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Low-grade fibromyxoid sarcoma: A report of eight cases with histologic, immunohistochemical, and ultrastructural study
Annals of
DIAGNOSTIC PATHOLOGY VOL 4, NO 4
AUGUST 2000
ORIGINAL ARTICLES
Low-Grade Fibromyxoid Sarcoma: A Report of Eight Cases With Histologic, Immunohistochemical, and Ultrastructural Study Michal Za´mecˇnı´k, MD, and Michal Michal, MD We present eight cases of low-grade fibromyxoid sarcoma (LGFS) of soft tissues. The patients, six men and two women, ranged in age from 28 to 44 years (median, 39 years). All tumors were subcutaneous. They were located in the lower extremity (three cases), inguinal/perineal region (two cases), trunk (one case), upper extremity (one case), and neck (one case). Grossly, the lesions were similar to those described in previous studies; fibrous and well circumscribed, with pseudocapsules, and without any necrosis or nodularity. In a single case of hemosiderin-rich tumor, rusty brown strips were seen on the cut surface. Histologically, the tumors were composed of alternating fibrous and myxoid areas with various cellularity and with swirling and whorled growth patterns. The cells were stellate or spindle shaped and displayed none to mild nuclear pleomorphism and hyperchromasia. Some hypercellular areas showed a fascicular or herring bone pattern similar to common fibrosarcomas. In addition to the known typical picture of LGFS, we also have seen some unusual features. The cells of myxoid areas were often arranged in rows, thus resembling ossifying fibromyxoid tumor or myxoid chondrosarcoma of soft tissues. In a single case, the tumor cells contained a large amount of hemosiderin and the cellular nests contained synovial metaplasia-like clefts. The intranuclear invaginations of cytoplasm represented another interesting finding that was present in all tumors in our series. They seem to be constant or at least frequent features of LGFS, which may assist in the differential diagnosis. The immunohistochemical and ultrastructural findings were consistent with the fibroblastic nature of LGFS. Four cases also showed features of possible histiocytic modulation of the neoplastic fibroblasts. Ann Diagn Pathol 4: 207-217, 2000. Copyright r 2000 by W.B. Saunders Company Index Words: Fibromyxoid sarcoma, sarcoma, soft tissue, intranuclear inclusion, bcl-2
From the Department of Pathology, Slovak Postgraduate Academy of Medicine, Derer’s Hospital, Bratislava, Slovak Republic; and the Soft Tissue Tumor ˇikl’s Department of Pathology, Faculty Hospital, Charles University, Registry, S Pilsen, Czech Republic. Address reprint requests to Michal Za´mecˇnı´k, MD, Department of Pathology, General Hospital, 911 71 Trencin, Slovak Republic. Copyright r 2000 by W.B. Saunders Company 1092-9134/00/0404-0008$10.00/0 doi:10.1053/adpa.2000.8122
S
O-CALLED ‘‘low-grade fibromyxoid sarcoma’’ (LGFS) was described by Evans1 in 1987, but with the exception of a single case report,2 no additional cases were reported in the 6 years following the original description. The existence of LGFS as a distinct entity had not been confirmed until 1993, when Evans reported 10 new cases.3-5 Several recent reports established LGFS as a distinct entity.6-12 To our knowledge, only 32 cases of LGFS have been reported.1-3,5-12 We
Annals of Diagnostic Pathology, Vol 4, No 4 (August), 2000: pp 207-217
207
208
Za ´mecˇnı´k and Michal Table 1. Clinical Data and Sizes of the Tumors
Case No.
Age (yr)/Sex
1
41/M
2 3 4 5 6 7 8
37/M 43/M 28/M 45/F 37/M 44/F 38/M
Location
Left supraclavicular region Chest wall Tuberositas tibiae area Groin Left groin Left groin Forearm Thigh
Size
6 cm 4 ⫻ 3 ⫻ 3 cm 5 ⫻ 3 ⫻ 3 cm 1.5 cm 5 cm 10 ⫻ 12 ⫻ 13 cm 3 ⫻ 3 ⫻ 4 cm 4 cm
report the pathologic features of eight additional cases of LGFS. Materials and Methods Paraffin blocks or unstained reserve slides were available in all cases. In addition to conventional stains, the following immunohistochemical stains using the avidin-biotin complex
Figure 2. A typical biphasic pattern of low-grade fibromyxoid sarcoma consists of perivascular cellular areas with collagenized fibroma-like areas between them (case 1). Longitudinal section of the cellular area reveals its architecture.
technique were performed in every case: S-100 protein (polyclonal), desmin (D33), vimentin (3B4), epithelial membrane antigen (EMA), cytokeratin (KL1), lysozyme (polyclonal), CD68 (KP1), bcl-2, muscle-specific actin (HHF-35) (all from Dako, Glostrup, Denmark), CD34 (Becton-Dickinson, San Jose, CA), alpha-smooth muscle actin (Sigma, St Louis, MO), and cytokeratin AE1/AE3 (Boehringer, Mannheim, Germany). For electron microscopy, wet formalin-fixed tissue was available in cases 1 and 3. The tissues were postfixed in osmium tetroxide and the specimens were subsequently dehydrated and embedded in Epon (LADD Research, Burlington, VT). Ultrathin sections were stained with uranyl acetate and lead citrate and examined under a transition electron microscope.
Results Clinical Presentation Figure 1. A low-grade fibromyxoid sarcoma shows wellcircumscribed margin (top), variable cellularity, and collagenization of the extracellular matrix (case 6).
