Review Article

Primary Leiomyosarcoma of Extragnathic Bone Clinicopathologic Features and Reevaluation of Prognosis Muyibat A. Adelani, MD; Stephen J. Schultenover, MD; Ginger E. Holt, MD; Justin M. M. Cates, MD, PhD

● Context.—Leiomyosarcoma most commonly involves the female genital tract and occasionally arises within the retroperitoneum, abdominal cavity, or the soft tissues of the extremity. Presentation as a primary bone tumor is extraordinarily uncommon, potentially leading to misdiagnosis. The prognosis is traditionally thought to be dismal. However, this conclusion is largely based on individual case reports and small series, in some of which the pathologic diagnosis is not well documented. Objective.—To review the clinicopathologic features of well-established cases of primary skeletal leiomyosarcoma and reevaluate the prognostic implications thereof. Data Sources.—A National Center for Biotechnology In-

formation PubMed search of the English language literature identified 104 authenticated cases of primary leiomyosarcoma of extragnathic bone. An additional 3 cases are reported and illustrated herein. Conclusions.—Approximately half of all patients with primary skeletal leiomyosarcoma either presented with metastatic disease or developed metastases within 1 year of diagnosis. The 5-year overall and disease-free survival rates were 59% and 41%, respectively, comparable to that of other skeletal sarcomas. As for other bone and soft tissue sarcomas, high histologic grade and tumor stage are predictive of poor outcome. (Arch Pathol Lab Med. 2009;133:1448–1456)

L

bone. Based on these prior reports, LMS of bone has been considered to portend a dismal prognosis.6–12 We present 3 cases and review the clinical, radiographic, and pathologic characteristics of this tumor. In addition, the prognosis of primary LMS of extragnathic bone is reevaluated, considering only those reported cases in which the published histomorphologic, immunophenotypic, and/or ultrastructural data are conclusive of smooth muscle differentiation.

eiomyosarcoma (LMS) is a malignant neoplasm with histologic, immunophenotypic, and ultrastructural evidence of smooth muscle differentiation. Excluding cutaneous LMS, most cases involve the female genital tract or, less commonly, the retroperitoneum, abdominal and pelvic cavities, or deep soft tissues of the extremities. Rarely, LMS may present as a primary tumor of bone, where it is hypothesized to arise from intraosseous blood vessels, pluripotent mesenchymal stem cells, or intermediate cellular forms such as myofibroblasts.1–4 Since the initial report by Evans and Sanerkin5 in 1965, 131 cases of primary LMS of extragnathic bone have been reported in the English literature. Because it is so uncommon, however, it is likely that primary LMS of bone is often misdiagnosed as undifferentiated pleomorphic sarcoma (previously known as malignant fibrous histiocytoma), fibrosarcoma, fibroblastic osteosarcoma, rhabdomyosarcoma, myofibroblastic sarcoma, or other unspecified sarcoma of bone. In contrast, some reported cases of LMS of bone appear to be better classified as one of these other unusual sarcomas of Accepted for publication January 7, 2009. From the Department of Orthopaedic Surgery, Washington University in St Louis, St Louis, Missouri (Dr Adelani); the Departments of Pathology, Vanderbilt University Medical Center (Drs Schultenover and Cates), and Pathology and Laboratory Medicine, Veteran Affairs Tennessee Valley Healthcare System (Dr Schultenover), Nashville, Tennessee; and the Department of Orthopaedic Surgery, Vanderbilt Orthopaedic Institute, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Holt). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Justin M. M. Cates, MD, PhD, Department of Pathology, Vanderbilt University Medical Center, Medical Center North C-3322, 1161 21st Ave S, Nashville, TN 37232 (e-mail: justin.m.cates@ vanderbilt.edu). 1448 Arch Pathol Lab Med—Vol 133, September 2009

MATERIALS AND METHODS A computerized search of the surgical pathology files at Vanderbilt University Medical Center (Nashville, Tennessee) from 1999 to 2008 yielded 3 cases of primary LMS of bone, after metastases were excluded. These cases were reviewed and clinical data were recorded from the patient’s electronic medical record. A literature search for primary LMS of extragnathic bone was conducted using MEDLINE. Key words used for this search were ‘‘leiomyosarcoma’’ and ‘‘bone.’’ The search was limited to reports written in the English language. Cases arising in the craniofacial bones and those determined to be metastases from other primary sites were excluded. Each case report or series was reviewed for pertinent clinical, radiographic, and pathologic data. Twenty-seven of the 131 reported cases of primary LMS of extragnathic bone were excluded because of inadequate illustrational evidence of smooth muscle differentiation defined by standard histomorphologic, immunophenotypic, or ultrastructural criteria.13,14 For purposes of comparison, all tumors were restaged according to the 6th edition of the American Joint Committee on Cancer TNM staging system for bone sarcomas.15 Histologic grades were recorded using a binary grading system (low or high grade) by conversion from the reported 3- or 4-tiered system grade (intermediate grade sarcomas in the 3-tiered system were considered high grade). For cases in which histologic grade was not explicitly reported, photomicrographs and accompanying histologic descriptions were reviewed and assessed for French Federation of Cancer Centers Sarcoma Group grading criteria (degree of difLeiomyosarcoma of Bone—Adelani et al

