MATERIALS AND METHODS
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Immunohistochemistry was performed on 5-µm paraffin embedded sections from all cases with the antibodies monoclonal smooth muscle actin (SMA) (Dako Co., Carpenteria, CA) (1:400 dilution), muscle specific actin (MSA) (Dako Co.) (1:160 dilution), desmin (Dako Co.) (1:100 dilution), 1 S-100 (Dako Co.) (1:4000 dilution), vimentin (Dako Co.) (1:400 dilution), and CD34 (Signet Laboratories, Dedham, MA) (1:40 dilution) on a Tech Mate™ automated immunostainer (Ventana Biotek, Tucson, AZ). Appropriate controls were used in every staining run. The detection step was performed using the streptavidin-biotin complex method (Signet Laboratories).
Glutaraldehyde fixed material was available for ultrastructural examination in Cases 1 and 3. The tissue was postfixed in 1% osmium tetroxide, dehydrated, and embedded in epor. Ultrathin (80-nanometer) sections were stained with uranyl acetate and lead citrate and examined in a transmission electron microscope at 60 kilovolts.
Fresh tissue obtained from Case 1 was submitted for cytogenetic analysis at the time of resection.
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In 1987 Evans1 first described two unique tumors that were characterized by a deceptively bland histology and an indolent metastasizing course. He subsequently added ten more cases to his series2 and firmly established the concept of LGFMS as a separate clinicopathologic entity. A subsequent series of 11 cases3 as well as individual case reports4–7 have reiterated the existence of LGFMS as a distinct neoplasm. These tumors predominately occurred in younger patients (ages 26–46 years) in the deep soft tissues of the thigh, inguinal region, shoulder, and perineum. The salient histologic features are a characteristic nonfascicular, whirled arrangement of fibroblastic-appearing cells within alternating areas of myxoid and fibrous stroma. The neoplasm has a low to moderate cellularity; the neoplastic cells are bland fibroblastic cells with minimal nuclear pleomorphism and rare mitotic figures. In addition, there is a rich capillary network in the myxoid areas within an otherwise hypovascular tumor. The tumor, although well circumscribed macroscopically, usually displays microscopic infiltration into the surrounding soft tissues.
The FNAB findings of our three cases revealed a myxoid lesion with low cellularity comprised of spindle cells with relatively bland, ovoid to tapered nuclei consistent with a fibroblastic origin. Although the myxoid areas were sampled, the rich capillary background observed on histology was not appreciated in the smears. In addition, there were no dense stromal fragments suggestive of the fibrous component of this tumor. Therefore, we do not believe the cytologic findings are specific enough to make a definitive diagnosis based on FNAB alone. However, correlation of cytologic and clinical features may reduce the diagnostic possibilities substantially.
To our knowledge, to date there have been no reports of the FNAB findings of LGFMS. In fact, the cytology literature is limited with regard to FNAB of myxoid soft tissue neoplasms.8, 9 These tumors, unified by their excessive production of mucopolysaccharide material, can be benign or malignant and may have a fibroblastic, chondroblastic, myoblastic, or neurogenic origin. The differential diagnosis of LGFMS on FNAB includes well recognized myxoid tumors such as superficial or intramuscular myxoma, aggressive angiomyxoma, myxoid liposarcoma, myxoid chondrosarcoma, and the low grade myxoid variant of malignant fibrous histiocytoma.10 In addition, myxoid variants of other tumors must be considered, such as myxoid neurofibroma or neurothekeoma; a tumor-like lesion, nodular fasciitis, has a myxoid component as well.
