Epithelioid leiomyosarcoma of the external deep soft tissue.
Abstract: Epithelioid leiomyosarcoma in the external deep soft tissue is extremely rare. Most epithelioid leiomyosarcomas occur in the uterus. We present a case of epithelioid leiomyosarcoma occurring in the muscle of the thigh of a 78-year-old man. Histologically, the tumor predominantly consisted of round or polygonal cells arranged in sheets with a focal spindle cell component. Immunohistochemical analysis revealed that the tumor cells expressed vimentin, [alpha]-smooth muscle actin, and [alpha]-sarcomeric actin. The tumor was negative for desmin, S100 protein, glial fibrillary acidic protein, pan-keratin, epithelial membrane antigen, CAM 5.2, HMB-45, leukocyte common antigen, factor VIII-associated antigen, and CD34. Electron microscopically, some tumor cells contained abundant actin-type filaments in their cytoplasm.
Subject: Leiomyosarcoma (Diagnosis)
Leiomyoma (Diagnosis)
Leg (Muscles)
Authors: Yamamoto, Tetsuji
Minami, Rieko
Ohbayashi, Chiho
Inaba, Mayumi
Pub Date: 04/01/2002
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2002 College of American Pathologists ISSN: 1543-2165
Issue: Date: April, 2002 Source Volume: 126 Source Issue: 4
Geographic: Geographic Scope: Japan Geographic Code: 9JAPA Japan
Accession Number: 84925647
Full Text: Epithelioid leiomyosarcoma is a special variant of smooth muscle cell tumor. Histologically, the tumor is characterized not by its spindled component (which is variably present), but by the presence of round and polygonal cells. This tumor has a striking predilection for the uterus. (1,2) It is extremely rare to encounter epithelioid leiomyosarcomas in deep soft tissues of the extremities, whereas the classic variant more commonly occurs at this site. (3) Herein we describe a case of an epithelioid leiomyosarcoma arising in the muscle of the thigh.

REPORT OF A CASE

A 78-year-old man presented with a 5-month history of a progressively enlarging, tender mass in the right popliteal region. A lateral radiograph of the distal femur showed increased soft tissue density and cortical erosion of the posterior aspect of the distal femur. No calcification was observed within the lesion. Computed tomographic scans and magnetic resonance imaging demonstrated a large mass involving the biceps femoris, medially compressing the femoral vessels (Figure 1). The mass was isointense with normal muscle on TI-weighted magnetic resonance images, and inhomogeneously hyperintense on T2-weighted images. A gallium scintigraphic scan showed markedly increased uptake of isotope in the lesion. Chest computed tomographic scans revealed multiple lesions consistent with metastatic disease. Abdominal computed tomographic scans found no mass lesion. The patient underwent an open biopsy. Pathologic diagnosis of the obtained specimens was epithelioid leiomyosarcoma. The patient subsequently underwent an above-knee amputation. Postoperative chemotherapy was not performed. Two months after surgery, the patient died suddenly of massive intrathoracic hemorrhaging from pulmonary lesions.

[FIGURE 1 OMITTED]

MATERIALS AND METHODS

Open biopsy and amputation specimens were submitted for pathologic examination. Hematoxylin-eosin stain was used for assessing morphology. Special stains included periodic acid-Schiff, phosphotungstic acid-hematoxylin, and reticulin fiber stain.

Paraffin-embedded tissues were immunohistochemically stained with primary antibodies against vimentin (monoclonal, prediluted, Dako, Kyoto, Japan), [alpha]-smooth muscle actin (monoclonal, prediluted, Shandon Lipshaw, Pittsburgh, Pa), desmin (monoclonal, prediluted, Shandon Lipshaw), S100 protein (polyclonal, prediluted, Shandon Lipshaw), glial fibrillary acidic protein (monoclonal, prediluted, Shandon Lipshaw), pan-keratin (polyclonal, prediluted, Dako), epithelial membrane antigen (monoclonal, prediluted, Shandon Lipshaw), CAM 5.2 (monoclonal, 1:5, Becton-Dickinson, San Jose, Calif), HMB-45 (monoclonal, 1:20, Enzo Diagnostics, New York, NY), leukocyte common antigen (monoclonal, prediluted, Shandon Lipshaw), factor VIII-associated antigen (monoclonal, prediluted, Dako), [alpha]-sarcomeric actin (monoclonal, 1:2000, Sigma, St Louis, MO), c-Kit (CD117, polyclonal, 1:50, Dako), and CD34 (monoclonal, 1:20, Dako).

Electron microscopic studies were performed on tissues obtained at biopsy. The fresh tissues were routinely processed for transmission electron microscopy.

