2011-01 Goldblum Common Morphologic Patterns

COMMON MORPHOLOGIC PATTERNS IN SOFT TISSUE TUMORS WITH AN EMPHASIS ON USEFUL ANCILLARY DIAGNOSTIC TECHNIQUES
John R. Goldblum, M.D.
Chairman, Department of Anatomic Pathology Cleveland Clinic Professor of Pathology Cleveland Clinic Lerner College of Medicine 9500 Euclid Avenue L25 Cleveland OH 44195 Ph 216-444-8238 Fx 216-445-2142
Common Morphologic Patterns in Soft Tissue Tumors
Email goldblj@ccf.org
Recognizing patterns at low magnification is one of the keys to organizing differential diagnoses in soft tissue sarcomas. Each pattern elicits a differential diagnosis, and often a combination of light microscopic and immunohistochemical features will allow one to classify a neoplasm with a given morphologic pattern. Below is a description of some of the more common morphologic patterns seen in soft tissue sarcomas with some practical points on the approach to tumors with these morphologic patterns.
MFH-Like Pattern
One of the more controversial issues in soft tissue pathology is whether a malignant fibrous histiocytoma (MFH) is a pathologic entity or a morphologic pattern. The concept of MFH was first introduced in the early 1960s by Dr. Stout and colleagues1,2 and was refined and accepted as an entity in the early 1970s through the efforts of Drs. Kempson and Kyriakos.3 Thereafter, several large studies supported the concept of MFH as a distinct clinicopathologic entity.4-6 Pleomorphic-storiform MFH is now regarded as the most common soft tissue sarcoma of adulthood.7 However, it has become increasingly recognized that a variety of other neoplasms may have focal MFH-like areas, and other tumors that resemble MFH in their entirety may show some specific line of cellular differentiation through the use of immunohistochemistry or electron microscopy. In 1986, Brooks suggested that at least a subgroup of neoplasms classified as MFH represent a final common pathway indicative of tumor progression.8 In 1992, Fletcher reassessed 159 cases of pleomorphic sarcoma that were classified originally as pleomorphic MFH and found that only 13% of these tumors could not be assigned to some other specific sarcoma category.9 Thus, in Fletchers opinion, if one uses a combination of morphologic, immunophenotypic and ultrastructural data, one can almost always identify a specific line of cellular differentiation in pleomorphic tumors resembling MFH, supporting the concept of MFH as a morphologic pattern as opposed to a distinct clinicopathologic entity. One could also argue that Dr. Fletcher eventually proved the point that he sought to disprove, that is, one is still left with a subgroup of pleomorphic sarcomas that cannot be further subclassified, and thus may truly represent MFH (as a diagnosis of exclusion). Regardless of this ongoing controversy, which probably will never be definitively answered, the practicing pathologist is not infrequently met with the challenge of classifying a pleomorphic malignant neoplasm, and the following discussion raises some practical points in the approach to such tumors.
When I encounter a soft tissue sarcoma with an MFH-like pattern, I first question whether that could be a component of a dedifferentiated sarcoma, particularly when dealing with a sarcoma in the retroperitoneum. For example, well-differentiated liposarcomas in the retroperitoneum are typically not detected until they reach an enormous size, given the lack of space constraints for their growth. Thus, it is not uncommon to find areas of dedifferentiation in liposarcomas in this location, given the supposition that dedifferentiation is a time-dependent phenomenon.10 Similarly, when I encounter a lesion in the bone with an MFH-like pattern, I also consider the possibility of that representing a portion of a dedifferentiated chondrosarcoma, as originally described by Dahlin et al.11 Thorough sampling is often required in order to recognize the lowgrade sarcoma from which the dedifferentiated MFH-like areas arose. More commonly, a variety of other sarcomas may have focal MFH-like areas or may be composed virtually entirely of MFH-like areas. In both of these circumstances, it is important to sample the tumor well and evaluate for lower grade areas that could allow for recognition of a specific sarcoma type. For example, in most cases of pleomorphic leiomyosarcoma, one can find lower grade areas recognizable as leiomyosarcoma that can be confirmed by immunohistochemistry. Similarly, pleomorphic MPNST and pleomorphic rhabdomyosarcoma may have lower grade areas that allow for their recognition. In the absence of these low-grade areas, immunohistochemistry plays an important role in determining a specific line of cellular differentiation. One could argue as to the necessity of this endeavor, given the similar therapeutic and prognostic implications of all of these high-grade pleomorphic sarcomas. However, for academic purposes, and possibly for future refinements in therapy, we attempt to identify a specific line of cellular differentiation in all pleomorphic MFH-like sarcomas. The following is a discussion of criteria for recognizing the various pleomorphic sarcomas.