The clinical data are summarized in Table 1. There were six men and two women with a median age of 39 years (range, 28 to 44 years). The tumors were located in
Low-Grade Fibromyxoid Sarcoma
209
revealed various grades of cellularity and had gradual transitions between them. The more abrupt transition between the fibrous and myxoid components (Fig 2) was seen focally in three cases (cases 1, 2, and 3). The fibrous parts of the tumors contained spindle-shaped cells in linear arrangement producing whorled (Fig 3) and swirling growth patterns. The cellularity of the tumors ranged from hypocellular fibroma-like areas with abundant collagen fibers to hypercellular fascicular structures. In cases 1 and 5, areas of hypercellularity revealed a herringbone pattern and resembled a low-grade fibrosarcoma (Fig 4). Small areas of hyalinized keloid-like fibrosis (Figs 5 and 6) were present in four tumors (cases 1, 5, 6, and 7). The myxoid areas contained the spindle to stellate-shaped cells set in an abundant intercellular matrix. Arborizing or elongated vessels resembling those of myxoid liposarcoma and myxofibrosarcoma were seen focally in five cases (cases 1 to 5) (Fig 7). The tumor cells were frequently centered around the capillaries, giving an impression of perivascu-
Figure 3.
A cellular wavy pattern of LGFS (case 4).
the subcutis in all cases. The most common site was the groin (three cases), followed by the lower extremity (two cases). Gross Findings All tumors were round to oval and well circumscribed with a thin pseudocapsule. Their diameter ranged from 1.5 to 13 cm. The consistency was firm and fibrous, and the cut surfaces were homogeneous, without nodularity or necrosis. In case 1, focal myxoid degeneration was described in the record. In case 3, numerous rusty brown strips were apparent on the cut surface. The gross findings in cases 1 and 2 were recorded as ‘‘the appearance reminding of fibroma or myoma.’’ Microscopic Findings The tumors were generally well circumscribed (Fig 1) and they had a thin fibrous pseudocapsule. A focal infiltration into the skeletal muscle was seen only in a single case (case 5). All tumors contained two basic components: fibrous and myxoid. Both components
Figure 4. (case 1).
The herringbone-like pattern of the cellular area
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blue positive and was periodic acid-Schiff negative. The intranuclear invaginations were both alcian blue and PAS periodic acid-Schiff negative. Immunohistochemically, the tumor cells revealed strong and diffuse positivity with antibodies to vimentin and bcl-2 in all cases (Fig 14). Four tumors (cases 2, 3, 5, and 6) were reactive focally for lysozyme and CD68. All other antibodies produced negative results. Ultrastructurally, the nuclear appearance was similar in both examined cases (cases 1 and 3). The nuclear outlines were irregular and produced deep indentations and processes. The chromatin was finely clumped. The tumor cells had small and inconspicuous nucleoli. The intranuclear cytoplasmic invaginations that were discernible at the light microscopic level were found in some nuclei at the ultrastructural level as well (Figs 15 and 16). In case 1 the cytoplasm contained abundant rough endoplasmic reticulum and free ribosomes and was rich in intermediate filaments (Fig 15). The cisternae of the
Figure 5. A collagenized area of the tumor resembles scar or keloid (case 6).
lar proliferative zones (Fig 2). The cells of the myxoid areas were arranged haphazardly. In four cases (cases 1 to 4) they produced the cell-cords (Fig 8), which focally formed a reticular network (Fig 9). Cytologically, the cells of both components revealed only a mild nuclear pleomorphism with hyperchromasia, and the nucleoli were not visible (Figs 3 and 10). The clear or eosinophilic invaginations of cytoplasm were seen in some of the nuclei in all tumors (Fig 11). This nuclear feature was prominent in three lesions (cases 1, 6, and 8), and less apparent in the remaining tumors. In case 3, numerous confluent areas with abundant brown pigment in tumor cells simulated melanotic tumor (Fig 12). The brown pigment was iron positive. Additional interesting findings seen in this tumor were the artifactual clefts and spaces inside the cellular areas of this tumor. Here, the cells formed a continuous layer on the surface of these spaces resembling a synovial metaplasia13,14 (Fig 13). The myxoid matrix of the tumors was slightly alcian
Figure 6. A high power view of the keloid-like fibrosis of the tumor (case 6).
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the tumor cells. In addition, some cells in case 3 showed numerous vacuoles and a few lysosomes, suggestive of histiocytic differentiation (Fig 17). Discussion Low-grade fibromyxoid sarcoma occurs in subcutaneous or deep soft tissues in adult patients. Including our patients, there have been 40 cases described in the literature to date.1-3,5-12 The mean age of the patients was 35 years (range, 6 to 65 years). Twenty-seven patients (68%) were male and 13 (32%) were female. The male predominance appears to be a typical feature of LGFS in most studies. Evans’ series5 was the only one in which such male predominance was not observed. Goodlad et al3 described 91% tumors in males, which is similar to the 75% male predominance found in our study. Therefore, we believe that LGFS is typically a tumor of males and that the lack of strong male predominance in the study of Evans probably represents
Figure 7. Prominent vascularization resembling myxoid liposarcoma (case 5).
endoplasmic reticulum were often dilated and contained finely granular contents. The filaments revealed neither periodicity nor dense bodies. Short cytoplasmic processes were found on the surface of a few cells. Intercellular space contained numerous collagen fibers. In case 3 the cells possessed thin filopodia-like processes (Fig 16), sometimes with rudimentary cell junctions between them. The tumor cells were more loosely organized in a clear-looking, abundant myxoid matrix containing a finely granular substance. The collagen fibers were sparse. The cytoplasm of the tumor cells contained moderate numbers of well-formed cisternae of rough endoplasmic reticulum and Golgi complexes. The endoplasmic reticulum was often dilated. The intermediate filaments were only found in some cells. We were unable to find any myofibroblastic features, such as pinocytic vesicles, microfilaments grouped into the dense bodies, or an external lamina. The ultrastructural findings indicate the fibroblastic differentiation of
Figure 8.
An arrangement of the cells into rows.
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melanotic tumor. Histologically, the LGFS was characterized by alternating fibrous and myxoid areas.1-3,5-12 The proliferation of bland-looking fibroblastic cells in a swirling or whorled pattern was characteristic. The cellularity was predominantly low to moderate, but fibrosarcoma-like fascicular or herringbone pattern occurred in two of our eight cases. The tumors were usually well circumscribed and encapsulated, but an infiltrative growth was seen in small areas, particularly in recurrent tumors. Some areas of most of the tumors in our series showed a prominent vascularization, which simulated myxoid liposarcoma. However, such areas were not present through whole lesions and areas more typical of LGFS always allowed the distinction from liposarcoma. The keloid-like fibrosis described in detail by Goodlad et al3 was observed in three cases. This pattern was often bland looking and pathologists should be aware of it.