actin, and desmin, consistent with LMS. The patient underwent 2 cycles of neoadjuvant Adriamycin and cisplatin. After results of staging studies were negative for distant disease, wide resection of the tumor was performed and followed by reconstruction with a tibial osteoarticular hemiallograft. Within 18 months, the allograft failed and he was converted to a total knee replacement. He has no signs of local recurrence or metastasis 8 years after surgery. Case 3. A 42-year-old woman complained of right ankle pain for 1 year. Radiographs demonstrated a solitary osteolytic lesion occupying the distal 6.5 cm of the fibula. Magnetic resonance imaging confirmed the presence of soft tissue extension involving the tibiofibular syndesmosis and peroneal tendons (Figure 1, B). Incisional biopsy revealed a low-grade LMS. Immunohistochemical studies confirmed the diagnosis. Staging studies revealed no distant disease. Radical resection and ankle arthrodesis was performed. The presence of coagulative tumor necrosis, significant cytologic atypia, and conspicuous mitotic activity observed on sampling the resection specimen prompted alteration of the diagnosis to high-grade LMS. Currently, the patient is undergoing adjuvant chemotherapy. Figure 1. A, Case 1. Plain radiograph demonstrates a lytic lesion with ill-defined borders in the distal femoral metaphysis. B, Case 2. T1weighted magnetic resonance imaging demonstrates a mass in the distal fibula associated with cortical destruction and involvement of tibiofibular syndesmosis.

ferentiation, mitotic activity, and tumor cell necrosis).16 Inadequate data were published for accurate grading of 22 of the 104 cases reviewed in this series. The prognostic value of clinical and pathologic parameters, including age, gender, anatomic location, associated pathologic fracture, histologic grade, American Joint Committee on Cancer stage, and local recurrence was evaluated by standard univariate methods using InStat v3.06 and Prism v5.01 (GraphPad Software, Inc, La Jolla, California).

RESULTS Case Summaries Case 1. A 34-year-old woman presented with a 1-year history of right knee pain. Radiographs showed a 6 ⫻ 4-cm osteolytic lesion with indistinct borders in the metaphysis of the distal femur (Figure 1, A). Magnetic resonance imaging revealed a 7-cm lesion that was hypointense on T1- and hyperintense on T2-weighted imaging; soft tissue extension was also observed. An incisional biopsy revealed atypical spindle cells suggestive of highgrade sarcoma. Immunohistochemical stains demonstrated strong and diffuse reactivity for muscle-specific actin (HHF-35), ␣-smooth muscle actin (1A4), and desmin. The diagnosis of LMS was made. Subsequent staging studies revealed no evidence of pulmonary metastasis. Six cycles of mesna, ifosfamide, Adriamycin, and dacarbazine were administered before wide surgical excision was performed. Eighteen months postoperatively, there is no evidence of disease recurrence. Case 2. A 46-year-old man presented with acute left knee pain and swelling. Radiographs showed a 6-cm osteolytic lesion involving the medial tibial plateau with associated soft tissue swelling and pathologic fracture. Incisional biopsy revealed fascicles of spindle cells with mild to moderate nuclear atypia. Immunohistochemical stains were positive for muscle-specific actin, ␣-smooth muscle Arch Pathol Lab Med—Vol 133, September 2009

CLINICOPATHOLOGIC SUMMARY Clinical Presentation and Radiographic Studies Primary LMS of bone is extremely rare, with only 107 well-documented cases reported, including the current series (Table 1). The incidence of this tumor is highest between the fourth and seventh decades (median age, 47 years; range, 9–87 years). Males and females are affected equally. Most patients (77%) cited pain as their primary complaint. Swelling was also a common presenting symptom. Sixteen of 80 evaluable cases (20%) presented with pathologic fracture. Similar to the more common primary sarcomas of bone, LMS most often involves the appendicular skeleton (Table 2). Potential risk factors were identified in approximately 10% of cases (Table 3). Plain radiographs characteristically show a solitary osteolytic lesion with a permeative appearance, indistinct margins, irregular cortical erosion, and minimal to no sclerosis or periosteal reaction. In the long bones, most cases are metaphyseal, with occasional extension into the diaphysis or epiphysis. Although intralesional calcifications are not considered typical radiographic features of LMS of bone or soft tissue, a recent study demonstrated that nearly 20% of these tumors may contain areas of calcification, mimicking more commonly mineralized neoplasms such as osteosarcoma.17 Computed tomography scans typically show an intramedullary lesion with associated cortical destruction and extension into the surrounding soft tissues. These findings can also be demonstrated by magnetic resonance imaging, in which the lesion is usually hypointense or isointense relative to skeletal muscle on T1-weighted imaging and hyperintense on T2-weighted imaging. The radiographic characteristics of histologically low-grade LMS of bone may be slightly different. The lesional margins are usually more distinct and may often be delimited by a surrounding rim of sclerotic bone, thereby mimicking benign tumors such as nonossifying fibroma or giant cell tumor of bone.1,18–20 Pathologic Features Grossly, LMS of bone often appears well circumscribed and is usually firm and white to gray, with areas of tumor Leiomyosarcoma of Bone—Adelani et al

1449

Table 1. Source, y Age, y/Sex

Reported Cases of Primary Leiomyosarcoma of Extragnathic Bone Grade

AJCC Stage

Evans and Sanerkin,5 1965 73/M Proximal tibia

High

NR

Biopsy

XRT

Met (1), DOD (1)

Overgaard et al, 18/F

Distal femur

High

IIB

Amputation

...

ANED (9)

Meister et al, 1978 75/M

Proximal humerus

NR

NR

Amputation

...

NR

Sanerkin, 1979 66/M 61/F

Distal fibula Proximal tibia

NR NR

NR NR

Curettage Amputation

XRT ...

ANED (27) NR

Shamsuddin et al,25 1980 80/M Distal fibula

NR

NR

Resection

...

NR

Wang et al,3 1980 65/M

Proximal tibia

NR

NR

Resection

...

ANED (6)

Gould et al,43 1982 42/M

Femoral diaphysis

High

IVB

ORIF

...

