Paraganglioma

A 53-year-old man presented with a 4-month history of increasing abdominal discomfort and distension. A large retroperitoneal mass was found on imaging. Image-guided needle core biopsy demonstrated a poorly differentiated malignant neoplasm. A 30 × 32 × 33-cm soft tissue mass was removed. Microscopically, the tumor consisted of predominantly epithelioid malignant cells arranged in a paraganglioma-like growth pattern. Immunohistochemically, these cells were strongly positive for neuron-specific enolase. Stains for synaptophysin and chromogranin, however, were negative. There was no ultrastructural evidence of neuroendocrine differentiation. Adjacent sarcomatous areas were composed of spindled cells arranged in storiform and fibrosarcoma-like growth patterns. A small area of well-differentiated liposarcoma was identified, and a diagnosis of dedifferentiated liposarcoma was established. To the best of our knowledge, this represents the first reported case of dedifferentiated liposarcoma with a paraganglioma-like histologic pattern. A brief review focusing on the morphologic variations of dedifferentiated liposarcoma is also presented.

(Arch Pathol Lab Med. 2004;128:788-791)

According to the current World Health Organization classification,1 well-differentiated liposarcoma (atypical lipomatous tumor) and dedifferentiated liposarcoma are 2 separate entities in the same histogenetic category; they share many clinical, morphologic, and cytogenetic features. Dedifferentiation is a histologie progression of a low-grade neoplasm to a higher-grade, less-differentiated lesion. The term dedifferentiated liposarcoma was first introduced by Evans.2 Dedifferentiated liposarcoma occurs most frequently in central body sites, especially the retroperitoneum.1-6 Tumors from this area usually carry the worst prognosis. Its frequency is much lower in deep muscles and rare in subcutaneous tissue.3-8 Most cases of dedifferentiated liposarcoma are found de novo, rather than in recurrence from well-differentiated liposarcoma.6 It appears that neither the extent nor the grade of the dedifferentiated component of the tumor has a significant influence on the subsequent clinical behavior.6,9

By definition, the pathologic diagnosis of dedifferentiated liposarcoma requires the identification of the 2 components, that is, well-differentiated liposarcoma and a cellular nonlipogenic sarcoma in the same lesion.1,2,6 For the dedifferentiated component, although histologic features of malignant fibrous histiocytoma (MFH) are most commonly observed,2-6 other sarcomatous phenotypes have been reported.2-15 More importantly, unusual histologic patterns mimicking carcinoma, melanoma, meningioma, lymphoma, or even angiosarcoma have been reported in the dedifferentiated areas4-8,13 and make the diagnosis of dedifferentiated liposarcoma challenging. In this report, we describe a case of dedifferentiated liposarcoma with unusual histologic and immunohistochemical features. Most of the tumor exhibited microscopic appearance highly suggestive of a malignant paraganglioma. Immunohistochemically, the tumor cells of this component were strongly and diffusely positive for neuron-specific enolase. To our knowledge, this represents the first reported case of dedifferentiated liposarcoma with a paraganglioma-like growth pattern.

REPORT OF A CASE

A 53-year-old, previously healthy man presented with a 4-month history of increasing abdominal discomfort and right-sided abdominal distension. He had a decreasing appetite with nausea, but no vomiting. Bowel movements were unchanged. He had lost approximately 29.5 kg during the past 4 months. Physical examination confirmed a mass occupying the entire right side of the abdomen, which extended below both the costal margin and the iliac crest. A computed tomographic scan of the abdomen showed the mass to be retroperitoneal and most consistent with a sarcoma. No metastatic disease was identified from the computed tomographic scan or a chest radiograph. An ultrasoundguided biopsy showed a poorly differentiated sarcoma. He was brought to the operating room and underwent excision of the mass with right hemicolectomy, nephrectomy, and adrenalectomy. The tumor abutted the inferior vena cava; however, it was removed without the tumor or vena cava being violated. The mass weighed more than 4.5 kg. The resection was uneventful. No adjuvant treatment was given.