Figure 9. The rows of cells create focally a reticular network (lower part of the figure).
a regional unexplained difference. The tumor locations in our study were similar to the previously reported cases. The most frequently reported location of LGFS has been in the lower extremity (32.5%), especially in the thigh, followed by the groin/perineum (20%) and the trunk (20%) (Table 2). Interestingly, no case of LGFS has ever been observed in the retroperitoneum and only a single tumor was described in the mesentery,5 indicating that the LGFS is typically a neoplasm of subcutaneous and deep soft tissues. At gross examination, LGFS is well circumscribed, its cut surface is firm and fibrous, and it may have focal gelatinous appearance. No typical macroscopic signs of malignancy, such as necrosis, hemorrhage, infiltrative border, or nodularity, were described in LGFS. The gross appearance of our tumors favored benign lesions. A fibroma or myoma diagnosis was considered at gross examination in some of our cases. Heavy hemosiderin depositions in one case caused a gross impression of a
Figure 10. A high grade of the atypism, which we were able to observed in our series. Such atypism was found mostly in fibrosarcoma-like areas (case 1).
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soft tissue and cutaneous meningioma,17,18 perineurioma,19 pleomorphic hyalinizing angiectatic tumor,20 giant cell angiofibroma,21 and low-grade myofibroblastic sarcoma.22 The distinction of these tumors from LGFS is usually not problematic because of their different histologic and/or immunohistochemical features. Some schwannomas, especially those of cellular type, and malignant peripheral nerve sheath tumors may cause difficulties to be distinguished from LGFS because these lesions are similarly composed of spindle cells and they may lack the S-100 protein positivity.23,24 However, their nuclei are more slender and wavy, and their growth patterns are more fascicular. Unlike LGFS, the malignant peripheral nerve sheath tumor is the infiltrating neoplasm with higher nuclear atypia. Similar to LGFS, the recently described pleomorphic hyalinizing angiectatic tumors20 expresses only vimentin, but it is usually infiltrative with more pleomorphic cellular population
Figure 11. (case 8).
Numerous cytoplasmic intranuclear invaginations
In addition to these typical features, we have also recorded some unusual features, such as intranuclear invaginations of the cytoplasm, the arrangement of the cells into rows, hemosiderin-rich cells, and the clefts resembling synovial metaplasia. The intranuclear cytoplasmic invaginations represent the most interesting finding. They were most often seen in myxoid and paucicellular areas. This nuclear feature was at first described by Shidham et al in their recently published case report.8 We believe that similar intranuclear inclusions are visible on photomicrographs of some of the previously reported LGFS.3,5,7 We have found intranuclear inclusions in all tumors, although it was prominent only in three of our eight cases and less apparent, but always present, in others. We conclude that the cytoplasmic nuclear invaginations are a characteristic and possibly constant feature of LGFS. The occurrence of intranuclear inclusions is known in several soft tissue tumors, such as schwannoma,15 malignant melanoma,16
Figure 12. Tumor area with abundant hemosiderin pigment. Several tissue clefts resemble synovial metaplasia (case 3).
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fibrous septa and frequent ossification. The cells of OFMT are S100 positive or they rarely react immunohistochemically with myoid markers. Myxoid chondrosarcomas have abundant myxoid matrix in all cases and lack the paucicellular and collagenized pattern typical of LGFS. The perineuriomas, both benign28,29 and malignant,30,31 express epithelial membrane antigen and do not show prominent alternation of cellularity. In addition, malignant perineurioma shows obvious malignant histological features, such as necrosis, infiltrative growth, high cellularity, and nuclear atypism with frequent mitoses. Immunohistochemically, besides already known vimentin positivity, we observed a strong and diffuse bcl-2 reactivity in all our cases. Low-grade fibromyxoid sarcoma may be added to the list of the bcl-2–positive soft tissue lesions.32 Although the list of bcl-2–positive soft tissue tumors is quite long, the diffuse and strong reactivity can be of help in diagnosis. Such bcl-2 immunoreactivity was observed in the following list of tumors,
Figure 13. A detailed view of the synovial metaplasia-like tissue clefts. Typical intranuclear cytoplasmic invaginations are also apparent.
and it contains characteristic dilated vessels with thick hyalinized walls. Perineuriomas and meningiomas differ from LGFS by constant epithelial membrane antigen positivity and they do not show high variations in cellularity.17-19 Unlike LGFS, giant cell angiofibroma21 contains giant multinucleated fibroblasts and angiectatic spaces and is immunoreactive for CD34. Low-grade myofibroblastic sarcoma22 is a diffusely infiltrative neoplasm and shows immunohistochemical and ultrastructural features of myofibroblastic differentiation. The arrangement of the cells into rows was seen in half of our cases. This feature may be particularly misleading because it resembles a similar cellular arrangement of ossifying fibromyxoid tumor (OFMT),25,26 myxoid chondrosarcoma,27 and perineuriomas.19,28-31 However, the glomoid cells of OFMT, as well as the chondroblast-like cells of myxoid chondrosarcoma, are quite different from the fibroblast-looking cells of LGFS. Moreover, OFMT is lobulated with
Figure 14. cases.