Met (at diagnosis)

Kawai et al,44 1983 60/F

Proximal femur

High

NR

Resection

A⫹C

Met (1), DOD (7)

High

IIA

Resection

...

ANED (32)

Site

42

Adjuvant Therapy

Procedure

Outcome (Months After Diagnosis)

1977

4

2

von Hochstetter et al,45 1984 60/F Proximal tibia

Berlin et al,7 1987 (Includes 5 cases previously reported by Angervall et al,21 1980) 46/M Proximal humerus High IIA Curettage ... 68/M Distal femur High IIA Resection ... 24/F Distal femur High IIA Resection XRT (Neoadj) 37/F Clavicle Low IA Resection ... 47/M Distal femur High IIA Amputation ... 9/M Proximal tibia High IIA Amputation ... 29/M Distal femur Low IA Amputation ... 74/F Distal femur Low IA Amputation ... 34/M Distal femur High IIA Amputation ... 53/F Acetabulum High IIA Resection ... 69/M Rib Low IA Resection ... 26/M Proximal tibia High IIB Amputation ... 70/M Proximal humerus High IIA Biopsy XRT 70/F Sacroiliac region High IIB Biopsy XRT 69/M Distal tibia High IIB Amputation ... 71/M Distal femur Low IA Resection ...

ANED (132) ANED (82) Met (79), AWD (96) ANED (70) ANED (94) ANED (148) Met (12), DOD (18) Met (45), DOD (81) Met (22), DOD (48) Met (8), LR (37), DOD (39) LR (26), Met (78), DOD (115) Met (15), DOD (18) Met (12), DOD (26) DOD (20) Met (3), AWD (38) Met (27), AWD (30)

Eady et al,19 1987 27/F

Proximal humerus

High

IVB

Amputation

...

Met (at diagnosis), AWD (32)

Kameda et al, 1987 62/F

Proximal femur

High

IIB

Resection

...

Met (12), DOD (19)

Proximal tibia

High

IB

Resection

...

ANED (12)

Marymont and Clanton, 1990 8/F Calcaneus

NR

NR

Amputation

...

ANED (38)

Myers et al, 35/F 70/M 32/F 60/F

NR NR NR NR

NR NR NR NR

Resection Resection Resection Resection

A A A A

Met (24), DOD (48) Met (2), DOD (11) Met (12), LR (72), AWD (78) ANED (23)

9

Young et al, 70/F

20

1988 46

24

1991 Proximal humerus Rib Distal femur Distal femur

(Neoadj) (Neoadj) (Neoadj) (Neoadj)

Young and Freemont,47 1991 56/F Distal femur 83/F Humeral diaphysis 62/M Proximal femur 78/F Femoral diaphysis

NR NR

NR NR

Resection Amputation

... ...

ANED (18) ANED (23)

NR NR

NR NR

Amputation Amputation

... ...

ANED (36) ANED (14)

Abdelwahab et al,48 1993 52/M Proximal femur

NR

NR

Resection

...

ANED (12)

Guse and Weis,22 1994 40/F Distal femur

High

IIA

Resection

...

Met (7), AWD (30)

1450 Arch Pathol Lab Med—Vol 133, September 2009

Leiomyosarcoma of Bone—Adelani et al

Table 1. Source, y Age, y/Sex

Continued

Site

Grade

AJCC Stage

Procedure

Distal femur Clavicle Distal femur Proximal tibia Proximal tibia Distal tibia Proximal tibia Finger

High High High High High Low High High

NR NR NR NR NR NR NR NR

Resection Biopsy Resection Resection Resection Resection Amputation Amputation

... Chemo Chemo Chemo, XRT (Neoadj) ... Chemo (Neoadj) Chemo ...

DOD (1) Met (5), DOD (5) LR (29), Met (42), DOD (60) Met (36), DOD (72) LR (NR), AWD (72) ANED (28) Met (6), ANED (72) ANED (62)

Abdelwahab et al,49 1995 40/M Ilium

NR

NR

Resection

...

NR

Khoddami et al,10 1996 64/M Rib 59/F Proximal tibia 67/F Distal femur 69/F Distal tibia 39/F Distal femur 73/F Distal femur 56/M Ilium

Low High High High Low Low High

III IIA IIA IIA IA IB IIA

Biopsy Resection Resection Amputation Resection Resection Chemo

Chemo Chemo Chemo Chemo ... ... ...

Met (12), DOD Met (42), AWD Met (15), AWD Met (12), DOD ANED (19) ANED (6) ANED (1)

Antonescu et al,1 1997 64/F Ilium and sacrum 33/M Distal femur 41/F Proximal humerus 47/M Proximal tibia 42/F Distal femur 21/F Distal femur 75/F Proximal tibia 42/M Distal femur 33/F Distal femur

High High High High High High High High High

NR NR NR NR NR NR NR NR NR

Resection Resection Resection Resection Resection Resection Resection Resection Resection

Met (NR), DOD (12) LR (NR), Met (NR), DOD (10) LR (NR), Met (NR), DOD (22) ANED (17) ANED (27) ANED (24) ANED (108) Met (NR), AWD (15) LR (NR), AWD (5)

Distal femur Sacroiliac region Proximal tibia Distal femur Sacrum Proximal tibia Proximal tibia Proximal tibia Proximal tibia Proximal tibia Proximal humerus Proximal tibia Proximal tibia Vertebra (L2) Clavicle Proximal tibia Proximal tibia

High High High High High High Low Low Low Low Low Low Low High High High High

NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR

Resection Resection Resection Resection Biopsy Resection Resection Curet/cryo Curet/cryo Curet/cryo Curet/cryo Curet/cryo Curet/cryo Resection Resection Biopsy Biopsy

... MTX, I⫹M, A⫹Ci MAID ... Chemo (Neoadj) A (Neoadj) ... I (Neoadj) MAID, C⫹V (Neoadj); I⫹A⫹M (Adj) ... ... ... Chemo (Neoadj) ... ... ... ... ... ... ... ... ... XRT Chemo, XRT ... ...