The patient presented for follow-up 5 months later with symptoms identical to those at initial presentation, namely, epigastric discomfort, nausea, and a right-sided abdominal swelling. There was an obvious recurrence on clinical examination. A computed tomographic scan showed the mass again in the right retroperitoneum. Taking into consideration the extent of the initial resection, the short interval to recurrence, the extent of the recurrence, and the patient's preferences, he was treated with supportive care. He died several weeks following diagnosis of the recurrence. An autopsy was not performed.

MATERIALS AND METHODS

Formalin-fixed, paraffin-embedded surgical specimen tissue blocks were sectioned at 5 µ for histologic and immunohistochemical studies. Immunohistochemical stains were performed with a standard streptavidin-biotin-peroxidase or Dako EnVision method with appropriate negative and positive controls. The following primary antibodies were used: cytokeratin AE1/AE3 (1:200; Dako A/S, Glostrup, Denmark), epithelial membrane antigen (1:100; Dako), vimentin (1:50; Dako), smooth muscle actin (1:100; Dako), clesniin (1:100; Dako), leukocyte common antigen (1:80; Dako), neuron-specific enolase (1:400; Dako), synaptophysin (1:25; Dako), chromogranin (1:100; BioGenex, San Ramon, Calif), SlOO protein (1:100; BioGenex), Mart-1 (1:100; NeoMarkers, Fremont, Calif), [alpha]-inhibin (1:20; Oxford Bioinnovations, Oxford, United Kingdom), CD34 (1:50; Dako), CD99 (1:100; Dako), and human placental-like alkaline phosphatase (1:50; Dako). Tissue for electron microscopic examination was taken from a paraffin block, processed according to standard procedures, and examined with a JEOL 1010 electron microscope (Tokyo, Japan).

PATHOLOGIC FINDINGS

The initial biopsy specimen consisted of a poorly differentiated malignant neoplasm with epithelioid and spindle-shaped cells (Figure 1, A). There were small areas of tumor necrosis and an abundant vasculature. Immunohistochemically, the tumor cells were negative for epithelial, lymphoid, and melanocytic markers, and the histogenesis could not be determined.

The excised mass measured 30 × 32 × 33 cm. It was nodular and variegated gray-white to tan with both firm and gelatinous areas. There were large areas of necrosis and scattered, small fatty areas grossly. Right kidney and adrenal gland were unremarkable and loosely attached to the mass with fibrofatty tissue. Microscopically, the tumor consisted of predominantly epithelioid malignant cells arranged in a paraganglioma-like pattern (Figure 1, B). Immunohistochemically, the tumor cells in the paraganglioma-like areas were strongly positive for neuron-specific enolase (Figure 1, C) and vimentin. Stains for synaptophysin and chromogranin, however, were negative. Other negative immunostains included Mart-1, [alpha]-inhibin, cytokeratin AE1/AE3, epithelial membrane antigen, CD34, leukocyte common antigen, smooth muscle actin, desmin, S100 protein, CD99, and human placental-like alkaline phosphatase. Ultrastructurally, the tumor cells in the same areas were rounded and contained irregular nuclei. Their cytoplasm showed scattered mitochondria and short profiles of rough endoplasmic reticulum. Neither neurosecretory granules nor neurotubules were noted. The cells formed nests, and no cells junctions were demonstrated. Bundles of collagen fibrils were present among the nests. Lumina, microvilli, and tonofilaments, features that indicate epithelial differentiation, were absent. Other areas of the tumor showed fibroblast-like cells with numerous lipid droplets.

Histologically, there were adjacent small areas of high-grade sarcoma that resembled high-grade myxoid MFH (Figure 1, D), as well as lower-grade foci in which the spindled neoplastic elements grew in a storiform or fibrosarcoma-like growth pattern (Figure 2, A). Transitional areas were present between these spindle cell regions and the predominant paraganglioma-like areas (Figure 2, B). Away from these nonlipogenic sarcomatous components there was a small area of well-differentiated liposarcoma composed of mature fat with many atypical stromal cells and a few typical lipoblasts (Figure 2, C and D).