Chondroblastic or lipoblastic myxoid tumors would not likely enter the differential diagnosis; these tumors would have greater cellularity, nuclear atypia, and characteristic cytoplasmic morphology. Neurogenic tumors, such as a myxoid variant of neurofibroma or neurothekeoma, may be considered; however, these tumors have long, slender, wavy nuclei with tapered ends that are not present in LGFMS. Because their cytologic appearance is so similar, it may be impossible to distinguish LGFMS from myxoma11 or superficial or intramuscular aggressive angiomyxoma12 on FNAB alone. Correlating the cytologic findings with the clinical and radiologic presentation can help narrow the differential diagnosis. For example, although the FNAB findings of nodular fasciitis13 or neurothekeoma may resemble LGFMS, the superficial location of the mass would steer one away from this diagnosis. However, a younger female patient with a perineal lesion could have either an aggressive angiomyxoma14 or LGFMS.
Histologically, the deceptively bland appearance of LGFMS makes its distinction from various benign and low grade malignant lesions challenging and may require extensive sampling and clinicopathologic correlation. Probably the greatest obstacle in achieving the correct diagnosis of this tumor is the lack of familiarity with this relatively new entity. Although there is a growing awareness, many pathologists still are unfamiliar with the features of this entity. However, careful histologic examination of the tumor will narrow the differential diagnosis considerably to lesions such as myxoma, myxoid neurofibroma, neurothekeoma, aggressive angiomyxoma, and low grade myxofibrosarcoma. Soft tissue myxomas usually are superficial or intramuscular, hypocellular, and hypovascular. Moreover, they lack the fibrous component of LGFMS.15 Immunohistochemical analysis and electron microscopy can help eliminate a neural etiology. Myxoid neurofibromas exhibit wavy nuclei and S-100 positivity that can help distinguish this lesion; neurothekeomas are superficial lesions that have a characteristic lobular pattern of growth; some exhibit S-100 protein positivity.16, 17 The distinction between LGFMS and low grade myxofibrosarcoma, considered the equivalent of the low grade myxoid variant of malignant fibrous histiocytoma, is important because of the significantly lower metastatic potential of low grade myxofibrosarcoma compared with LGFMS.18, 19 These lesions share the same immunohistochemical profile20 and ultrastructural features.21 Histologically, myxofibrosarcoma is a multinodular mass that is uniformly myxoid, lacking a significant fibrous component, and contains small, collapsed, curvilinear blood vessels; in addition, there is more nuclear pleomorphism and hyperchromasia than in LGFMS.22
Immunohistochemistry in our three cases revealed strong positivity with vimentin only; no staining was observed with SMA, MSA, desmin, S-100, or CD34 in the sections examined. In addition, a lack of staining with neuron specific enolase, neurofilaments, glial fibrillary acidic protein, and factor VIII has been reported.4, 6 These findings support a fibroblastic origin of LGFMS. Previous studies have documented focal positivity for SMA, MSA, desmin, or cytokeratin,3, 5, 7 which is believed to be in keeping with focal myofibroblastic differentiation within these tumors.23
The ultrastructural features of the neoplastic cells in our two cases confirmed a fibroblastic origin for this tumor. To our knowledge the electron microscopic findings of LGFMS have been documented in only one previously reported case.3 The authors found both spindle shaped cells and stellate cells with abundant dilated RER, free ribosomes, and large numbers of intermediate filaments. No actin filaments with dense bodies were present. The ultrastructural features were consistent with fibroblasts. Based on the immunohistochemical and ultrastructural findings, we believe LGFMS is a fibroblastic neoplasm and myofibroblastic differentiation, if present, is very focal and most likely not universal.
Cytogenetic analysis performed on one case revealed no detectable chromosomal abnormalities. Enlarged satellites on the short arm of a single chromosome 22 were found; this is a normal variant with no known clinical significance.
In the current study we have presented clinical, cytologic, pathologic, cytogenetic, immunohistochemical, and ultrastructural findings of three cases of LGFMS. This is a tumor of fibroblastic origin whose recognition based only on FNAB is nearly impossible; however, correlation with clinical features can reduce the diagnostic possibilities significantly. Histologic separation from various benign and low grade sarcomas is challenging as well. Recognition of this lesion is important for proper surgical treatment and long term follow up because metastases may occur many years later.