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Leiomyosarcoma is a type of sarcoma which is a neoplasm of smooth muscle. (When benign, it is called a leiomyoma.)

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Malignant Gastrointestinal Leiomyosarcoma and Gastrointestinal Stromal Tumor With Prominent Osteoclast-like Giant Cells
From Archives of Pathology & Laboratory Medicine, 4/1/04 by Insabato, Luigi

Context.-One case of leiomyosarcoma and one case of gastrointestinal stromal tumor with prominent osteoclast-like giant cells have so far been reported in the digestive tract.

Objective.-To ascertain the clinicopathologic features and biologic behavior of these tumors, we report 3 additional cases of leiomyosarcoma of the gastrointestinal tract and one malignant gastrointestinal stromal tumor.

Design.-Histologic and immunohistochemical examinations were performed. Clinical and follow-up data were recorded, and the literature was reviewed.

Results.-The age of the patients ranged from 50 to 68 years (mean, 62 years). One of the lesions arose in the stomach, one in the ileum, and 2 in the colon. Three tumors showed a strong positivity for muscle actin and desmin and were diagnosed as leiomyosarcomas, 2 of them showing spindle cells and 1 of them showing epithelioid cells. The fourth tumor reacted strongly positive for c-Kit (CD117) and vimentin, and it was diagnosed as an epithelioid malignant gastrointestinal stromal tumor. All tumors were characterized by numerous osteoclast-like giant cells that were unevenly distributed and that, using immunohistochemistry, reacted strongly with CD68.

Conclusions.-Malignant stromal tumors with osteoclast-like giant cells of the gastrointestinal tract are rare entities, are more commonly of a myogenic origin such as leiomyosarcoma, and seem to have an aggressive behavior.

(Arch Pathol Lab Med. 2004;128:440-443)

The occurrence of osteoclast-like giant cells (OGCs) in extraskeletal tumors, though uncommon, is well known, particularly in malignant epithelial tumors such as OGC carcinomas of the breast1 and pancreas2 and in mesenchymal tumors of varying types.3,4 Moreover, their presence, albeit rare, is well documented in leiomyosarcomas of the uterus,5,6 and it has been reported in deep soft tissue.7 OGCs are generally thought to represent a peculiar nonneoplastic tissue response. We report 3 cases of leiomyosarcoma of the gastrointestinal tract and 1 case of malignant gastrointestinal stromal tumor (GIST), all characterized by prominent stromal OGCs. To our knowledge, in the English literature, only 1 case of epithelioid leiomyosarcoma with OGCs in the rectum8 and 1 case of malignant spindle cell GIST with OGCs9 have been reported.


Four cases of nonepithelial malignant tumors of the gastrointestinal tract with prominent OGCs were collected from the files of the Departments of Pathology of the University "Federico II" Naples, Italy and the University of Basel, Switzerland. The clinicopathologic data are summarized in Table 1.

Case 1

A 65-year-old man presented with a huge fungating mass of the stomach, encountered on endoscopy. The patient underwent a gastrectomy, and he died of pulmonary metastases 24 months after surgery.

Case 2

A 50-year-old man underwent a small intestinal large resection for a 7-cm iliac mass encountered on computed tomography examination. The patient was alive and without evidence of disease 6 years after diagnosis.

Case 3

A 65-year-old man underwent a descending colon re-section for a mass that was 10 cm in diameter. He died of disease with multiple visceral metastases 28 months after surgery.

Case 4

A 68-year-old woman underwent a descending colon resection for a huge mass that was 11 cm in diameter. She died of disease due to lung and abdominal metastases 6 months after surgery.