COMMENT

Dedifferentiated liposarcoma is a biphasic malignant neoplasm composed of an atypical lipomatous tumor (well-differentiated liposarcoma) and a cellular nonlipogenic (dedifferentiated) sarcoma. Its pathologic diagnosis relies on the identification of these 2 components by light microscopy.1-6 For atypical lipomatous tumor, the key is to identify atypical stromal cells with hyperchromatic, enlarged, and irregular nuclei.1-6 It may be difficult to identify typical lipoblasts. For the dedifferentiated component, in most (~90%) cases, dedifferentiated areas have an appearance similar to MFH-like sarcomas. All patterns of MFH may be seen, including pleomorphic, myxoid, giant cell, and inflammatory subtypes.1-9 Less commonly, other sarcomatous phenotypes mimic fibrosarcoma, dermatofibrosarcoma protuberans, hemangiopericytoma, and malignant peripheral nerve sheath tumor. Multiple histologic patterns may be present in the same tumor. Rare sarcoma subtypes that may be present in the dedifferentiated component include rhabdomyosarcoma, leiomyosarcoma, chondrosarcoma, and osteosarcoma.3-15

The most difficult situation for a pathologist, perhaps, is when he or she encounters a dedifferentiated liposarcoma with an unusual histologic pattern. Indeed, the growth patterns in the dedifferentiated component can resemble carcinoma, melanoma, lymphoma, meningioma, or even angiosarcoma.4-13 These patterns are misleading if the well-differentiated liposarcoma component is missing. This is particularly true when there is a limited amount of tissue available for evaluation, such as a core biopsy specimen. We experienced such a challenging situation in the current case when we only had a core biopsy.

The present tumor demonstrated a wide range of morphology and contained both low- and high-grade sarcomatous components. However, the paraganglioma-like growth pattern seen in the majority of the tumor tissue in the present case has not been previously reported. This finding is particularly important, since the tumor cells were strongly and diffusely positive for neuron-specific enolase, a commonly used but less specific neuroendocrine marker. However, the lack of reactivity of the tumor cells to more specific neuroendocrine markers, synaptophysin and chromogranin, argues against the diagnosis of paraganglioma. Negative ultrastructural evidence of neuroendocrine differentiation in the tumor cells further excluded the diagnosis of malignant paraganglioma. The ultrastructural features of the current tumor also differed from those reported in the epithelioid areas of pleomorphic liposarcomas.16 In this case, the well-differentiated Iiposarcomatous component was clearly recognized by the presence of atypical stromal cells and typical lipoblasts in the fatty area, which was the most helpful evidence for the final diagnosis.

Hemangiopericytoma-like growth pattern has been reported previously in dedifferentiated liposarcoma.5-9 Hemangiopericytoma and paraganglioma share some morphologic features, including an abundant vasculature. However, the vasculature in a hemangiopericytoma is characteristically composed of numerous, variably ectatic or compressed, thin-walled, branching vessels often having a stag-horn configuration. The current lesion does not show these features. It consists of more regularly distributed capillary vessels surrounded by nested epithelioid neoplastic cells, which is characteristic for a paraganglioma. Histologically, the current lesion is more like a paraganglioma than a hemangiopericytoma. Immunohistochemically, the absence of CD34 reactivity coupled with expression of neuron-specific enolase provides further support for excluding hemangiopericytoma.

To the best of our knowledge, this is the first reported case of dedifferentiated liposarcoma with a predominantly paraganglioma-like histologic pattern. This case is also unusual because of its multiple growth patterns and the mixed low- and high-grade areas present in the same tumor. It would be very difficult to make a correct diagnosis if the well-differentiated liposarcomatous component was missing. To avoid the misdiagnosis of dedifferentiated liposarcoma, it is essential to adequately sample the tumor both in the fatty and nonfatty areas when grossing the specimen. It is also very important for the surgeon to completely excise the entire lesion, including the fatty component. Communication between the pathologist and both the surgeon and the radiologist may be helpful in establishing an accurate diagnosis of dedifferentiated liposarcoma.

