Primary Leiomyosarcoma of the Pancreas.

A Case Report and Review of the Literature

Primary sarcomas of the pancreas are extremely rare, accounting for 0.1% of malignant pancreatic (non-islet) neoplasms.[1] In most instances, malignancies of sarcomatous appearance involving this organ are undifferentiated (sarcomatoid) carcinomas or pancreatic extensions of retroperitoneal and gastroduodenal sarcomas. Malignant mesenchymal tumors arising within the pancreas include leiomyosarcomas, malignant peripheral nerve sheath tumors, malignant fibrous histiocytomas, liposarcomas, rhabdomyosarcomas, and hemangiopericytomas.[2] However, most have been reported in small series or as single cases without definitive evidence of cell differentiation by electron microscopy or immunohistochemistry.[1,3-8] These investigations may be relevant in definitively confirming the cell lineage of the tumor because sarcomas of different histogenesis, especially pleomorphic tumors, may display similar histologic features.[19] We describe an additional case of primary pancreatic leiomyosarcoma, with discussion of the clinical, histologic, and immunohistochemical characteristics of this neoplasm.

REPORT OF A CASE

A 76-year-old man presented with a 5-month history of persistent high fever He was otherwise asymptomatic, with no anorexia, weight loss, or jaundice. Physical examination and a complete laboratory profile were unremarkable. Preoperative investigations included a computed tomography (CT) scan, which demonstrated a large, solid mass replacing the tail of the pancreas, without invasion of surrounding tissues (Figure 1). There was no evidence of liver involvement. Chest radiographs and a scintigraphic bone scan were negative. Laparotomy revealed a large, well-circumscribed tumor located in the tail of the pancreas. It protruded mainly anteriorly and was intimately associated with the pancreatic parenchyma posteriorly. No direct invasion of adjacent structures, including the retroperitoneal fat, was found. Distal pancreatectomy with splenectomy was performed. The patient remained well for 9 months. He was then readmitted with dull epigastric pain and a spiking fever Sonography of the upper abdomen, followed by laparotomy, demonstrated recurrence in the form of a multiloculated, cystic mass with a thick, irregular wall. The patient died 1 year following initial surgery. Neither a confirmatory biopsy nor an autopsy study was performed.

[Figure 1 ILLUSTRATION OMITTED]

MATERIALS AND METHODS

The operative specimen was fixed in 10% neutral buffered formalin. One section for each centimeter of tumor diameter was embedded in paraffin and stained with hematoxylin-eosin for routine histology. Five additional sections were submitted after a preliminary evaluation, bringing the total up to 13. Immunohistochemical studies were performed on serial sections with the streptavidin-biotin complex method (Dako labeled streptavidinbiotin [LSAB] kit, Dako Corporation, Carpinteria, Calif), using a panel of antibodies against the following antigens: cytokeratin (monoclonal antibody [MoAb] clone AE1/AE3; BioGenex, San Ramon, Calif); epithelial membrane antigen (EMA) (MoAb clone E29/EP1; Dako); vimentin (MoAb clone V9; BioGenex); musclespecific actin (MSA) (MoAb clone HHF35; Dako); [Alpha]-smooth muscle actin (MoAb clone 1A4; Sigma Chemical Co, St Louis, Mo); S100 protein (polyclonal; Dako); neuron-specific enolase (NSE) (MoAb clone MIG-N3; BioGenex); laminin (MoAb clone 4C7; Dako); and type IV collagen (MoAb clone CIV 22; Dako).

PATHOLOGIC FINDINGS

On macroscopic examination, an 8.0 x 7.0 x 6.5-cm firm, solid mass replacing the tail of the pancreas was noted. The cut surface was fleshy, with yellow areas of necrosis. The spleen was unremarkable.

Histologic examination revealed a nonencapsulated spindle cell proliferation with expanding margins and entrapment of the residual ductal, acinar, and endocrine structures (Figure 2). The tumor cells were arranged in bundles and fascicles, intersecting at right angles and occasionally displaying a cartwheel pattern. The nuclei were generally elongated and occasionally cigar shaped with blunt ends. The cytoplasm was weakly to distinctly eosinophilic. Foci of round rather than spindle-shaped cell, with a diffuse pattern of growth, comprised less than 10% of the tumor mass. Despite extensive tumor sampling, conventional adenocarcinomatous or squamous elements were not found. Nuclear atypia and pleomorphism were marked in the more densely cellular areas, where frequent mitotic figures, up to 12 mitoses per 10 high-power fields (HPFs), could be identified.

[Figure 2 ILLUSTRATION OMITTED]

The resected peripancreatic lymph nodes and surgical margins were free of tumor. Immunohistochemical analyses demonstrated strong positive cytoplasmic labeling for vimentin, MSA, and [Alpha]-smooth muscle actin. Laminin and type IV collagen decorated the cell surface, whereas desmin, CD34, S100 protein, cytokeratin, and NSE were not detectable (Figure 3, A and B).