ANED (6) LR (6), AWD (7) LR (32), AWD (32) ANED (48) NR Met (NR), AWD (84) LR (24), Met (NR), ANED (72) ANED (10) ANED (6) ANED (96) ANED (60) ANED (6) NR Met (NR), DOD (6) Met (NR), DOD (24) ANED (6) NR

Proximal tibia

Jundt et al,23 1994 87/M 51/M 21/F 34/F 49/M 59/M 11/M 38/M

45/F 64/F 77/M 21/F 42/F 65/M 54/F 58/F 51/M 27/F 39/M 32/M 21/F 36/M 50/F 51/M 36/M Da Silva et al,50 1997 48/M

Adjuvant Therapy

Outcome (Months After Diagnosis)

(48) (90) (31) (24)

NR

IVA

Biopsy

MAID, XRT

Met (at diagnosis), DOD (21)

Amstalden et al,18 1998 29/M Proximal tibia 22/M Distal femur

High High

IIB IIB

Resection Amputation

... B⫹Ac⫹C, A⫹Ci

Met (18), DOD (18) Met (6), DOD (6)

Wirbel et al,12 1998 33/M 54/M 30/F 43/F 42/F

Proximal tibia Ilium/acetabulum Femoral diaphysis Iliosacral joint Distal femur

High High High High High

NR NR NR NR NR

Amputation Amputation Resection Amputation Resection

A ... XRT ... A

Met (3), AWD (25) LR (16), Met (19), DOD (20) Met (14), DOD (27) Met (6), DOD (6) ANED (5)

Aoki et al,6 1998 30/M

Sternum

NR

NR

Resection

I⫹Vd⫹A⫹D (Neoadj); A⫹Ci (Adj)

ANED (46)

Lopez-Barea et al,51 1999 51/F Proximal tibia

High

IIA

Resection

XRT

ANED (36)

Ochiai et al,11 2000 69/M

High

IIA

Biopsy

XRT

Met (4), DOD (6)

Vertebra (C7)

Arch Pathol Lab Med—Vol 133, September 2009

Leiomyosarcoma of Bone—Adelani et al

1451

Table 1. Source, y Age, y/Sex

Site

Grade

AJCC Stage

Continued Adjuvant Therapy

Procedure

Outcome (Months After Diagnosis)

Inoue et al,52 2001 59/F

Patella

Low

IA

Resection

...

ANED (20)

Shen et al, 36/M

Distal femur

High

IIB

Resection

Chemo (Neoadj)

Met (NR), AWD (NR)

Distal femur

NR

NR

Resection

33

Goto et al, 24/F

53

2001 2002

Proximal femur

NR

NR

Resection

P⫹CI (Neoadj); P⫹Ci⫹I Met (28), AWD (54) (Adj) XRT (Neoadj) ANED (36)

Nishida et al,54 2002 47/F

Vertebra (L2)

NR

NR

Resection

XRT (Neoadj)

ANED (25)

Caron et al,55 2004 41/M

Distal femur

Low

IA

Resection

...

ANED (12)

Endo et al,8 2005 67/F

Distal femur

Low

IA

Resection

...

ANED (24)

Narvaez et al,56 2005 35/M

Distal tibia

Low

IA

Resection

...

ANED (60)

Templeton,57 2005 76/M

Ilium

41/F

NR

NR

Resection

...

ANED (36)

Rigopoulou et al,58 2007 42/M Proximal humerus

High

IIB

Resection

...

ANED (24)

Gonzalez-Billalabeitia et al,59 2008 33/F Distal tibia

Low

IA

Resection

...

ANED (48)

Current series 34/F Distal femur High IIA Resection A⫹I (Neoadj) ANED (18) 46/M Proximal tibia Low IA Resection A⫹Ci (Neoadj) ANED (121) 42/F Distal fibula High IIA Resection Chemo ANED (6) Abbreviations: A, Adriamycin; Ac, actinomycin; Adj, adjuvant; AJCC, American Joint Committee on Cancer; ANED, alive with no evidence of disease; AWD, alive with evidence of disease; B, bleomycin; C, cyclophosphamide; Chemo, chemotherapy; Ci, cisplatin; Curet/cryo, curettage/ cryosurgery; D, dacarbazine; DOD, dead of disease; I, ifosfamide; LR, local recurrence; M, mesna; MAID, mesna, Adriamycin, ifosfamide, and dacarbazine; Met, metastasis; MTX, methotrexate; Neoadj, neoadjuvant; NR, not reported; ORIF, open reduction, internal fixation; P, pirarubicin; V, vincristine; Vd, vindesine; XRT, external beam radiation therapy.

Table 2.

Anatomic Sites of Origin of Primary Skeletal Leiomyosarcoma

Anatomic Location

No.

Distal femur Proximal tibia

31 28

Pelvis Sacroiliac region Ilium Acetabulum Sacrum

10 4 4 1 1

Proximal humerus Proximal femur Distal tibia Clavicle Rib Vertebral bodya Femoral diaphysis Distal fibula Humeral diaphysis Sternum Finger Patella Calcaneus a Two involved the lumbar spine and one arose in

8 5 5 3 3 3 3 3 1 1 1 1 1 the cervical spine.