A strong immunoreactivity for bcl-2 was seen in all
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histochemical CD34 positivity, patternless structure lacking whorls and wires, and hemangiopericytoma-like areas34,35 easily differentiate solitary fibrous tumor from LGFS. The admixture of hemosiderin-rich cells and the synovium-like clefts caused some similarity to fibrotized variant of giant cell tumor of tendon sheath36 or to peripheral nerve sheath tumor with degenerative changes.15 The typical patterns of LGFS seen in other parts of the tumor should prevent misdiagnosis. Moreover, the cells of giant cell tumor of tendon sheath have a more histiocytic appearance, and ancient schwannoma differs from LGFS by thick vessels and S-100 protein positivity. The immunohistochemical and ultrastructural results in our cases were similar to the previous reports.2,3,6-12 The immunoreactivity for vimentin only, and the ultrastructural finding of abundant rough endoplasmic reticulum, ribosomes, large numbers of intermediate filaments, and lack of thin filaments with densities suggest the fibroblastic differentiation of LGFS. In addition, a few cells in our case 3 showed some features of histiocytic differentiation (intracytoplasmic vacuoles and some lysosomes), which may represent the functional modulation of the neoplastic fibroblasts. Such modulation of immature fibroblastic cell is often seen in the group of so-called ‘‘fibrohistiocytic tumors.’’37 This ultrastructural finding is also consistent with immunohistochemical expression of lysozyme or CD68 seen in four of our eight cases. In summary, we report eight cases of LGFS. In addition to well-known features, we found intranuclear invaginations of cytoplasm and diffuse strong bcl-2 positivity to be constant features of LGFS. Some unusual features, such as arrangement of the cells into rows, hemosiderin deposition, synovial metaplasia-like clefts, keloid-like fibrosis, and focally prominent vascularization may cause differential diagnostic difficulties and pathologists should be aware of them as well.
Figure 15. The ultrastructure of the fibroblast-like tumor cell of LGFS (case 1). A small intranuclear cytoplasmic invagination, intermediate filaments, and abundant rough endoplasmic reticulum are seen. (Original magnification ⫻6,000.)
most of which are morphologically quite different from LGFS: spindle cell lipoma, dendritic fibromyxolipoma,33 Kaposi’s sarcoma, spindle cell component of synovial sarcoma, and solitary fibrous tumor. Of these bcl-2– positive tumors, only solitary fibrous tumors sometime resemble LGFS histologically. However, immuno-
Table 2. Review of Locations of Published and Present Tumors Location
No. of Cases (%)
Neck Upper extremity Trunk Mesentery Buttock Groin and perineum Lower extremity
3 (7.5) 5 (12.5) 8 (20) 1 (2.5) 2 (5) 8 (20) 13 (32.5)
Figure 16. The ultrastructure of LGFS. The tumor cell shows prominent intranuclear invagination and thin cell processes (case 3). (Original magnification ⫻6,000.)
Figure 17. The ultrastructure of LGFS. The histiocyte-like cell contains irregularly shaped nucleus, numerous intracytoplasmic vacuoles, and a few lysosomes. (Original magnification ⫻6,000.)
Low-Grade Fibromyxoid Sarcoma
References 1. Evans HL: Low-grade fibromyxoid sarcoma. A report of two metastasizing neoplasms having a deceptively benign appearance. Am J Clin Pathol 1987;88:615-619 2. Devaney DM, Dervan P, O’Neill S, et al: Low-grade fibromyxoid sarcoma. Histopathology 1990;17:463-479 3. Goodlad JR, Mentzel T, Fletcher CDM: Low-grade fibromyxoid sarcoma: Clinicopathological analysis of eleven cases in support of a distinct entity. Histopathology 1995;26:229-237 4. Enzinger FM, Weiss SW: Fibrosarcoma, in Soft Tissue Tumors (ed 3). St Louis, MO, Mosby, 1995, p 269-291 5. Evans HL: Low-grade fibromyxoid sarcoma. A report of 12 cases. Am J Surg Pathol 1993;17:595-600 6. Nichols GE, Cooper PH: Low-grade fibromyxoid sarcoma: Case report and immunohistochemical study. J Cutan Pathol 1994;21:356362 7. Ugai K, Kizaki T, Morimoto K, et al: A case of low-grade fibromyxoid sarcoma of the thigh. Pathol Int 1994;44:793-799 8. Shidham VB, Ayala GE, Lahaniatis JE, et al: Low-grade fibromyxoid sarcoma: Clinicopathologic case report with review of the literature. Am J Clin Oncol 1999;22:150-155 9. Husek K, Janicek P, Jelinek O: Low-grade fibromyxoid sarcoma. Cesk Patol 1998;34:139-141 10. Dvornik G, Barbareschi M, Gallotta P, et al: Low grade fibromyxoid sarcoma. Histopathology 1997;30:274-276 11. Canpolat C, Evans HL, Corpron C, et al: Fibromyxoid sarcoma in a four-year-old child: Case report and review of the literature. Med Pediatr Oncol 1996;27:561-564 12. Fukunaga M, Ushigome S, Fukunaga N: Low-grade fibromyxoid sarcoma. Virchows Arch 1996;429:301-303 13. Goldring SR, Schiller AL, Roelke M, et al: The synovial-like membrane at the bone-cement interface in loose total hip replacements and its proposed role in bone lysis. J Bone Joint Surg Am 1983;65:575-584 14. Michal M, Zamecnik M: Synovial metaplasia in lipoma. Am J Dermatopathol 1998;20:285-289 15. Enzinger FM, Weiss SW: Benign tumors of peripheral nerves, in Soft Tissue Tumors (ed 3). St Louis, MO, Mosby, 1995, pp 821-888 16. Barr RJ, King DF: The significance of pseudoinclusions within the nuclei of melanocytes of certain neoplasms, in Ackerman AB (ed): Pathology of Malignant Melanoma. New York, NY, Masson, 1981, pp 269-272 17. Rosenblum MK: Meningothelial tumors and related lesions, in Rosai J (ed): Ackerman’s Surgical Pathology (ed 8). St Louis, MO, Mosby, 1996, pp 2320-2328 18. Lopez DA, Silvers DN, Helwig EB: Cutaneous meningiomas—A clinicopathologic study. Cancer 1974;34:728-744 19. Zamecnik M, Gomolcak P: A case of perineurioma. Gen Diagn Pathol 1997;143:261 (letter) 20. Smith ME, Fisher C, Weiss SW: Pleomorphic hyalinizing