RESULTS

Gross pathologic examination of specimens obtained during the open biopsy showed tan to white, friable, soft tumor tissues. A sagittal cut section of the amputated specimen revealed a mass, measuring 8 x 9 x 13 cm, located in the biceps femoris. The mass was ill-defined and extended longitudinally into the muscle. The mass contained large necrotic areas. The solid portions of the tumor were tan to white and soft, with hemorrhagic foci. The posterior surface of the distal femoral cortex was eroded. The medullary cavity of the bone was sclerotic. The femoral artery and vein were compressed medially and were adherent to the tumor. However, there was no intraluminal involvement by the tumor tissues. The media of the vessels was separated from the tumor, and there was no evidence of tumor arising from the vascular smooth muscle.

Microscopically, the tumor predominantly consisted of crowded, round to polygonal cells with distinct cell borders, arranged in sheets (Figure 2). The cells had round or oval vesicular nuclei with multiple prominent nucleoli. The nucleus was randomly located within the cell. The majority of cells had abundant, finely granular, slightly eosinophilic cytoplasm. Some cells possessed clear vacuolated cytoplasm. Mitotic figures were frequent (6-8 per 10-high power fields). Intercellular stroma was scanty and composed of collagen fibers. In some areas, there were small, densely packed, rounded cells with scanty eosinophilic cytoplasm, infiltrating between muscle fibers. In other areas, the tumor tissues consisted of closely associated, fusiform or short spindle-shaped cells with deep eosinophilic cytoplasm, arranged in an organoid pattern. The nuclei of the spindle cells had a coarse chromatin pat tern and were blunt-ended. Tumor vascularity was prominent throughout. At the periphery of the tumor, scattered multinucleated osteoclast-type giant cells were observed.

[FIGURE 2 OMITTED]

Periodic acid-Schiff stain failed to demonstrate glycogen particles in the cytoplasm of the cells. Phosphotungstic acid-hematoxylin stain failed to identify intracytoplasmic myofilaments in either the round or spindle cells. Reticulin fiber stain demonstrated a delicate reticulin network made up of individual cells and small nests.

Immunohistochemically, the cells were diffusely positive for vimentin and [alpha]-smooth muscle actin, and were focally positive for [alpha]-sarcomeric actin. The cells stained negatively for desmin, S100 protein, glial fibrillary acidic protein, keratin, epithelial membrane antigen, CAM 5.2, HMB-45, leukocyte common antigen, factor VIII-associated antigen, c-Kit, and CD34.

Electron microscopically, the tumor was composed of polygonal cells with oval nuclei and electron-lucent cytoplasm. The cytoplasmic processes were poorly developed. The cells were devoid of external laminae. The cytoplasm contained numerous mitochondria, fragmented rough endoplasmic reticula, small lipid droplets, and free ribosomes. Intracytoplasmic pinocytotic vesicles were rarely found. Some cells possessed abundant, randomly arranged thin microfilaments in their cytoplasm (Figure 3). There were some fusiform dense bodies associated with these actin filaments. No intercellular junctions were observed. There were few collagen fibers detected in the extracellular matrix.

[FIGURE 3 OMITTED]

COMMENT

In the past, the gastrointestinal tract was considered as the chief location for the occurrence of epithelioid leiomyosarcoma by virtue of the fact that these mesenchymal neoplasms were largely considered smooth muscle in origin. (1,2) Recent evidence indicates that the vast majority of these gastrointestinal stromal tumors are not true smooth muscle tumors, but arise from a cell that is phenotypically related to the interstitial cell of Cajal and share c-Kit (CD117; stem cell factor receptor) expression. (4) Epithelioid leiomyosarcoma is most commonly encountered in the uterus and is rarely reported in other sites. Epithelioid smooth muscle tumors are rarely encountered outside the abdominal cavity, (5-10) with only a few case reports and small series documenting tumors arising in bone or soft tissue. (8) Suster (10) reported 5 cases of epithelioid leiomyosarcoma in the skin and subcutaneous tissue. Suh et al (9) described an additional case of epithelioid leiomyosarcoma involving the skin of the nose. Chen and Ma (5) reported a case of "benign intravenous leiomyoblastoma" involving the veins and venules of the skin and subcutis in a foot. These reported epithelioid leiomyosarcomas or leiomyomas in the external soft tissues were superficially located. We found only 1 article, by Dobashi et al, (6) describing an epithelioid leiomyosarcoma in the external deep soft tissue. They discussed a 59-year-old patient with a primary tumor in his shoulder, which grew into the subclavian vein with extension into the right atrium. The current case is unique because the tumor mass was located in the biceps femoris with no macroscopic or microscopic association with large vessels.