1452 Arch Pathol Lab Med—Vol 133, September 2009

necrosis or hemorrhage in some cases (Figure 2). The histologic features of LMS of bone are identical to LMS arising in more common anatomic locations.13,14 The classic pattern is that of fascicles of spindle-shaped cells, intersecting at wide, often perpendicular angles (Figure 3, A). Tumor cells have blunt-ended, cigar-shaped nuclei and abundant, eosinophilic, often fibrillary cytoplasm. Occasionally, multinucleated giant cells may be seen.1,9,12,18,21–25 Despite the gross circumscription of these tumors, extensive infiltration of adjacent trabecular bone is seen on microscopic examination (Figure 3, B). Importantly, there is no associated osteoid or chondroid matrix deposition by tumor cells. Most primary LMS of bone are of high histologic grade; only 23 of 85 (27%) previously reported cases were low grade. Immunohistochemistry is often required for accurate diagnosis, particularly for poorly differentiated anaplastic tumors. Muscle-specific actin was positive in 56 of 60 reported cases (93%), and ␣-smooth muscle actin was positive in 59 of 62 cases (95%). Desmin staining can be helpful, but only about half of the reported cases (42 of 74) were positive for it (Figure 4, A). It should be noted that these markers are not specific for smooth muscle and are positive in myofibroblastic sarcoma and pleomorphic rhabdomyosarcoma. Focal or weak staining may also be seen in undifferentiated pleomorphic sarcoma and osteoLeiomyosarcoma of Bone—Adelani et al

Table 3.

Potential Risk Factors Associated With Primary Leiomyosarcoma (LMS) of Bone

Risk Factor With Source, y

Indication

Years Prior to LMS

Location

Radiation therapy Abdelwahab et al,48 1995 Antonescu et al,1 1997 Antonescu et al,1 1997 Aoki et al,6 1998 Berlin et al,7 1987 Wirbel et al,12 1998

Testicular seminoma Mediastinal seminoma Breast cancer Mediastinal seminoma Giant cell tumor Cervical cancer

16 11 18 11 31 11

Ilium Vertebra (L2) Clavicle Sternum Distal femur Sacroiliac joint

Chemotherapy Antonescu et al,1 1997 Antonescu et al,1 1997

Leukemia Non-Hodgkin lymphoma

10 35

Proximal tibia Proximal tibia

Paget disease of bone Young and Freemont,47 1991 Antonescu et al,1 1997

NA NA

NR NR

Femoral diaphysis NR

12

Distal femur

Orthopaedic implant Caron et al,55 2004 ACL reconstruction Abbreviations: ACL, anterior cruciate ligament; NA, not applicable; NR, not reported.

sarcoma.26,27 H-caldesmon and smooth muscle myosin may be used to demonstrate smooth muscle differentiation and exclude myofibroblastic sarcoma but have not been extensively studied in this diagnostic setting.8,28–30 In equivocal cases, ultrastructural examination can confirm

the presence of smooth muscle differentiation, particularly when myofibroblastic sarcoma is a diagnostic consideration.28,29,31 Cytokeratin expression was described in 10 of 29 cases (34%) of LMS of bone. However, 8 of these 10 keratinpositive cases are from 2 studies published more than 10 years ago in which the immunohistochemical protocols are not described in detail.23,24 Similarly, 4 of 5 reported S100-positive cases were presented in a single report.12 Only one of an additional 20 cases stained for S100 protein was reportedly positive.10 The cytopathologic features of LMS are dependent on the histologic grade of the neoplasm. Well-differentiated tumors often yield hypocellular smears containing fascicles of spindle cells with relatively abundant dense fibrillar to granular cytoplasm, elongated, blunt-ended nuclei, and minimal nuclear atypia.32 Single intact cells are usually scant. In contrast, aspirates of high-grade LMS are typically cellular and composed of many single or small, disorganized groups of variably sized spindle cells that show pronounced nuclear pleomorphism, hyperchromasia, and prominent nucleoli (Figure 4, B). Sanerkin2 initially described the presence of numerous binucleate and multinucleated giant cells in fine-needle aspirates. Evidence of smooth muscle differentiation in high-grade LMS may be extremely difficult to discern in cytologic specimens without the assistance of ancillary studies. Treatment and Prognosis

Figure 2. A firm, gray-white intramedullary mass with a central area of hemorrhage and necrosis in resection specimen from case 1. Arch Pathol Lab Med—Vol 133, September 2009

Before definitive therapy is initiated, the possibility of metastasis from another site of origin, most commonly the gynecologic tract or retroperitoneum, must be excluded. Radiographic features that would suggest the possibility of metastasis include multiple, small tumors or involvement of unusual anatomic sites, such as the axial skeleton or proximal femur.24,33–35 Although LMS arising in soft tissue could theoretically involve adjacent bone, concern for this possibility should be extremely low, as even highgrade soft tissue sarcomas tend to follow the path of least resistance and are more likely to slowly erode cortical bone rather than aggressively invade the underlying medullary cavity.36 Once the diagnosis of primary LMS of bone is conLeiomyosarcoma of Bone—Adelani et al

1453

Figure 3. A, Characteristic growth pattern of leiomyosarcoma composed of perpendicular fascicles of spindle cells with cigar-shaped nuclei and abundant eosinophilic cytoplasm (hematoxylin-eosin, original magnification ⫻200). B, Tumor infiltrates preexisting trabeculae of bone, indicative of an aggressive growth pattern (hematoxylin-eosin, original magnification ⫻40). Figure 4. A, Immunohistochemical stain from case 3 demonstrating strong and diffuse immunoreactivity for desmin (original magnification ⫻400). B, Fine-needle aspiration specimen showing variably sized spindle cells with pronounced nuclear pleomorphism, hyperchromasia, and prominent nucleoli, indicative of high-grade sarcoma (Papanicolaou, original magnification ⫻1000).

firmed, the treatment of choice is wide surgical resection. Approximately 20% of reported cases were treated by amputation; however, most of these cases predated limb salvage techniques. Both chemotherapy and external beam radiation therapy have been used to augment surgical Table 4.