Three tumors (cases 1, 2, and 3) were leiomyosarcomas; 1 was a malignant GIST (case 4). Grossly, all tumors were fairly large and well circumscribed, ranging from 7 to 11 cm (Figure 1, a and b). In 2 leiomyosarcomas (cases 1 and 3) and in the GIST (case 4) (Figure 1, b), the tumor was only slightly cohesive to the gastrointestinal wall, with foci of necrosis on the cut surface. In the leiomyosarcoma of case 2, the tumor was polypoid and protruding into the intestinal lumen (Figure 1, a). Histologically, 2 leiomyosarcomas (cases 1 and 2) were composed of neoplastic spindle cells with eosinophilic cytoplasm and spindle-shaped nuclei arranged in a fascicular pattern (Figure 2, a). The leiomyosarcoma of case 3 was composed of neoplastic epithelioid cells with a more diffuse pattern (Figure 2, b). The tumor cells had slightly eosinophilic cytoplasm and pleomorphic nuclei with prominent nucleoli. All 3 leiomyosarcomas (cases 1, 2, and 3) showed hypercellularity, nuclear pleomorphism, and foci of necrotic tissue, along with high mitotic activity (2 mitoses per high-power field). In 2 cases (cases 1 and 3), the tumor diffusely infiltrated the outer layers of the gastrointestinal wall. In one case (case 2), the tumor developed predominantly in the submucosa, forming a polypoid tumor mass in the intestinal lumen. The GIST (case 4) showed characteristics of a highly cellular tumor (Figure 3, a) and was predominantly composed of epithelioid cells with slightly pleomorphic nuclei, a vesicular-appearing chromatin pattern and prominent nucleoli, small foci of necrosis, and high mitotic activity (>15/50 high-power fields). In all of the tumors, an abundant number of irregularly scattered OGCs were observed. These benign stromal giant cells showed abundant, strongly eosinophilic, well-defined cytoplasm, with numerous small, round or ovoid nuclei and inconspicuous nucleoli (Figure 3, a; inset). These features were observed on the cytologic smears obtained in 2 other cases as well (cases 2 and 3) by scraping the cut surface of the tumor. The smears were moderately cellular and were composed of neoplastic spindle cells in the leiomyosarcoma of case 2 and of slightly cohesive epithelioid cells with pleomorphic nuclei and prominent nucleoli in the leiomyosarcomas of case 3, both of which were mixed with numerous OGCs.

A panel of immunostains, including antibodies against vimentin, CD117, CD34, desmin, smooth muscle actin, S100 protein, neuron-specific enolase, Ki-67, and CD68, was applied to representative sections of the tumors using the avidin-biotin complex technique (Table 2).

Immunohistochemically, the 3 leiomyosarcomas showed reactivity for vimentin and muscle actin and, focally, for desmin and were negative for CD117, CD34, neuron-specific enolase, and S100 protein. The GIST was strongly positive for CD117 and vimentin, slightly positive for S100 protein, and negative for CD34. Ki-67 staining showed a high proliferative rate (50%) in 2 leiomyosarcomas (cases 1 and 3); 1 leiomyosarcoma (case 2) and the GIST (case 4) showed a low proliferative rate (20%). OGCs strongly reacted with CD68 (Figure 3, b) but failed to be stained with myogenic markers (Table 3).

The gross and microscopic findings described in the first 3 cases, along with the immunohistochemical characteristics, excluded the possibility of a benign smooth muscle tumor and were consistent with the diagnosis of leiomyosarcoma. The GIST (case 4) was a highly cellular tumor, with pleomorphic nuclei, necrosis, and high mitotic activity (>15 mitoses per 50 high-power fields), and it was considered a high-risk tumor, according to the criteria of Miettinen et al.10 Moreover, since this tumor had given distant metastases, it was considered a malignant GIST.