The histopathologic and immunohistochemical features of this tumor support the diagnosis of epithelioid leiomyosarcoma. The tumor was predominantly composed of round or polygonal cells with slightly eosinophilic cytoplasm arranged in sheets.

Immunohistochemically, the present tumor revealed positive reactivity for [alpha]-smooth muscle actin and [alpha]-sarcomeric actin, but was negative for desmin. It is generally recognized that epithelioid leiomyosarcomas in the external soft tissues do not express desmin to the extent that conventional leiomyosarcomas do. (1) In reviewing immunohistochemical results of epithelioid leiomyosarcomas superficially located in soft tissues, Suster (10) reported that all 5 cases they studied were positive for vimentin and muscle-specific actin HHF35, but were negative for desmin. Suh et al (9) also described similar immunohistochemical findings in a case occurring in the skin.

Ultrastructural findings of epithelioid smooth muscle cell tumors vary in each case. Some investigators observed typical characteristics of smooth muscle cells, including well-formed external laminae, pinocytotic vesicles, numerous cytoplasmic thin filaments, and subplasmalemmal dense patches. (2) However, others have revealed the lack of ultrastructural proof of smooth muscle cell differentiation in a number of cases. (1) Many of the latter cases probably represent examples of the gastrointestinal stromal tumor. The tumor we describe shows ultrastructural features consistent with smooth muscle differentiation. Although many of the tumoral cells were undifferentiated, some cells exhibited ultrastructural evidence of true smooth muscle differentiation.

The histological differential diagnosis in the current case includes malignant melanoma, metastatic carcinoma, epithelioid sarcoma, and metastatic epithelioid leiomyosarcoma from the uterus. Malignant melanoma and metastatic carcinoma were excluded due to the immunohistochemical absence of HMB-45 and keratin expression. In contrast to epithelioid sarcoma, epithelioid leiomyosarcoma lacks the strong and diffuse expression of keratin markers and the overabundance of intermediate filaments detected on ultrastructural evaluation. Metastatic epithelioid leiomyosarcoma from other organs was ruled out through clinical and radiological findings.

The biological behavior of epithelioid leiomyosarcomas in deep external soft tissues is unknown, although the current tumor behaved as a full malignancy. Further studies of additional cases are necessary to accurately access the prognosis of these rare sarcomas.

Accepted for publication August 17, 2001.

References

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(2.) Knapp RH, Wick MR, Goellner JR. Leiomyoblastomas and their relationship to other smooth-muscle tumors of the gastrointestinal tract: an electron-microscopic study. Am J Surg Pathol. 1984;8:449-461.

(3.) Hashimoto H, Daimaru Y, Tsuneyoshi M, Enjoji M. Leiomyosarcoma of the external soft tissues. Cancer. 1986;57:2077-2088.

(4.) Miettinen M, Lasota J. Gastrointestinal stromal tumors: definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch. 2001;438:1-12.

(5.) Chen KTK, Ma CK. Intravenous leiomyoblastoma. Am J Surg Pathol. 1983; 7:591-596.

(6.) Dobashi Y, Nasuno S, Noguchi T, Kameya T. Neuron-specific enolase-producing epithelioid leiomyosarcoma with gross vascular invasion and intracardiac involvement. Arch Pathol Lab Med. 1998;122:1116-1119.

(7.) James CL, Leon ASY. Epithelioid leiomyosarcoma of the left atrium: immunohistochemical and ultrastructural findings. Pathology. 1989;21:308-313.

(8.) Lopez-Barea F, Rodriguez-Peralto JL, Sanchez-Herrera S, Gonzalez-Lopez J, Burgos-Lizaldez E. Primary epithelioid leiomyosarcoma of bone: case report and literature review. Virchows Arch. 1999;434:367-371.

(9.) Suh KS, Jang MS, Chae YS, Kim ST. Epithelioid leiomyosarcoma of the skin. J Dermatol. 1998;25:121-125.

(10.) Suster S. Epithelioid leiomyosarcoma of the skin and subcutaneous tissue: clinicopathologic, immunohistochemical, and ultrastructural study of five cases. Am J Surg Pathol. 1994;18:232-240.

From the Departments of Orthopaedic Surgery (Dr Yamamoto) and Pathology (Drs Minami, Ohbayashi, and Inaba), Kobe University School of Medicine, Kobe, Japan.

Reprints: Tetsuji Yamamoto, MD, Department of Orthopaedic Surgery, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuoku, Kobe 650-0017, Japan (e-mail: yamatetu@med.kobe-u.ac.jp).
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