Sites of Distant Metastases From Primary Skeletal Leiomyosarcoma

Anatomic Location

No.

Lung Skeletal Spine or skull Liver Skin Soft tissues Adrenal gland Kidney Bladder Mediastinum Central nervous system Pleura

33 13 7 7 4 2 2 1 1 1 1 1

1454 Arch Pathol Lab Med—Vol 133, September 2009

treatment, although the efficacy of chemotherapy has not been confirmed. Some authors have reported that LMS of bone is relatively radioresistant.1,11 For example, in their review of 33 cases (26 of which were extragnathic), Antonescu et al1 were not able to demonstrate a therapeutic benefit of adjuvant therapy in the treatment of primary LMS of bone. Efficacy of adjuvant therapy was difficult to evaluate in this series because of the lack of uniformity in treatment regimens and the limited number of cases available for comparison. Therefore, recommendations regarding adjuvant therapy for primary LMS of bone are difficult to substantiate. Of the 49 cases for which tumor stage could be assigned, 7 patients (all with high-grade LMS) presented with metastatic disease and 1 patient with low-grade LMS had discontinuous tumors within a rib (stage III). Similar to other primary sarcomas of bone, the most common site of metastasis is the lung; skeletal metastases (particularly to the axial skeleton) were also common (Table 4). Univariate Kaplan-Meier analysis of the reported cases demonstrated that tumors of advanced American Joint ComLeiomyosarcoma of Bone—Adelani et al

Table 5.

Overall and Disease-Free Survival of Patients With Primary Skeletal Leiomyosarcoma No.

5-Year Overall Survival Rate, %

Median Overall Survival, Months

5-Year Disease-Free Survival Rate, %

Median Disease-Free Survival, Months

AJCC TNM Stage Stage I Stage IIA Stage IIB Stage III or IV

15 17 9 8

91 60 29 0

115 ⬎148 19 11 P ⬍ .001

53 46 15 0

⬎148 42 15 11 P ⬍ .001

Histologic grade High grade Low grade

58 22

48 84

15 115 P ⫽ .04

29 63

20 72 P ⫽ .008

Abbreviations: AJCC, American Joint Committee on Cancer.

mittee on Cancer TNM stage and high histologic grade are associated with adverse outcomes (Table 5). Patients with stage I and IIA tumors show prolonged overall and disease-free survival compared with those with stage IIB, III, or IV tumors (Figure 5, A). A post hoc comparison limited to patients with nonmetastatic, high-grade LMS confirmed that patients with stage IIA tumors (ⱕ8 cm in greatest dimension) have longer overall survival compared with patients with stage IIB tumors (⬎8 cm in greatest dimension; log-rank test, P ⫽ .007). High histologic grade also correlated with decreased overall and disease-free survival (Table 5; Figure 5, B). Among cases with a reported follow-up duration of at least 2 years, 24 of 47 patients (51%) with high-grade tumors died a median of 19 months after definitive surgery (range, 1–72 months). An additional 11 patients (23%) were alive with disease at last follow-up. Distant metastasis occurred in 27 patients (57%) with high-grade LMS (median interval to metastasis, 12 months; range, 3–84 months). During comparable follow-up intervals, 4 deaths (29%) occurred in 14 patients with low-grade LMS (median survival interval, 65 months; range, 18–115 months). Two additional patients (14%) with low-grade LMS were alive with metastatic disease 30 and 72 months after sur-

gery. Six patients (43%) with low-grade LMS developed metastatic disease (median metastasis-free interval, 36 months; range, 12–78 months). Local recurrence was relatively uncommon, occurring in 15% of patients with high-grade LMS and 14% of patients with low-grade LMS, usually within 3 years of initial surgical resection. Locally recurrent disease had no discernible impact on overall survival (log-rank test, P ⫽ .73). Although tumors arising in the axial skeleton correlated with decreased overall survival, this analysis was confounded by the tendency for axial tumors to present in advanced American Joint Committee on Cancer stage (Fisher exact test, P ⫽ .007). Patients with postradiation LMS had significantly shorter median overall survival (15 months) than those with tumors not arising in previously irradiated fields (115 months; log-rank test, P ⫽ .01). Due to the small number of cases available for comparison, it is unclear whether LMS of bone arising in the setting of previous chemotherapy, Paget disease of bone, or adjacent to orthopedic implants portends a worse prognosis, as demonstrated for other primary bone sarcomas.37–40 There were no statistically significant differences in either overall or disease-free survival based on age, sex, or associated pathologic fracture.

Figure 5. Kaplan-Meier curves depicting differences in overall survival according to American Joint Committee on Cancer TNM stage (A) and disease-free survival by histologic grade (B). For analysis of tumor stage, cases were categorized as stage I (n ⫽ 15), stage IIA (n ⫽ 17), stage IIB (n ⫽ 9), and stage III or IV (n ⫽ 8). Differences in survival curves were determined using the log-rank test. Arch Pathol Lab Med—Vol 133, September 2009