Pleomorphic Liposarcoma
Immunohistochemistry is not necessary for recognizing this lesion. The only criterion for the diagnosis is the presence of multivacuolated lipoblasts, defined as large cells containing multiple punched-out intracytoplasmic vacuoles, typically indenting or scalloping an atypical hyperchromatic nucleus. The major difficulty here is separating pleomorphic sarcomas that infiltrate fat from those with true pleomorphic lipoblasts.
Dedifferentiated Liposarcoma
Although it has become recently recognized that not all dedifferentiated liposarcomas have high-grade sarcomatous areas,12 for the purposes of this discussion, the recognition of a highgrade dedifferentiated liposarcoma requires recognition of a well-differentiated liposarcoma either in the same neoplasm, or clearly antedating the presence of the high-grade sarcoma.
Pleomorphic MPNST
As with non-pleomorphic variants of MPNST, this tumor can be recognized when there is a demonstrable origin from a major nerve, a demonstrable pre-existing benign peripheral nerve sheath tumor or ultrastructural evidence of Schwann cell differentiation. S100 protein immunoreactivity in a pleomorphic sarcoma should not be taken as definitive evidence of a pleomorphic MPNST, as S-100 protein may be seen in a variety of other pleomorphic sarcomas. However, S-100 protein immunoreactivity in a pleomorphic sarcoma in a patient with neurofibromatosis may be taken as indirect evidence of that lesion being an MPNST.
Pleomorphic Leiomyosarcoma
The tumor cells tend to be arranged into more of a fascicular growth pattern, as opposed to a storiform growth pattern typical of MFH. In addition, cells have blunt-ended vesicular nuclei, often with a perinuclear vacuole as well as densely eosinophilic cytoplasm. One can confirm this diagnosis by either ultrastructural or immunohistochemical (smooth muscle actin and/or desmin) analysis.
Pleomorphic Rhabdomyosarcoma
Once one is sure that one is excluding the possibility of entrapped non-neoplastic skeletal muscle, the presence of large cells with eosinophilic cytoplasm and cross striations should raise the possibility of this diagnosis. Confirmation with immunohistochemical stains (muscle specific actin, desmin, myoglobin, MyoD1 or myogenin) or ultrastructural analysis (alternating thick and thin filaments with Z-bands) is necessary.
Extraskeletal Osteosarcoma
The only criterion for recognizing this lesion is the presence of bone or osteoid that is produced by cytologically malignant cells. Probably even more important than being able to recognize a specific line of cellular differentiation in an MFH-like tumor, one should also consider the possibility that one is dealing with a pseudosarcoma, i.e., a non-mesenchymal malignant neoplasm that phenotypically resembles an MFH. Certainly, melanoma should always be entertained in the differential diagnosis, and an S-100 is probably always worth doing to exclude this diagnosis. In addition, particularly in mucosal or organ-based MFH-like lesions, the possibility of a sarcomatoid carcinoma should be strongly entertained and confirmed with the use of immunohistochemistry, particularly cytokeratins.
2.
References 1. Kauffman SL, Stout AP. Histiocytic tumors (fibrous xanthoma and histiocytoma) in children. Cancer 1961;14:469-482. OBrien JE, Stout AP. Malignant fibrous xanthomas. Cancer 1964;17:1445-1455. 3. Kempson RL, Kyriakos M. Fibroxanthosarcoma of the soft tissues. A type of malignant fibrous histiocytoma. Cancer 1972;29:961-976. 4. Enjoji M, Hashimoto H, Tsuneyoshi M, Iwasaki H. Malignant fibrous histiocytoma. A clinicopathologic study of 130 cases. Acta Pathol Jpn 1980;30:727-741. 5. Kearney MM, Soule EH, Ivins JC. Malignant fibrous histiocytoma. A retrospective study of 167 cases. Cancer 1980;45:167-178. 6. Weiss SW, Enzinger FM. Malignant fibrous histiocytoma. An analysis of 200 cases. Cancer 1978;41:2250-2266. 7. Enzinger FM, Weiss SW. Malignant fibrous histiocytic tumors. In: Soft Tissue Tumors, 3rd ed. St. Louis: C. V. Mosby, 1995. 8. Brooks JJ. The significance of double phenotypic patterns and markers in human sarcomas. A new model of mesenchymal differentiation. Am J Pathol 1986;125:113-123. 9. 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(3):213-228. 10. 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(11):1051-1058. 11. Dahlin DC, Beaubout JW. Dedifferentiation of low-grade chondrosarcomas. Cancer 1971;28:461-466.