Mesenchymal tumors of the gastrointestinal tract may occur in any portion of the intestine-but mostly, in the large intestine-and they show immunohistochemical evidence of smooth muscle differentiation, while most GISTs occur in the stomach and small intestine. The latter has been recognized as a distinct pathologic entity, showing immunopositivity for c-Kit (CD117) and CD34, which suggests a histogenetic origin from interstitial Cajal cells or from their mesenchymal precursor cells.11

Extraskeletal neoplasms with OGCs are uncommon. They are most frequently reported in malignant epithelial tumors of the breast1 and pancreas2; quite rarely, they are reported in other sites,12 including soft tissue tumors.3,4 The primary giant cell tumor of soft tissue is a rare tumor located in both superficial and deep soft tissue. Recently, a rare occurrence of a giant cell tumor of soft tissue occurring primarily in the dermis was described,13 and 2 cases of primarily mediastinal giant cell tumors have also been reported.14 Moreover, a series of 8 cases of a variant of soft tissue leiomyosarcoma with OGCs mimicking the giant cell variant of malignant fibrous histiocytoma has been reported.7 This variant of leiomyosarcoma has also recently been recognized in the uterus.5,6 In the English literature, only 1 case of epithelioid leiomyosarcoma with OGCs in the rectum8 and 1 case of malignant spindle cell GIST in the small intestine and abdominal wall9 have been reported. We report 4 cases of malignant stromal tumors with prominent OGCs. Two tumors were spindle cell leiomyosarcomas (gastric and ileac); 1 was an epithelioid leiomyosarcoma of the colon; and 1 was an epithelioid GIST of the colon. The significance of OGCs in tumors, as well as their pathogenic mechanisms of formation, remains obscure.

Recent analyses of bone giant cell tumors reveal that neoplastic spindle cells may secrete a variety of cytokines and differentiation factors, including MCP1 (monocyte chemoattractant protein 1), ODF (osteoclast differentiation factor), and M-CSF (macrophage colony-stimulating factor). These molecules are monocyte chemoattractants and are essential for osteoclast differentiation, which suggests that the neoplastic spindle cell stimulates blood monocyte immigration into tumor tissues, enhancing their fusion into osteoclast-like multinucleate giant cells.15,16

Malignant giant cells can be recognized in leiomyosarcomas and GISTs, while OGCs are benign stromal cells that immunohistochemically express CD68 but not myogenic markers. The distinction between sarcomatoid carcinoma, leiomyosarcoma, and GIST can be particularly difficult when only the spindle cell component is present. Diffuse strong staining for myogenic markers support the diagnosis of leiomyosarcoma, and CD117 positivity strongly favors the diagnosis of GIST, whereas positivity for keratin and vimentin should support the diagnosis of sarcomatoid carcinoma.17

Recently, rare variants of GISTs have been described as stromal tumors with myxoid stroma18 and as stromal tumors with prominent signet ring cell features.19 Even more recently, Zambrano et al20 reported 6 cases of an osteoclast-rich tumor of the gastrointestinal tract with features resembling clear cell sarcomas of the soft parts. Since these tumors were immunoreactive for S100 protein and negative for CD117 and CD34, they had likely been segregated from GISTs.

In the present study, we described 4 cases of malignant stromal tumors with prominent OGCs-3 leiomyosarcomas and 1 GIST.

Given these experiences, stromal tumors with prominent OGCs in the digestive tract are more common in tumors of a myogenic origin such as leiomyosarcoma than in other types of sarcoma, and these tumors seem to have an aggressive outcome.


1. Pettinato G, Manivel JC, Picone A, Petrella G, Insabato L. Alveolar variant of infiltrating lobular carcinoma of the breast with stromal osteoclast-like giant cells. Pathol Res Pract. 1989;185:388-394.

2. Sakai Y, Kupelioglu AA, Yanagisawa A, et al. Origin of giant cells in osteoclast-like giant cell tumors of the pancreas. Hum Pathol. 2000;31:1223-1229.

3. Guccion JG, Enzinger FM. Malignant giant cell tumor of soft parts: an analysis of 32 cases. Cancer. 1972:29:1518-1529.

4. Salm R, Sissous HA. Giant-cell tumors of soft tissue. J Pathol. 1972;107:27-39.

5. Darby AJ, Papadaki L, Beilby JOW. An unusual leiomyosarcoma of the uterus containing osteoclast-like giant cells. Cancer. 1975;36:495-504.