[Figure 3 ILLUSTRATION OMITTED]

The morphologic and immunohistochemical features of the tumor were consistent with a leiomyosarcoma with pleomorphic areas (high-grade leiomyosarcoma).

COMMENT

We report a case of primary pancreatic leiomyosarcoma. The tumor was solitary and located within the anatomic boundaries of the pancreas. No direct invasion of neighboring structures was demonstrated, and a complete clinical evaluation of the patient excluded secondary pancreatic involvement by a sarcoma of the retroperitoneal tissue or gastrointestinal tract. Immunoreactivity for MSA and [Alpha]-smooth muscle actin, coupled with positive labeling with basement membrane components (ie, laminin and type IV collagen) and negative staining for cytokeratin and EMA, qualified this tumor as a smooth muscle sarcoma.

Leiomyosarcomas arising in the pancreas must be differentiated histologically from sarcomatoid carcinomas and other nonmyogenic spindle cell sarcomas, namely fibrosarcomas, malignant fibrous histiocytomas, and malignant peripheral nerve sheath tumors. The differential diagnosis should also include myofibroblastic proliferations (so-called inflammatory myofibroblastic tumors), which have been occasionally reported in the pancreaticobiliary region.[20] In order to arrive at a correct diagnosis, extensive sampling should be performed to identify any areas of well-formed fascicles of spindle cells with blunt-ended nuclei intersecting at right angles, displayed by typical myogenic tumors. Immunohistochemical analyses are of great value in evaluating spindle cell tumors with prominent cellular pleomorphism and/or a focally storiform pattern, supposed to be of smooth muscle origin. They reveal positivity for muscle markers (ie, MSA, [Alpha]-smooth muscle actin, and desmin) with negative reactions for epithelial (ie, cytokeratin, EMA, and CEA) and neural (ie, S100 protein) antigens. Immunoreactivity for MSA is consistent with a myogenic line of differentiation, and staining with [Alpha]-smooth muscle actin seems to be a valuable marker for smooth muscle, whereas reactivity for desmin is more variable, depending on fixation, and is less consistently found in leiomyosarcomas.[21] However, the expression of either smooth muscle actin or desmin should not be equated with myogenic differentiation because myofibroblasts may also exhibit this immunophenotype in a variety of neoplastic and nonneoplastic conditions. Electron microscopy or immunohistochemical demonstration of basement membrane components (ie, laminin and type IV collagen) outlining individual tumor cells provides additional evidence of smooth muscle lineage.[22] Smooth muscle tumors may display epithelioid features, consisting of round to polygonal cells with variable nuclear pleomorphism and atypia. The immunophenotype allows them to be distinguished from carcinomas on the basis of their reactivity for muscle markers, notwithstanding their occasional keratin positivity.[2,21]

As leiomyosarcomas most commonly arise in the female genital tract, gastrointestinal tract, and soft tissues of the extremities and retroperitoneum, careful clinical evaluation is mandatory to rule out a primary extrapancreatic neoplasm.

To the best of our knowledge, only 21 cases of pancreatic leiomyosarcoma have been reported in the literature, in addition to the case described here (Table).

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This tumor primarily affects adults in the fifth decade of life or older (mean age, 53.6 years; range 14 to 80 years) with a nearly equal male-to-female ratio. The presenting signs and symptoms, including an abdominal mass or swelling, pain, and weight loss, are nonspecific. The tumors have ranged in size from 3 to 25 cm in greatest dimension (median, 11 cm). The largest tumors frequently underwent cystic degeneration, at times mimicking a pancreatic pseudocyst at sonography or CT examination. Although in some cases the huge size of the pancreatic mass was suggestive of a nonepithelial malignancy, the diagnosis was usually made postoperatively.

The rare incidence and incomplete clinicopathological documentation of the reported cases make it difficult to characterize the clinical behavior and identify reliable prognostic factors in primary leiomyosarcomas of the pancreas (Table).

Nine of the 22 cases were stated to have locoregional or metastatic disease at presentation. In one patient, the lesion was discovered at autopsy.[3] Another patient underwent bypass surgery and died 9 months after onset of symptoms.[8] Chemotherapy was employed in a third patient who died within 33 months of diagnosis.[16] Survival data are not available in the remaining 6 cases that were nonresectable.

Thirteen cases appeared to be localized at the time of diagnosis and susceptible to surgical resection. Of the 8 patients for whom follow-up information is available, 4 patients, including the present one, died of their tumors 9 to 48 months after diagnosis,[9,10,17] whereas 4 patients were alive and free of disease at 12, 36, 48, and 120 months after initial surgical treatment.[4,12,14,18]

Although size is a decisive factor with regard to tumor resectability, it does not seem to affect the clinical course after surgical resection. However, available published data indicate that mitotic counts of more than 10 mitoses/10 HPFs appear to be associated with a shortened interval to an adverse outcome.

