting symptom is abdominal pain, reported in approximately 40% of patients, a finding observed in 9% of cellular fibromas in the largest series of the literature. Fibromas are rarely associated with clinical or pathological evidence of steroid hormone production at the time of diagnosis but they have been reported to be associated with increased CA-125, raising clinical suspicion for ovarian carcinoma. Sizable tumors (>10 cm) may also be associated with ascites alone in 10 to 15% of cases and with Meigs' Syndrome (ascites and pleural effusion) in a very small percentage of patients, both typically disappearing after removal of the tumor. In a recent series of cellular fibromas reported by Irving and colleagues 3 patients had symptoms related to ascites, including one with pleural effusion (Meigs' Syndrome).

Pathologic Features
Fibromas are typically unilateral tumors except in the Gorlin Syndrome (bilateral in approximately 75% of cases). These tumors range in size from microscopic to more than 20 (average 6) cm. They may be mainly polypoid or pedunculated. The tumors have a smooth or lobulated surface and a homogeneous, firm, white cut section and those associated with the Gorlin Syndrome typically show multinodular growth. Watery fluid secondary to edema and cyst formation are frequent findings. Calcification is seen in 10% of usual fibromas but it is almost always present in fibromas associated with the Gorlin Syndrome. Hemorrhage but no necrosis may be seen. The gross appearance of cellular fibroma overlaps with that seen in conventional fibroma, however, they tend to be larger in size, they may have a softer, white to yellow cut surface. It is not infrequent for cellular fibromas to be associated with ovarian surface adhesions, adhesions to surrounding structures or rupture.

On microscopic examination, these tumors may be well circumscribed, but non-encapsulated, or may merge irregularly with the surrounding ovarian stroma. Typical fibromas are composed of fascicles of spindle cells that may display a striking storiform arrangement. The cells have very scant cytoplasm and oval to elongated wavy nuclei with pointy ends, a minimal degree of cytologic atypia and rare mitotic activity. The cells may be separated by variable amounts of edema and hyaline bands. Calcified plaques may also be seen, but they are not as common as seen in thecomas. Unusual features include increased cellularity, increased mitotic activity (>3/10 high power fields), sex cord-like differentiation (<10% of the tumor), intracytoplasmic hyaline droplets, bizarre nuclei and Verocay-like areas. More than one feature may be present in the same tumor. Tumors may show small areas of hemorrhage but necrosis is typically absent (except in case of infarction).

Cellular fibroma is defined as a tumor with similar cellularity to that seen in a diffuse adult granulosa cell tumor and this subset represents about 10% of all ovarian fibromas. It is much less frequently associated with edema, hyaline bands but frequently shows areas of conventional fibroma. Even though these tumors are densely cellular, they show only minimal degree of cytologic atypia, a requirement to establish this diagnosis. However, increased mitotic activity is not infrequent. A recent study has shown that cellular fibromas had a mean mitotic count of 1.5 /10 high power fields (with a highest mitotic rate ranging from 0 to 3) while in mitotically active cellular fibromas the mean mitotic rate was 6.7/10 high power fields (ranging from 4 to 19), with 15% of tumors having 10 to 19 mitoses/10 high power fields. In contrast to conventional fibromas, both cellular fibromas and mitotically active cellular fibromas may show necrosis that appears sharply demarcated from the surrounding viable tumor, particularly around islands of perivascular tumor, a morphologic appearance that overlaps with that described in tumor cell necrosis in uterine smooth muscle tumors.

Immunohistochemistry
Fibromas typically stain diffusely for vimentin, frequently show positivity for smooth muscle actin and much less frequently may express CD34 and desmin. In some tumors, rare cells show weak positivity for inhibin and calretinin.

Genetics
It has been shown that patients with the Gorlin syndrome have mutations in the human homologue of Drosophila patched gene (PTCH), localized in chromosome 9q22.3. Some sporadic typical and cellular fibromas have shown loss of heterozygosity (LOH) at 19p13.3, with the highest frequency at microsatellite marker D9S15, which localizes proximal to the PTCH gene. In one study LOH at 19p13.3 was seen in 50% of cellular fibromas and 25% of conventional fibromas, but not in fibrosarcomas. These results indicate that sporadic cellular fibromas may arise through similar genetic pathways as cases associated with the Gorlin syndrome.

Differential Diagnosis
Conventional fibroma should be distinguished from other benign non-neoplastic stromal proliferations including stromal hyperplasia, fibromatosis/massive edema as well as thecomas. Cellular and mitotically active fibroma should be distinguished from both benign and malignant, primary or metastatic tumors to the ovary and for this reason may represent a real diagnostic challenge. asfd Cellular mitotically active fibroma vs luteinized thecoma These tumors share with cellular mitotically active fibroma the following features: dense cellularity, brisk mitotic activity, and absence of cytologic atypia. However, in contrast to cellular fibroma where the cellularity tends to be homogeneous throughout the tumor, luteinized stromal cells are and tumors are typically unilateral, luteinized thecomas only rarely found, alternating hypo- and hypercellular areas, have abundant luteinized cells, typically involve both ovaries and are associated with sclerosing peritonitis. Furthermore hormonal manifestations are common in luteinized thecoma but extremely unusual in cellular fibroma.

Cellular mitotically active fibroma vs diffuse adult granulosa cell tumor
Some adult granulosa cell tumors have a striking fibromatous background and at low power may be misdiagnosed as a cellular fibroma. However, at higher magnification the cells show grooved nuclei and in other areas of the tumor one can identify more characteristic patterns of growth of this tumor.