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angiectatic tumor of soft parts. A low-grade neoplasm resembling neurilemoma. Am J Surg Pathol 1996;20:21-29 21. Dei Tos AP, Seregard S, Calonje E, et al: Giant cell angiofibroma. A distinctive orbital tumor in adults. Am J Surg Pathol 1995;19:1286-1293 22. Mentzel T, Dry S, Katenkamp D, et al: Low-grade myofibroblastic sarcoma. Analysis of 18 cases in the spectrum of myofibroblastic tumors. Am J Surg Pathol 1998;22:1228-1238 23. Martorell MA, Calabuig MC, Llombart-Bosch A, et al: Primary omental tumor with ultrastructural features of cellular schwannoma and absence of S-100 antigen reactivity. Pathol Res Pract 1989;185:480485 24. Enzinger FM, Weiss SW: Malignant tumors of peripheral nerves, in Soft Tissue Tumors (ed 3). St Louis, MO, Mosby, 1995, pp 889-928 25. Enzinger FM, Weiss SW, Liang ChY: Ossifying fibromyxoid tumor of soft parts. Am J Surg Pathol 1989;13:817-827 26. Zamecnik M, Michal M, Simpson RHW, et al: Ossifying fibromyxoid tumor of soft parts: A report of 17 cases with emphasis on unusual histological features. Ann Diagn Pathol 1997;1:73-81 27. Enzinger FM, Shiraki M: Extraskeletal myxoid chondrosarcoma. An analysis of 34 cases. Hum Pathol 1972;3:421-435 28. Tsang WYW, Chan JKC, Chow LTC, et al: Perineurioma. An uncommon soft tissue neoplasm distinct from localized hypertrophic neuropathy and neurofibroma. Am J Surg Pathol 1992;16:756-763 29. Michal M: Extraneural retiform perineuriomas. A report of four cases. Pathol Res Pract 1999;195:759-763 30. Hirose T, Sumimoto M, Kudo E, et al: Malignant peripheral nerve sheath tumor (MPNST) showing perineurial cell differentiation. Am J Surg Pathol 1989;13:613-620 31. Zamecnik M, Michal M: Malignant peripheral nerve sheath tumor with perineurial cell differentiation (malignant perineurioma). Pathol Int 1999;49:69-73 32. Suster S, Fisher C, Moran CA: Expression of bcl-2 oncoprotein in benign and malignant spindle cell tumors of soft tissue, skin, serosal surfaces, and gastrointestinal tract. Am J Surg Pathol 1998;22:863-872 33. Suster S, Fisher C, Moran CA: Dendritic fibromyxolipoma: Clinicopathologic study of a distinctive benign soft tissue lesion that may be mistaken for a sarcoma. Ann Diagn Pathol 1998;2:111-120 34. Klemperer P, Rabin CB: Primary neoplasms of the pleura. A report of five cases. Arch Pathol 1931;11:385-412 35. Zamecnik M, Michal M: Solitary fibrous tumor (‘‘fibrous mesothelioma’’). A report of two extraserosal cases. Cesk Patol 1998;34:58-62 36. Enzinger FM, Weiss SW: Benign tumors and tumorlike lesions of synovial tissue, in: Soft Tissue Tumors (ed 3). St Louis, MO, Mosby, 1995, pp 735-755 37. Erlandson RA: Fibrohistiocytic tumors, in Diagnostic Transmission Electron Microscopy of Tumors With Clinicopathological, Immunohistochemical, and Cytogenetic Correlations. New York, NY, Raven Press, 1994, pp 367-375
DIAGNOSTIC PATHOLOGY VOL 4, NO 4
AUGUST 2000
ORIGINAL ARTICLES
Low-Grade Fibromyxoid Sarcoma: A Report of Eight Cases With Histologic, Immunohistochemical, and Ultrastructural Study Michal Za´mecˇnı´k, MD, and Michal Michal, MD We present eight cases of low-grade fibromyxoid sarcoma (LGFS) of soft tissues. The patients, six men and two women, ranged in age from 28 to 44 years (median, 39 years). All tumors were subcutaneous. They were located in the lower extremity (three cases), inguinal/perineal region (two cases), trunk (one case), upper extremity (one case), and neck (one case). Grossly, the lesions were similar to those described in previous studies; fibrous and well circumscribed, with pseudocapsules, and without any necrosis or nodularity. In a single case of hemosiderin-rich tumor, rusty brown strips were seen on the cut surface. Histologically, the tumors were composed of alternating fibrous and myxoid areas with various cellularity and with swirling and whorled growth patterns. The cells were stellate or spindle shaped and displayed none to mild nuclear pleomorphism and hyperchromasia. Some hypercellular areas showed a fascicular or herring bone pattern similar to common fibrosarcomas. In addition to the known typical picture of LGFS, we also have seen some unusual features. The cells of myxoid areas were often arranged in rows, thus resembling ossifying fibromyxoid tumor or myxoid chondrosarcoma of soft tissues. In a single case, the tumor cells contained a large amount of hemosiderin and the cellular nests contained synovial metaplasia-like clefts. The intranuclear invaginations of cytoplasm represented another interesting finding that was present in all tumors in our series. They seem to be constant or at least frequent features of LGFS, which may assist in the differential diagnosis. The immunohistochemical and ultrastructural findings were consistent with the fibroblastic nature of LGFS. Four cases also showed features of possible histiocytic modulation of the neoplastic fibroblasts. Ann Diagn Pathol 4: 207-217, 2000. Copyright r 2000 by W.B. Saunders Company Index Words: Fibromyxoid sarcoma, sarcoma, soft tissue, intranuclear inclusion, bcl-2
From the Department of Pathology, Slovak Postgraduate Academy of Medicine, Derer’s Hospital, Bratislava, Slovak Republic; and the Soft Tissue Tumor ˇikl’s Department of Pathology, Faculty Hospital, Charles University, Registry, S Pilsen, Czech Republic. Address reprint requests to Michal Za´mecˇnı´k, MD, Department of Pathology, General Hospital, 911 71 Trencin, Slovak Republic. Copyright r 2000 by W.B. Saunders Company 1092-9134/00/0404-0008$10.00/0 doi:10.1053/adpa.2000.8122
S
O-CALLED ‘‘low-grade fibromyxoid sarcoma’’ (LGFS) was described by Evans1 in 1987, but with the exception of a single case report,2 no additional cases were reported in the 6 years following the original description. The existence of LGFS as a distinct entity had not been confirmed until 1993, when Evans reported 10 new cases.3-5 Several recent reports established LGFS as a distinct entity.6-12 To our knowledge, only 32 cases of LGFS have been reported.1-3,5-12 We
Annals of Diagnostic Pathology, Vol 4, No 4 (August), 2000: pp 207-217
207
208
Za ´mecˇnı´k and Michal Table 1. Clinical Data and Sizes of the Tumors
Case No.