6. Chen KTK. Leiomyosarcoma with osteoclast-like giant cells. Am J Surg Pathol. 1995;19:487-488.

7. Mentzel T, Calonje E, Fletcher CDM. Leiomyosarcoma with prominent osteoclast-like giant cells. Am J Surg Pathol. 1994;18:258-265.

8. Terada T, Kanenon E, Maeta H, Horie S, Ohta T. Epithelioid leiomyosarcoma with osteoclast-like giant cells in the rectum. Arch Pathol Lab Med. 2000;124: 438-440.

9. Leung KM, Wong S, Chow TC, Lee KC. A malignant gastrointestinal tumor with osteoclast-like giant cells. Arch Pathol Lab Med. 2002;126:972-974.

10. Miettinen M, El-Rifai W, Sobin LH, Lasota J. Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. Hum Pathol. 2002;33:478-483.

11. Sirkar K, Hewlet BR, Huizinga JD, et al. Interstitial cells of Cajal as precursor of gastrointestinal stromal tumor. Am J Surg Pathol. 1999;23:377-389.

12. Baschinsky DY, Frankel WL, Niemann TH. Gastric carcinoma with osteoclast-like giant cells. Am J Gastroenterol. 1999;94:1678-1681.

13. Hoist VA, Elenitsas R. Primary giant cell tumor of soft tissue. J Cutan Pathol. 2001;28:492-495.

14. Fu K, Moran CA, Suster S. Primary mediastinal giant cell tumors: a clinicopathologic and immunohistochemical study of two cases. Ann Diagn Pathol. 2002;6:100-105.

15. Zheng MH, Fan Y, Smith A, Wisocki S, Papadimitriou JM, Wood DJ. Gene expression of monocyte chemoattractant protein-1 in giant cell tumors of bone osteoclastoma: possible involvement in cd68 + macrophage-like cell migration. J Cell Biochem. 1998;70:121-129.

16. Quinn JM, Elliott J, Gillespie MT, Martin TJ. A combination of osteoclast differentiation factor and macrophage-colony stimulating factor is sufficient for both human and mouse osteoclast formation in vitro. Endocrinology. 1998;139: 4424-4427.

17. Di Vizio D, Insabato L, Conso G, Zafonte BT, Ferrara G, Pettinato G. Sarcomatoid carcinoma of the colon: report of a case with literature review. Tumori. 2001;87:431-435.

18. Suster S, Sorace D, Moran CA. Gastrointestinal stromal tumors with prominent myxoid matrix. Clinicopathologic, immunohistochemical, and ultrastructural study of nine cases of a distinctive morphologic variant of myogenic stromal tumor. Am J Surg Pathol. 1995;19:59-70.

19. Suster S, Fletcher CD. Gastrointestinal stromal tumors with prominent signet-ring cell features. Mod Pathol. 1996;9:609-613.

20. Zambrano E, Reyes-Mugica M, Franchi A, Rosai J. An osteoclast-rich tumor of the gastrointestinal tract with features resembling clear cell sarcoma of soft parts: report of cases of a GIST simulators. Int J Surg Pathol. 2003;11:75-81.

Luigi Insabato, MD, PhD; Dolores Di Vizio, MD, PhD; Giuseppe Ciancia, MD; Guido Pettinato, MD; Luigi Tornillo, MD; Luigi Terracciano, MD

Accepted for publication December 10, 2003.

From the Dipartimento di Anatomia Patologica, Facolta di Medicina, Universita "Federico II," Napoli, Italy (Drs Insabato, Di Vizio, Ciancia, and Pettinato), and the Institute fur Patologie, Universitatsspital, Basel, Switzerland (Drs Tornillo and Terracciano).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Luigi Insabato, MD, PhD, Dipartimento di Anatomia Patologica, Facolta di Medicina, Universita "Federico II," Via S. Pansini 5, 80131 Naples, Italy (e-mail:

Copyright College of American Pathologists Apr 2004
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