Although the histologic features of the recently described low grade fibromyxoid sarcoma are well established, to the authors' knowledge there are no reports in the literature describing the cytologic features of this tumor by fine-needle aspiration. Recognition of this lesion is important because of its indolent but metastasizing nature.
The authors retrospectively reviewed their surgical pathology files for cases of low grade fibromyxoid sarcoma with a preoperative fine-needle aspiration biopsy (FNAB); three such cases were found. Immunohistochemical studies were performed in all three tumors, ultrastructural examination was performed in two tumors, and fresh tissue for cytogenetic analysis was obtained in one tumor.
All FNABs showed similar features. The aspirates were relatively hypocellular with an abundant myxoid background; the neoplastic cells contained oval to spindle shaped nuclei with minimal pleomorphism. No capillaries or areas of fibrous tissue were identified. Cytogenetic study of one case revealed no chromosomal abnormalities. The histologic findings were characteristic for this lesion. By immunohistochemistry the tumor cells showed diffuse and strong reactivity for vimentin only; at the ultrastructural level the neoplastic spindle cells had characteristics of fibroblasts.
In 1987, Evans reported two unique cases of an indolent but metastasizing soft tissue neoplasm with a deceptively benign histologic appearance.1 He designated this tumor a low grade fibromyxoid sarcoma (LGFMS), and solidified the concept with the report of ten additional cases in 1993.2 Although the histologic appearance of this tumor now is well established, to our knowledge there have been no published reports regarding the cytologic features of LGFMS. To our knowledge this report is the first description of fine-needle aspiration biopsy (FNAB) cytology in three cases of histologically confirmed LGFMS; in addition, immunohistochemical, ultrastructural, and cytogenetic studies were performed. The findings support a fibroblastic origin for this neoplasm.
A 71-year-old white man was undergoing workup for constipation; a computed tomography (CT) scan revealed an incidental 5-cm mass in the left upper anterior thigh adherent to the periosteum of the femur, near the inguinal ligament. A CT-guided FNAB was performed and the mass was diagnosed as a “myxoid spindle cell neoplasm.” The lesion was resected with negative surgical margins; the patient received no additional therapy. Clinical follow-up, including radiographic studies, had not detected recurrent tumor at 3 years of follow-up.
A 35-year-old African-American woman presented with a 7-cm painful left buttock mass that had been present for 1 year. The mass was palpable by digital rectal examination but did not involve the mucosa. A superficial FNAB yielded 15 mL of red-brown mucoid fluid; a diagnosis of “myxoid spindle cell lesion, myxoma versus mucocele” was rendered. A local excision was performed on an outpatient basis; surgical margins were positive. Additional surgery was planned, but the patient was lost to follow-up.
A 51-year-old Hispanic female presented with a 1-year history of a painful, slowly enlarging, firm, fixed mass in the subcutaneous tissue of her left posterior flank. Six years previously she had undergone resection of a chest wall tumor at the same site that was diagnosed as benign schwannoma. A CT scan of her lower chest and abdomen revealed a 2-cm extrathoracic nodule in the left posterior flank as well as a 1.5-cm intrathoracic mass in the area of the previously resected tenth rib. A superficial FNAB of the subcutaneous mass was performed and diagnosed as “spindle cell neoplasm, favor low grade sarcoma.” The patient underwent wide local resection. Intraoperatively, two previously undetected metastatic pulmonary nodules also were excised. No postoperative chemotherapy or radiation therapy was administered. There was no evidence of recurrent tumor for 3 years, after which time the patient was lost to follow-up.
MATERIALS AND METHODS
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.
FNAB Cytologic Findings
The smears were rather hypocellular with scattered bland spindle cells in an abundant background of myxoid matrix. The cells mostly were intact with ovoid to spindle nuclei measuring approximately 15 µm; the nuclei contained fine powdery chromatin without nucleoli. The cytoplasm was loose and tapered along the long axis of the nuclei (Fig. 1). There was no nuclear pleomorphism and no mitoses were observed. Although the majority of the smears contained single dispersed cells, there were rare densely cellular aggregates that still retained bland nuclear features (Fig. 2). Occasional foamy histiocytes were present in the background. No capillaries or fibrous stromal fragments were identified.
The smears contained scattered spindle cells embedded in a prominent myxoid background. The spindle cells were bland with the same nuclear features observed in Case 1. There were rare foci of thicker myxoid material that had increased numbers of the same type of spindle cells (Fig. 3). Occasional background histiocytes were present. There were no capillaries or fibrous stromal fragments identified.
The smears were more cellular compared with Cases 1 and 2. The background was myxoid with numerous small ovoid and spindle cells. The nuclei were similar to the first case, measuring approximately 15 µm with powdery fine chromatin without nucleoli; minimal nuclear pleomorphism was identified (Fig. 4). No mitoses were identified. Larger, hypercellular fragments were not identified. No capillaries or fibrous stromal fragments were identified.
Macroscopic and Microscopic Pathologic Findings
Macroscopically, the tumors were well circumscribed, firm, and yellow-tan. The tumors from the first two patients had glistening and myxoid areas; there were small foci of cystic degeneration in the Case 1 (Fig. 5) and a large central cystic area in Case 2. The tumor from the patient in Case 3 was solid with very little macroscopic evidence of myxoid change. Microscopically, a pseudocapsule surrounded the tumors; however, focal infiltration into the adjacent soft tissues was identified. The tumors were comprised of bland, fibroblastic spindle cells arranged in a whirling growth pattern within a fibromyxoid background (Fig. 6). The myxoid areas were characterized by low cellularity with a prominent capillary network. However, in some areas the spindle cells were concentrated around blood vessels. Alternating with the myxoid regions were fibrous areas with varying degrees of cellularity, including some hypocellular areas comprised nearly entirely of dense collagenous tissue (Fig. 7). There was minimal nuclear pleomorphism and mitotic figures were very rare.
Despite the histologic similarities between the three cases, there were some differences. The contrast between the fibrous and myxoid areas was prominent in the patients with the primary inguinal and buttock tumors (Cases 1 and 2), but was more subtle in the patient with the recurrent chest wall lesion (Case 3). Although the nuclear morphology uniformly was bland and necrosis was absent, there were zones of greater cellularity and increased mitotic activity, ranging up to two per ten high-power fields in the patient with the recurrent chest wall lesion (Case 3). The metastatic pulmonary lesion resected from the patient in Case 3 exhibited bland cytologic features similar to those of the recurrent lesions (Fig. 8).
The following immunohistochemical stains were performed on representative sections from each case: SMA, MSA, desmin, S-100, CD34, and vimentin. All stains were negative except for vimentin, which was strongly positive in all three tumors.
Ultrastructural analysis was performed on Cases 1 and 3. The tumors were comprised of spindle shaped fibroblastic cells separated by electronlucent myxocollagenous stroma. The cytoplasmic membrane, which terminated in long, slender processes, was coated with flocculent material of moderate electron density. The nuclei contained one moderately large nucleolus with inconspicuous chromatin; the nuclear contours were undulating with frequent indentations. The cytoplasm predominantly was comprised of dilated rough endoplasmic reticulum (RER) containing amorphous material (Fig. 9); occasional mitochondria were identified as well. Intracytoplasmic intermediate filaments were observed; however, actin-type microfilaments and dense bodies were not identified. The ultrastructural features were interpreted as those of fibroblasts.
Three cells were karyotyped from 4-day and 8-day cultures and all were found to be 46, XY. One of the No. 22 chromosomes had enlarged satellites on the short arm. This is a normal variant and to our knowledge is of no known clinical significance.
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.