Age (yr)/Sex
1
41/M
2 3 4 5 6 7 8
37/M 43/M 28/M 45/F 37/M 44/F 38/M
Location
Left supraclavicular region Chest wall Tuberositas tibiae area Groin Left groin Left groin Forearm Thigh
Size
6 cm 4 ⫻ 3 ⫻ 3 cm 5 ⫻ 3 ⫻ 3 cm 1.5 cm 5 cm 10 ⫻ 12 ⫻ 13 cm 3 ⫻ 3 ⫻ 4 cm 4 cm
report the pathologic features of eight additional cases of LGFS. Materials and Methods Paraffin blocks or unstained reserve slides were available in all cases. In addition to conventional stains, the following immunohistochemical stains using the avidin-biotin complex
Figure 2. A typical biphasic pattern of low-grade fibromyxoid sarcoma consists of perivascular cellular areas with collagenized fibroma-like areas between them (case 1). Longitudinal section of the cellular area reveals its architecture.
technique were performed in every case: S-100 protein (polyclonal), desmin (D33), vimentin (3B4), epithelial membrane antigen (EMA), cytokeratin (KL1), lysozyme (polyclonal), CD68 (KP1), bcl-2, muscle-specific actin (HHF-35) (all from Dako, Glostrup, Denmark), CD34 (Becton-Dickinson, San Jose, CA), alpha-smooth muscle actin (Sigma, St Louis, MO), and cytokeratin AE1/AE3 (Boehringer, Mannheim, Germany). For electron microscopy, wet formalin-fixed tissue was available in cases 1 and 3. The tissues were postfixed in osmium tetroxide and the specimens were subsequently dehydrated and embedded in Epon (LADD Research, Burlington, VT). Ultrathin sections were stained with uranyl acetate and lead citrate and examined under a transition electron microscope.
Results Clinical Presentation Figure 1. A low-grade fibromyxoid sarcoma shows wellcircumscribed margin (top), variable cellularity, and collagenization of the extracellular matrix (case 6).
The clinical data are summarized in Table 1. There were six men and two women with a median age of 39 years (range, 28 to 44 years). The tumors were located in
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revealed various grades of cellularity and had gradual transitions between them. The more abrupt transition between the fibrous and myxoid components (Fig 2) was seen focally in three cases (cases 1, 2, and 3). The fibrous parts of the tumors contained spindle-shaped cells in linear arrangement producing whorled (Fig 3) and swirling growth patterns. The cellularity of the tumors ranged from hypocellular fibroma-like areas with abundant collagen fibers to hypercellular fascicular structures. In cases 1 and 5, areas of hypercellularity revealed a herringbone pattern and resembled a low-grade fibrosarcoma (Fig 4). Small areas of hyalinized keloid-like fibrosis (Figs 5 and 6) were present in four tumors (cases 1, 5, 6, and 7). The myxoid areas contained the spindle to stellate-shaped cells set in an abundant intercellular matrix. Arborizing or elongated vessels resembling those of myxoid liposarcoma and myxofibrosarcoma were seen focally in five cases (cases 1 to 5) (Fig 7). The tumor cells were frequently centered around the capillaries, giving an impression of perivascu-
Figure 3.
A cellular wavy pattern of LGFS (case 4).
the subcutis in all cases. The most common site was the groin (three cases), followed by the lower extremity (two cases). Gross Findings All tumors were round to oval and well circumscribed with a thin pseudocapsule. Their diameter ranged from 1.5 to 13 cm. The consistency was firm and fibrous, and the cut surfaces were homogeneous, without nodularity or necrosis. In case 1, focal myxoid degeneration was described in the record. In case 3, numerous rusty brown strips were apparent on the cut surface. The gross findings in cases 1 and 2 were recorded as ‘‘the appearance reminding of fibroma or myoma.’’ Microscopic Findings The tumors were generally well circumscribed (Fig 1) and they had a thin fibrous pseudocapsule. A focal infiltration into the skeletal muscle was seen only in a single case (case 5). All tumors contained two basic components: fibrous and myxoid. Both components
Figure 4. (case 1).
The herringbone-like pattern of the cellular area
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blue positive and was periodic acid-Schiff negative. The intranuclear invaginations were both alcian blue and PAS periodic acid-Schiff negative. Immunohistochemically, the tumor cells revealed strong and diffuse positivity with antibodies to vimentin and bcl-2 in all cases (Fig 14). Four tumors (cases 2, 3, 5, and 6) were reactive focally for lysozyme and CD68. All other antibodies produced negative results. Ultrastructurally, the nuclear appearance was similar in both examined cases (cases 1 and 3). The nuclear outlines were irregular and produced deep indentations and processes. The chromatin was finely clumped. The tumor cells had small and inconspicuous nucleoli. The intranuclear cytoplasmic invaginations that were discernible at the light microscopic level were found in some nuclei at the ultrastructural level as well (Figs 15 and 16). In case 1 the cytoplasm contained abundant rough endoplasmic reticulum and free ribosomes and was rich in intermediate filaments (Fig 15). The cisternae of the
Figure 5. A collagenized area of the tumor resembles scar or keloid (case 6).