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COMMENT Presentation of LMS as a primary bone tumor is extraordinarily uncommon. Despite publication of one relatively large series, the clinical, radiographic, and histopathologic features of these tumors and their associated prognostic factors are not well defined.1 The radiologic differential diagnosis is often broad and includes fibroblastic osteosarcoma, dedifferentiated chondrosarcoma, or undifferentiated pleomorphic sarcoma. Depending on the dominant morphologic features, the pathologic differential diagnosis can also be quite diverse. Immunohistochemical or ultrastructural analysis is required to confirm the diagnosis in many cases. Primary LMS of bone has traditionally been considered to have a dismal prognosis.6–12 However, this conclusion was based on a limited number of case reports and small series, some of which were poorly documented. In this review, the 5-year overall survival rate of LMS of bone (59%) is similar to those of conventional intramedullary osteosarcoma and Ewing sarcoma (each approximately 50%) and chondrosarcoma (68%).41 We thank Jean McClure for editorial assistance. References 1. Antonescu CR, Erlandson RA, Huvos AG. Primary leiomyosarcoma of bone: a clinicopathologic, immunohistochemical, and ultrastructural study of 33 patients and a literature review. Am J Surg Pathol. 1997;21:1281–1294. 2. Sanerkin NG. Primary leiomyosarcoma of the bone and its comparison with fibrosarcoma. Cancer. 1979;44:1375–1387. 3. Wang TY, Erlandson RA, Marcove RC, Huvos AG. Primary leiomyosarcoma of bone. Arch Pathol Lab Med. 1980;104:100–104. 4. Meister P, Konrad E, Gokel JM, Remberger K. Case report 59. Skeletal Radiol. 1978;2:265–267. 5. Evans DM, Sanerkin NG. Primary leiomyosarcoma of bone. J Pathol Bacteriol. 1965;90:348–350. 6. Aoki T, Ozeki Y, Watanabe M, Tanaka S, Isaki H, Terahata S. Development of primary leiomyosarcoma of the sternum postirradiation: report of a case. Surg Today. 1998;28:1326–1328. 7. Berlin O, Angervall L, Kindblom LG, Berlin IC, Stener B. Primary leiomyosarcoma of bone: a clinical, radiographic, pathologic-anatomic, and prognostic study of 16 cases. Skeletal Radiol. 1987;16:364–376. 8. Endo K, Takahashi M, Matsui Y, Hasegawa T, Yasui N. Bone tumor of the distal femur in a 67-year-old woman. Clin Orthop Relat Res. 2005;440:262–268. 9. Kameda N, Kagesawa M, Hiruta N, Akima M, Ohki M, Matsumoto T. Primary leiomyosarcoma of bone: a case report and review of the literature. Acta Pathol Jpn. 1987;37:291–303. 10. Khoddami M, Bedard YC, Bell RS, Kandel RA. Primary leiomyosarcoma of bone: report of seven cases and review of the literature. Arch Pathol Lab Med. 1996;120:671–675. 11. Ochiai H, Yamakawa Y, Fukushima T, Yamada H, Hayashi T. Primary leiomyosarcoma of the cervical spine causing spontaneous compression fracture: report of an autopsy case. Neuropathology. 2000;20:60–64. 12. Wirbel RJ, Verelst S, Hanselmann R, Remberger K, Kubale R, Mutschler WE. Primary leiomyosarcoma of bone: clinicopathologic, immunohistochemical, and molecular biologic aspects. Ann Surg Oncol. 1998;5:635–641. 13. Evans HL, Shipley J. Leiomyosarcoma. In: Fletcher CDM, Unni KK, Mertens F, eds. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2002:131–134. World Health Organization Classification of Tumours. 14. Weiss SW, Goldblum JR. Leiomyosarcoma. In: Enzinger FM, Weiss SW, eds. Soft Tissue Tumors. 4th ed. St Louis, MO: The CV Mosby Co; 2001:727–748. 15. Green FL, Page DL, Fleming ID, et al. AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer-Verlag; 2002:193–200. 16. Kempson RL, Fletcher CDM, Evans HL, Hendrickson MR, Sibley RK. Tumors of the Soft Tissues. Washington, DC: Armed Forces Institute of Pathology; 2001:507. Atlas of Tumor Pathology; 3rd series, fascicle 30. 17. Bush CH, Reith JD, Spanier SS. Mineralization in musculoskeletal leiomyosarcoma: radiologic-pathologic correlation. AJR Am J Roentgenol. 2003;180: 109–113. 18. Amstalden EM, Barbosa CS, Gamba R. Primary leiomyosarcoma of bone: report of two cases in extragnathic bones. Ann Diagn Pathol. 1998;2:103–110. 19. Eady JL, McKinney JD, McDonald EC. Primary leiomyosarcoma of bone: a case report and review of the literature. J Bone Joint Surg Am. 1987;69:287– 289. 20. Young CL, Wold LE, McLeod RA, Sim FH. Primary leiomyosarcoma of bone. Orthopedics. 1988;11:615–618. 21. Angervall L, Berlin O, Kindblom LG, Stener B. Primary leiomyosarcoma of bone: a study of five cases. Cancer. 1980;46:1270–1279.