References

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2. Evans HL. Liposarcoma: a study of 55 cases with reassessment of its classification. Am J Surg Pathol. 1979;3:507-523.

3. Weiss SW, Rao VK. Well-differentiated liposarcoma (atypical lipoma) of deep soft tissue of the extremities, retroperitoneum, and miscellaneous sites: a follow-up study of 92 cases with analysis of the incidence of "dedifferentiation." Am J Surg Pathol. 1992;16:1051-1058.

4. Evans HL, Khurana KK, Kemp BL, Ayala AG. Heterologous elements in the dedifferentiated component of dedifferentiated liposarcoma. Am J Surg Pathol. 1994;18:1150-1157.

5. McCormick D, Mentzel T, Beham A, Fletcher CD. Dedifferentiated liposarcoma: clinicopathologic analysis of 32 cases suggesting a better prognostic subgroup among pleomorphic sarcomas. Am I Surg Pathol. 1994;18:1213-1223.

6. Henricks WH, Chu YC, Goldblum JR, Weiss SW. Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg Pathol. 1997;21:271-281.

7. Nascimento AG, Kurtin PJ, Guillou L, Fletcher CD. Dedifferentiated liposarcoma: a report of nine cases with a peculiar neural like whorling pattern associated with metaplastic bone formation. Am J Surg Pathol. 1998;22:945-955.

8. Fanburg-Smith JC, Miettinen M. Liposarcoma with meningothelial-like whorls: a study of 17 cases of a distinctive histological pattern associated with dedifferentiated liposarcoma. Histopathology. 1998;33:414-124.

9. Elgar F, Goldblum JR. Well-differentiated liposarcoma of the retroperitoneum: a dinicopathologic analysis of 20 cases, with particular attention to the extent of low-grade dedifferentiation. Mod Pathol. 1997;10:113-120.

10. Tallini G, Erlandson RA, Brennan MF, Woodruff JM. Divergent myosarcomatous differentiation in retroperitoneal liposarcoma. Am J Surg Pathol. 1993;17:546-556.

11. Suster S, Wong TY, Moran CA. Sarcomas with combined features of liposarcoma and leiomyosarcoma: study of two cases of an unusual soft-tissue tumor showing dual lineage differentiation. Am I Surg Pathol. 1993;17:905-911.

12. Shanks JH, Banerjee SS, Eyden BP. Focal rhabdomyosarcomatous differentiation in primary liposarcoma. J Clin Pathol. 1996;49:770-772.

13. Hasegawa T, Seki K, Hasegawa F, et al. Dedifferentiated liposarcoma of retroperitoneum and mesentery: varied growth patterns and histological grades-a dinicopathologic study of 32 cases. Hum Pathol. 2000;31:717-727.

14. Yamamoto T, Matsushita T, Marui T, et al. Dedifferentiated liposarcoma with chondroblastic osteosarcomatous dedifferentiation. Pathol Int. 2000;50:558-561.

15. Salzano RP Jr, Tomkiewicz Z, Africano WA. Dedifferentiated liposarcoma with features of rhabdomyosarcoma. Conn Med. 1991;55:200-202.

16. Huang HY, Antonescu CR. Epithelioid variant of pleomorphic liposarcoma: a comparative immunohistochemical and ultrastructural analysis of six cases with emphasis on overlapping features with epithelial malignancies. Ultrastruct Pathol. 2002;26:299-308.

Dating Liu, MD, PhD; Guillermo Quinonez, MD; Steven Latosinsky, MD

Accepted for publication February 11, 2004.

From the Departments of Pathology (Drs Liu and Quinonez) and Surgery (Dr Latosinsky), University of Manitoba, Winnipeg. Dr Liu is currently with the Department of Pathology, ACM Medical Laboratory, Rochester, NY.

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

Reprints: Dating Liu, MD, PhD, Department of Pathology, ACM Medical Laboratory, 160 Elmgrove Park, Rochester, NY 14624 (e-mail: dliu@acmlab.com).

Copyright College of American Pathologists Jul 2004
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