lar proliferative zones (Fig 2). The cells of the myxoid areas were arranged haphazardly. In four cases (cases 1 to 4) they produced the cell-cords (Fig 8), which focally formed a reticular network (Fig 9). Cytologically, the cells of both components revealed only a mild nuclear pleomorphism with hyperchromasia, and the nucleoli were not visible (Figs 3 and 10). The clear or eosinophilic invaginations of cytoplasm were seen in some of the nuclei in all tumors (Fig 11). This nuclear feature was prominent in three lesions (cases 1, 6, and 8), and less apparent in the remaining tumors. In case 3, numerous confluent areas with abundant brown pigment in tumor cells simulated melanotic tumor (Fig 12). The brown pigment was iron positive. Additional interesting findings seen in this tumor were the artifactual clefts and spaces inside the cellular areas of this tumor. Here, the cells formed a continuous layer on the surface of these spaces resembling a synovial metaplasia13,14 (Fig 13). The myxoid matrix of the tumors was slightly alcian
Figure 6. A high power view of the keloid-like fibrosis of the tumor (case 6).
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the tumor cells. In addition, some cells in case 3 showed numerous vacuoles and a few lysosomes, suggestive of histiocytic differentiation (Fig 17). Discussion Low-grade fibromyxoid sarcoma occurs in subcutaneous or deep soft tissues in adult patients. Including our patients, there have been 40 cases described in the literature to date.1-3,5-12 The mean age of the patients was 35 years (range, 6 to 65 years). Twenty-seven patients (68%) were male and 13 (32%) were female. The male predominance appears to be a typical feature of LGFS in most studies. Evans’ series5 was the only one in which such male predominance was not observed. Goodlad et al3 described 91% tumors in males, which is similar to the 75% male predominance found in our study. Therefore, we believe that LGFS is typically a tumor of males and that the lack of strong male predominance in the study of Evans probably represents
Figure 7. Prominent vascularization resembling myxoid liposarcoma (case 5).
endoplasmic reticulum were often dilated and contained finely granular contents. The filaments revealed neither periodicity nor dense bodies. Short cytoplasmic processes were found on the surface of a few cells. Intercellular space contained numerous collagen fibers. In case 3 the cells possessed thin filopodia-like processes (Fig 16), sometimes with rudimentary cell junctions between them. The tumor cells were more loosely organized in a clear-looking, abundant myxoid matrix containing a finely granular substance. The collagen fibers were sparse. The cytoplasm of the tumor cells contained moderate numbers of well-formed cisternae of rough endoplasmic reticulum and Golgi complexes. The endoplasmic reticulum was often dilated. The intermediate filaments were only found in some cells. We were unable to find any myofibroblastic features, such as pinocytic vesicles, microfilaments grouped into the dense bodies, or an external lamina. The ultrastructural findings indicate the fibroblastic differentiation of
Figure 8.
An arrangement of the cells into rows.
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melanotic tumor. Histologically, the LGFS was characterized by alternating fibrous and myxoid areas.1-3,5-12 The proliferation of bland-looking fibroblastic cells in a swirling or whorled pattern was characteristic. The cellularity was predominantly low to moderate, but fibrosarcoma-like fascicular or herringbone pattern occurred in two of our eight cases. The tumors were usually well circumscribed and encapsulated, but an infiltrative growth was seen in small areas, particularly in recurrent tumors. Some areas of most of the tumors in our series showed a prominent vascularization, which simulated myxoid liposarcoma. However, such areas were not present through whole lesions and areas more typical of LGFS always allowed the distinction from liposarcoma. The keloid-like fibrosis described in detail by Goodlad et al3 was observed in three cases. This pattern was often bland looking and pathologists should be aware of it.
Figure 9. The rows of cells create focally a reticular network (lower part of the figure).
a regional unexplained difference. The tumor locations in our study were similar to the previously reported cases. The most frequently reported location of LGFS has been in the lower extremity (32.5%), especially in the thigh, followed by the groin/perineum (20%) and the trunk (20%) (Table 2). Interestingly, no case of LGFS has ever been observed in the retroperitoneum and only a single tumor was described in the mesentery,5 indicating that the LGFS is typically a neoplasm of subcutaneous and deep soft tissues. At gross examination, LGFS is well circumscribed, its cut surface is firm and fibrous, and it may have focal gelatinous appearance. No typical macroscopic signs of malignancy, such as necrosis, hemorrhage, infiltrative border, or nodularity, were described in LGFS. The gross appearance of our tumors favored benign lesions. A fibroma or myoma diagnosis was considered at gross examination in some of our cases. Heavy hemosiderin depositions in one case caused a gross impression of a
Figure 10. A high grade of the atypism, which we were able to observed in our series. Such atypism was found mostly in fibrosarcoma-like areas (case 1).
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soft tissue and cutaneous meningioma,17,18 perineurioma,19 pleomorphic hyalinizing angiectatic tumor,20 giant cell angiofibroma,21 and low-grade myofibroblastic sarcoma.22 The distinction of these tumors from LGFS is usually not problematic because of their different histologic and/or immunohistochemical features. Some schwannomas, especially those of cellular type, and malignant peripheral nerve sheath tumors may cause difficulties to be distinguished from LGFS because these lesions are similarly composed of spindle cells and they may lack the S-100 protein positivity.23,24 However, their nuclei are more slender and wavy, and their growth patterns are more fascicular. Unlike LGFS, the malignant peripheral nerve sheath tumor is the infiltrating neoplasm with higher nuclear atypia. Similar to LGFS, the recently described pleomorphic hyalinizing angiectatic tumors20 expresses only vimentin, but it is usually infiltrative with more pleomorphic cellular population
Figure 11. (case 8).