Cellular mitotically active fibroma vs fibrosarcoma
Initial histologic criteria to differentiate cellular mitotically active fibroma from fibrosarcoma were proposed by Prat and Scully in 1981 in a study of 17 fibromatous tumors. In that study, mitotic activity was the most important feature while cytologic atypia was less helpful. Fibromatous tumors with 3 or less mitoses/10 high power fields and grade 1 or 2 of nuclear pleomorphism were classified as a cellular fibroma while tumors with 4 or more mitoses and grade 2 to 3 nuclear pleomorphism were classified as a fibrosarcoma. Other differences included younger age patients, smaller tumor size, only rare presence of adhesions, and lower stage in cellular fibromas. However, a recent study of 75 cellular fibromas, including 40 mitotically active tumors, has shown that tumors with mitotic activity higher than 3/10 high power fields still behaved in a benign fashion, even when the tumor had adhesions or extraovarian involvement but the tumor cells did not show more than mild cytologic atypia. In contrast to the initial study by Prat and Scully, the authors of this study found that cytologic atypia played a key role in the classification of cellular fibromatous neoplasms. They concluded that tumors showing bland cytologic features are benign as they are associated with good outcome despite their high mitotic rates. On the other hand, tumors with moderate to severe nuclear atypia and high mitotic activity should be classified as fibrosarcoma and should be treated accordingly.

Cellular mitotically active fibroma vs smooth muscle neoplasms
Smooth muscle tumors of the ovary are rare and frequently diagnosed as fibroma or fibrosarcoma depending on their degree of cytologic atypia and mitotic activity. Even though both tumor types show a fascicular growth of the cells, smooth muscle tumors are composed of long fascicles but do not show the typical storiform arrangement as seen in fibromas. In smooth muscle tumors collagen formation is not striking, cells have conspicuous cytoplasm, and cigar-shaped nuclei whereas fibromas are typically associated with collagen formation, scant cytoplasm and wavy nuclei. Immunohistochemical stains are of limited value as fibromas frequently express smooth muscle markers. However, in general, diffuse positivity for desmin strongly favors a smooth muscle tumor over a fibroma.

Cellular mitotically active fibroma vs primary or metastatic endometrial stromal sarcoma
It has been reported that endometrial/oid stromal tumors may show fibroblastic differentiation either in primary or metastatic sites. Furthermore, it is also well known that when primary or metastatic endometrial stromal tumors involve the ovary they may simulate the growth patterns of pure stromal tumors because of their prominent fibromatous background. In these cases, extensive sampling will show typical areas of endometrial stromal neoplasia composed of small cells with oval nuclei growing in a diffuse pattern associated with small "arteriole-like" vessels. Primary ovarian endometrioid stromal tumors are frequently associated with endometriosis while metastatic endometrial stromal tumors frequently involve both ovaries. In the latter, it is always important to be aware of the patient's previous clinical history. Immunohistochemistry may be of help in difficult cases as endometrial stromal tumors are typically CD10 positive. In contrast, the only study evaluating CD10 in pure stromal tumors of the ovary showed that all typical fibromas and all but one fibrosarcoma (positive in less than 5% of cells) were CD10 negative. Even though that study did not include cellular mitotically active fibromas, it is reasonable to hypothesize from the previous results that these tumors would lack CD10 positivity.

Cellular mitotically active fibroma vs gastrointestinal stromal tumor
Gastrointestinal stromal tumors (GIST) may secondarily involve the ovaries and may be found before the primary tumor has been diagnosed. In the only series (5 cases) reported in the literature, 2 tumors were discovered before the primary gastric and small bowel tumors (18 months and 27 years respectively) while the other 3 were removed synchronously with the primary tumor. In the former situation, it is not unusual that the initial diagnostic considerations would include an ovarian smooth muscle tumor, a cellular mitotically active fibroma or a fibrosarcoma. GIST may show different morphologic appearances depending on their origin in the gastrointestinal tract. However, in general, these tumors are composed of fascicles of fairly uniform spindle-shaped cells, sheets of epithelioid cells, or an admixture thereof. Only the former pattern of growth may be confused with a fibroma, as the latter is typically composed of intersecting fascicles of spindle cells, although often showing a storiform pattern. Furthermore, fibromas typically lack a sizable component of epithelioid cells although they may contain scattered luteinized cells. Cellularity and collagen matrix may vary from tumor to tumor, thus, densely cellular tumors associated with collagen formation may closely mimic a fibroma/cellular mitotically active fibroma, even more so as many GISTs only show mild degree of cytologic atypia and variable mitotic activity. Nuclear palisading, another feature seen in some GISTs, may be observed in cellular mitotically active fibromas. Other histologic features seen in GIST but not fibromas or cellular fibromas include skenoid fibers and paranuclear cytoplasmic vacuoles. Skenoid fibers represent PAS positive aggregates of extracellular collagen fibers that on electron microscopy are characterized by a concentric lamellar appearance. In difficult cases, immunohistochemistry may be helpful. GISTs are typically c-kit positive and frequently CD34 positive with variable positivity for smooth muscle markers including smooth muscle actin, myosin and caldesmon. They are typically negative for desmin. Although fibromas may be positive for smooth muscle markers, they are negative for c-kit and only some tumors show focal CD34 positivity.

Treatment and Prognosis
Cellular mitotically active fibromas behave in a benign fashion even in cases associated with ovarian adhesions or extraovarian extension. Thus, these tumors should be treated conservatively with surgery. Long-term follow up is advised particularly for those patients with tumor rupture or adhesions as they may recur locally. It is important to distinguish these tumors from fibrosarcoma, the latter associated with an aggressive behavior and require aggressive treatment.

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