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22. Guse TR, Weis LD. Leiomyosarcoma of the femur in a patient with a history of retinoblastoma: a case report. J Bone Joint Surg Am. 1994;76:904–906. 23. Jundt G, Moll C, Nidecker A, Schilt R, Remagen W. Primary leiomyosarcoma of bone: report of eight cases. Hum Pathol. 1994;25:1205–1212. 24. Myers JL, Arocho J, Bernreuter W, Dunham W, Mazur MT. Leiomyosarcoma of bone: a clinicopathologic, immunohistochemical, and ultrastructural study of five cases. Cancer. 1991;67:1051–1056. 25. Shamsuddin AK, Reyes F, Harvey JW, Toker C. Primary leiomyosarcoma of bone. Hum Pathol. 1980;11:581–583. 26. Hasegawa T, Hirose T, Kudo E, Hizawa K, Usui M, Ishii S. Immunophenotypic heterogeneity in osteosarcomas. Hum Pathol. 1991;22:583–590. 27. Ueda T, Araki N, Mano M, et al. Frequent expression of smooth muscle markers in malignant fibrous histiocytoma of bone. J Clin Pathol. 2002;55:853– 858. 28. Fisher C. Myofibrosarcoma. Virchows Arch. 2004;445:215–223. 29. Fisher C. Myofibroblastic malignancies. Adv Anat Pathol. 2004;11:190– 201. 30. Watanabe K, Ogura G, Tajino T, Hoshi N, Suzuki T. Myofibrosarcoma of the bone: a clinicopathologic study. Am J Surg Pathol. 2001;25:1501–1507. 31. Montgomery E, Goldblum JR, Fisher C. Myofibrosarcoma: a clinicopathologic study. Am J Surg Pathol. 2001;25:219–228. 32. DeMay RM. The Art and Science of Cytopathology. Chicago, IL: ASCP Press; 1996. 33. Shen SH, Steinbach LS, Wang SF, Chen WY, Chen WM, Chang CY. Primary leiomyosarcoma of bone. Skeletal Radiol. 2001;30:600–603. 34. Fornasier VL, Paley D. Leiomyosarcoma in bone: primary or secondary?: a case report and review of the literature. Skeletal Radiol. 1983;10:147–153. 35. Meltzer CC, Fishman EK, Scott WW Jr. Computed tomography appearance of bone metastases of leiomyosarcoma. Skeletal Radiol. 1992;21:445–447. 36. Delsmann BM, Pfahler M, Nerlich A, Refior HJ. Primary leiomyosarcoma affecting the ankle joint. Foot Ankle Int. 1996;17:420–424. 37. Deyrup AT, Montag AG, Inwards CY, Xu Z, Swee RG, Unni K. Sarcomas arising in Paget disease of bone: a clinicopathologic analysis of 70 cases. Arch Pathol Lab Med. 2007;131:942–946. 38. Keel SB, Jaffe KA, Nielsen GP, Rosenberg AE. Orthopaedic implant-related sarcoma: a study of twelve cases. Mod Pathol. 2001;14:969–977. 39. McDonald DJ, Enneking WF, Sundaram M. Metal-associated angiosarcoma of bone: report of two cases and review of the literature. Clin Orthop Relat Res. 2002;396:206–214. 40. Sim FH, Cupps RE, Dahlin DC, Ivins JC. Postradiation sarcoma of bone. J Bone Joint Surg Am. 1972;54:1479–1489. 41. Damron TA, Ward WG, Stewart A. Osteosarcoma, chondrosarcoma, and Ewing’s sarcoma: National Cancer Data Base Report. Clin Orthop Relat Res. 2007;459:40–47. 42. Overgaard J, Frederiksen P, Helmig O, Jensen OM. Primary leiomyosarcoma of bone. Cancer. 1977;39:1664–1671. 43. Gould VE, Patel NS, Dardi LE, Memoli VA. Painful lytic lesion of the left femur in an adult male. Ultrastruct Pathol. 1982;3:301–307. 44. Kawai T, Suzuki M, Mukai M, Hiroshima K, Shinmei M. Primary leiomyosarcoma of bone: an immunohistochemical and ultrastructural study. Arch Pathol Lab Med. 1983;107:433–437. 45. von Hochstetter AR, Eberle H, Ruttner JR. Primary leiomyosarcoma of extragnathic bones: case report and review of literature. Cancer. 1984;53:2194– 2200. 46. Marymont JV, Clanton TO. Leiomyosarcoma of the os calcis. Foot Ankle. 1990;10:239–242. 47. Young MP, Freemont AJ. Primary leiomyosarcoma of bone. Histopathology. 1991;19:257–262. 48. Abdelwahab IF, Hermann G, Kenan S, Klein MJ, Lewis MM. Case report 794. Skeletal Radiol. 1993;22:379–381. 49. Abdelwahab IF, Kenan S, Hermann G, Klein MJ, Lewis MM. Radiationinduced leiomyosarcoma. Skeletal Radiol. 1995;24:81–83. 50. Da Silva LF, Mejjad O, Vittecoq O, et al. Leiomyosarcoma of the tibia: report of a case. Rev Rhum Engl Ed. 1997;64:835–838. 51. 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. 52. Inoue S, Tanaka K, Sakamoto A, Matsuda S, Tsuneyoshi M, Iwamoto Y. Primary leiomyosarcoma of the patella. Skeletal Radiol. 2001;30:530–533. 53. Goto T, Ishida T, Motoi N, et al. Primary leiomyosarcoma of the femur. J Orthop Sci. 2002;7:267–273. 54. Nishida J, Kato S, Shiraishi H, et al. Leiomyosarcoma of the lumbar spine: case report. Spine. 2002;27:42E–46E. 55. Caron JJ, Pambuccian SE, Steen JT, Cheng EY. Leiomyosarcoma of the distal femur after anterior cruciate ligament reconstruction. Clin Orthop Relat Res. 2004;419:214–217. 56. Narvaez JA, De Lama E, Portabella F, Ortega R, Condom E. Subperiosteal leiomyosarcoma of the tibia. Skeletal Radiol. 2005;34:42–46. 57. Templeton K. Leiomyosarcoma of bone. Am J Orthop. 2005;34:249–251. 58. Rigopoulou A, Vlychou M, Ostlere SJ, Gibbons CL, Athanasou NA. A primary leiomyosarcoma of bone containing pseudoepithelial plexiform elements. Skeletal Radiol. 2007;36:791–796. 59. Gonzalez-Billalabeitia E, Quintela-Fandino M, Alemany I, et al. Coexistence of two rare sarcomas: primary leiomyosarcoma of bone and epithelioid hemangioendothelioma of the liver. Sarcoma. 2008;2008:416085. doi:10.1155/ 2008/416085.

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