In conclusion, although the number of the cases reviewed here is small, leiomyosarcoma of the pancreas is a highly malignant neoplasm and usually pursues an aggressive clinical course, like its counterpart arising in deep soft tissues. An attempt at complete tumor resection can offer patients the best hope for prolonged survival.

References

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[2.] Solcia E, Capella C, Kloppel G. Tumors of the Pancreas. Washington, DC: Armed Forces Institute of Pathology; 1997:211. Atlas of Tumor Pathology; 3rd series, fascicle 20.

[3.] Ross CF. Leiomyosarcoma of the pancreas. Br J Surg. 1951;39:53-56.

[4.] Berman JK, Levene N. Sarcoma of the pancreas. Arch Surg. 1956;73:894-896.

[5.] Feinberg SB, Margulis AR, Lober P. Roentgen findings in leiomyosarcoma of the pancreas. Minn Med. 1957;36:505-506.

[6.] Becker WF, Welsh RA, Pratt HS. Cystadenoma and cystadenocarcinoma of the pancreas. Ann Surg. 1965;161:845-860.

[7.] Oyamada C, Abe M, Masuya T, Nagamitsu S, Maeda Y. A case of leiomyosarcoma of the pancreas with a cystic formation. Diagn Ther (Jpn). 1970;58:155-158.

[8.] Carda AP, Hebrero SM, Benita L, Rodriguez A, Moreno G. Leiomiosarcoma de pancreas asociado a pseudoquistes. Rev Esp Enferm Apar Dig. 1976;48:731-738.

[9.] Ishikawa O, Matsui Y, Aoki Y, Iwanaga T, Terasawa T, Wada A. Leiomyosarcoma of the pancreas and review of the literature. Ami Surg Pathol. 1981 ;5:597-602.

[10.] Tulha AN, Concone H, Camargo VI, Pessoa A. Pancreatic leiomyosarcoma. Report of a surgically treated case. Rev Assoc Med Bras. 1982;28:188-189.

[11.] Murata K, Tsuchiya T, Ayakawa Y, Miyata N, Suzuki M, Kato K. Primary leiomyosarcoma of the pancreas. Nippon Igaku Hoshasen Gakkai Zasshi. 1990; 50:1215-1223.

[12.] Lakhoo K, Mannell A. Pancreatic leiomyosarcoma. A case report. S Afr J Surg. 1991 ;29:59-60.

[13.] de Alava E, Torramade J, Vazquez JJ. Leiomyosarcoma of the pancreas. Virchows Arch. 1993;422:419-422.

[14.] Peskova M, Fried M. Pancreatic tumor of mesenchymal origin--an unusual surgical finding. Hepatogastroenterology. 1994;41:201-203.

[15.] Sato T, Asanuma Y, Nanjo H, et al. A resected case of giant leiomyosarcoma of the pancreas. J Gastroenterol. 1994;29:223-227.

[16.] Ishii H, Okada S, Okazaki N, Nose H, et al. Leiomyosarcoma of the pancreas: report of a case diagnosed by fine needle aspiration biopsy. Jpn J Clin Oncol. 1994;24:42-45.

[17.] Aranha GV, Simples PE, Veselik K. Leiomyosarcoma of the pancreas. Int J Pancreatol. 1995;17:95-97.

[18.] Owen CH, Madden JF, Clavien PA. Spindle cell stromal tumor of the pancreas: treatment by pancreatoduodenectomy. Surgery. 1997;122:105-111.

[19.] Fletcher CDM. Pleomorphic malignant fibrous histiocytoma: fact or fiction? A critical reappraisal based on 159 tumors diagnosed as pleomorphic sarcoma. Am J Surg Pathol. 1992; 16:213-228.

[20.] Walsh SV, Evangelista F, Khettry U. Inflammatory myofibroblastic tumor of the pancreatobiliary region. Am J Surg Pathol. 1998;22:412-418.

[21.] Enzinger FM, Weiss SW. Soft Tissue Tumors. St Louis, Mo: Mosby; 1995.

[22.] Leong AS-Y, Vinyuvat S, Suthipintawong C, Leong FJ. Patterns of basal lamina immunostaining in soft-tissue and bony tumors. Appl Immunohistochem. 1997;5:1-7.

Accepted for publication June 8, 2000.

From the Department of Pathology (Drs Nesi, Ragionieri, and Amorosi) and the Department of General Surgery (Dr Pantalone), University of Florence V.le Morgagni, 85, 50134 Florence, Italy.