Numerous cytoplasmic intranuclear invaginations
In addition to these typical features, we have also recorded some unusual features, such as intranuclear invaginations of the cytoplasm, the arrangement of the cells into rows, hemosiderin-rich cells, and the clefts resembling synovial metaplasia. The intranuclear cytoplasmic invaginations represent the most interesting finding. They were most often seen in myxoid and paucicellular areas. This nuclear feature was at first described by Shidham et al in their recently published case report.8 We believe that similar intranuclear inclusions are visible on photomicrographs of some of the previously reported LGFS.3,5,7 We have found intranuclear inclusions in all tumors, although it was prominent only in three of our eight cases and less apparent, but always present, in others. We conclude that the cytoplasmic nuclear invaginations are a characteristic and possibly constant feature of LGFS. The occurrence of intranuclear inclusions is known in several soft tissue tumors, such as schwannoma,15 malignant melanoma,16
Figure 12. Tumor area with abundant hemosiderin pigment. Several tissue clefts resemble synovial metaplasia (case 3).
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fibrous septa and frequent ossification. The cells of OFMT are S100 positive or they rarely react immunohistochemically with myoid markers. Myxoid chondrosarcomas have abundant myxoid matrix in all cases and lack the paucicellular and collagenized pattern typical of LGFS. The perineuriomas, both benign28,29 and malignant,30,31 express epithelial membrane antigen and do not show prominent alternation of cellularity. In addition, malignant perineurioma shows obvious malignant histological features, such as necrosis, infiltrative growth, high cellularity, and nuclear atypism with frequent mitoses. Immunohistochemically, besides already known vimentin positivity, we observed a strong and diffuse bcl-2 reactivity in all our cases. Low-grade fibromyxoid sarcoma may be added to the list of the bcl-2–positive soft tissue lesions.32 Although the list of bcl-2–positive soft tissue tumors is quite long, the diffuse and strong reactivity can be of help in diagnosis. Such bcl-2 immunoreactivity was observed in the following list of tumors,
Figure 13. A detailed view of the synovial metaplasia-like tissue clefts. Typical intranuclear cytoplasmic invaginations are also apparent.
and it contains characteristic dilated vessels with thick hyalinized walls. Perineuriomas and meningiomas differ from LGFS by constant epithelial membrane antigen positivity and they do not show high variations in cellularity.17-19 Unlike LGFS, giant cell angiofibroma21 contains giant multinucleated fibroblasts and angiectatic spaces and is immunoreactive for CD34. Low-grade myofibroblastic sarcoma22 is a diffusely infiltrative neoplasm and shows immunohistochemical and ultrastructural features of myofibroblastic differentiation. The arrangement of the cells into rows was seen in half of our cases. This feature may be particularly misleading because it resembles a similar cellular arrangement of ossifying fibromyxoid tumor (OFMT),25,26 myxoid chondrosarcoma,27 and perineuriomas.19,28-31 However, the glomoid cells of OFMT, as well as the chondroblast-like cells of myxoid chondrosarcoma, are quite different from the fibroblast-looking cells of LGFS. Moreover, OFMT is lobulated with
Figure 14. cases.
A strong immunoreactivity for bcl-2 was seen in all
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histochemical CD34 positivity, patternless structure lacking whorls and wires, and hemangiopericytoma-like areas34,35 easily differentiate solitary fibrous tumor from LGFS. The admixture of hemosiderin-rich cells and the synovium-like clefts caused some similarity to fibrotized variant of giant cell tumor of tendon sheath36 or to peripheral nerve sheath tumor with degenerative changes.15 The typical patterns of LGFS seen in other parts of the tumor should prevent misdiagnosis. Moreover, the cells of giant cell tumor of tendon sheath have a more histiocytic appearance, and ancient schwannoma differs from LGFS by thick vessels and S-100 protein positivity. The immunohistochemical and ultrastructural results in our cases were similar to the previous reports.2,3,6-12 The immunoreactivity for vimentin only, and the ultrastructural finding of abundant rough endoplasmic reticulum, ribosomes, large numbers of intermediate filaments, and lack of thin filaments with densities suggest the fibroblastic differentiation of LGFS. In addition, a few cells in our case 3 showed some features of histiocytic differentiation (intracytoplasmic vacuoles and some lysosomes), which may represent the functional modulation of the neoplastic fibroblasts. Such modulation of immature fibroblastic cell is often seen in the group of so-called ‘‘fibrohistiocytic tumors.’’37 This ultrastructural finding is also consistent with immunohistochemical expression of lysozyme or CD68 seen in four of our eight cases. In summary, we report eight cases of LGFS. In addition to well-known features, we found intranuclear invaginations of cytoplasm and diffuse strong bcl-2 positivity to be constant features of LGFS. Some unusual features, such as arrangement of the cells into rows, hemosiderin deposition, synovial metaplasia-like clefts, keloid-like fibrosis, and focally prominent vascularization may cause differential diagnostic difficulties and pathologists should be aware of them as well.
Figure 15. The ultrastructure of the fibroblast-like tumor cell of LGFS (case 1). A small intranuclear cytoplasmic invagination, intermediate filaments, and abundant rough endoplasmic reticulum are seen. (Original magnification ⫻6,000.)
most of which are morphologically quite different from LGFS: spindle cell lipoma, dendritic fibromyxolipoma,33 Kaposi’s sarcoma, spindle cell component of synovial sarcoma, and solitary fibrous tumor. Of these bcl-2– positive tumors, only solitary fibrous tumors sometime resemble LGFS histologically. However, immuno-
Table 2. Review of Locations of Published and Present Tumors Location
No. of Cases (%)
Neck Upper extremity Trunk Mesentery Buttock Groin and perineum Lower extremity
3 (7.5) 5 (12.5) 8 (20) 1 (2.5) 2 (5) 8 (20) 13 (32.5)
Figure 16. The ultrastructure of LGFS. The tumor cell shows prominent intranuclear invagination and thin cell processes (case 3). (Original magnification ⫻6,000.)
Figure 17. The ultrastructure of LGFS. The histiocyte-like cell contains irregularly shaped nucleus, numerous intracytoplasmic vacuoles, and a few lysosomes. (Original magnification ⫻6,000.)
Low-Grade Fibromyxoid Sarcoma
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