12. 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(3):271-281.
Myxoid Soft Tissue Tumors and Tumor-Like Lesions

The pathologist need not panic when one comes across one of these lesions because these entities can be separated from one another when one pays attention to certain key features when evaluating these lesions. For example, evaluation of the cellularity of the lesion, as well as the arrangement of the cells with respect to one another is absolutely critical in distinguishing these lesions from one another. While some lesions are characterized by extremely low cellularity (intramuscular myxoma), others are characteristically much more cellular (nodular fasciitis). Similarly, these cells may stand apart from one another, with little cell-cell contact (myxoid liposarcoma), or they may be arranged into nests or chains (myxoid chondrosarcoma). Nuclear pleomorphism, although somewhat subjective, is also useful in this evaluation, given that some lesions totally lack nuclear pleomorphism (intramuscular myxoma), whereas others are characterized by a high degree of cytologic atypia (myxofibrosarcoma). Another often underappreciated feature in this evaluation is the presence or absence of an underlying vasculature. While some lesions are characteristically of low vascularity (intramuscular myxoma), others are characterized by an intricate vascular network that allows one to recognize the lesion as malignant (myxoid liposarcoma and myxfibrosarcoma). Occasionally, the evaluation of the myxoid stroma using histochemical techniques may also be useful. Hyaluronic acid and chondroitin sulfate are the most common mucosubstances found in these lesions, and one or the other of these substances is often typical of a particular lesion. For example, intramuscular myxoma, myxoid liposarcoma and myxofibrosarcoma are characterized by hyaluronic acid-rich myxoid stroma, whereas myxoid chondrosarcoma and chordoma are characterized by a chondroitin sulfate-rich myxoid stroma. Although Alcian blue (pH2.5) stains both hyaluronic acid and chondroitin sulfate, pretreatment with hyaluronidase will result in the loss of Alcian blue positivity if the stroma is made up of hyaluronic acid. In contrast, chondroitin sulfate-rich stroma is hyaluronidase resistant. Benign myxoid soft tissue lesions that enter into this differential diagnosis include nodular fasciitis, intramuscular myxoma and angiomyxoma, among others. The malignant lesions may include myxoid liposarcoma, myxofibrosarcoma, extra-skeletal myxoid chondrosarcoma and low-grade fibromyxoid sarcoma (Evans' tumor). Nodular fasciitis is a self-limited, reactive lesion often mistaken for a sarcoma due to its high cellularity, rapid growth and brisk mitotic activity.1 In Montgomery and Meis' series of 53 cases, only 43% of the cases were correctly diagnosed, and 21% of these cases were misdiagnosed as some type of sarcoma2. This lesion typically presents as a rapidly growing mass of short
duration, and is most common in young patients (average age: 34 years), although essentially any age group may be affected. The upper extremity is the most common site; other fairly common sites include the trunk, lower extremities and head and neck region (although virtually any superficial site in the body may be involved). Most lesions are less than 3.0 cm, but I have seen examples as large as 6.0 cm. Most cases are subcutaneous, but some are in skeletal muscle, causing further concern that the lesion is a sarcoma. Histologically, nodular fasciitis has many appearances, varying dramatically in cellularity and amount of myxoid stroma both between lesions, and within the same lesion. Most cells are plump, immature tissue culture fibroblasts or myofibroblasts that show little nuclear pleomorphism. Mitoses are characteristically numerous, but atypical mitoses are not present. The cells are arranged into short, irregular bundles or fascicles, but never form long, sweeping fascicles, and are deposited in a hyaluronic acid-rich myxoid matrix that occasionally forms microcysts. Other helpful histologic features include cleft-like spaces, red blood cell extravasation, rare giant cells and, occasionally, metaplastic bone or cartilage. In older lesions, there is an increased amount of stromal fibrosis with a less prominent myxoid matrix. Immunohistochemically, the majority of cells stain for smooth-muscle actin, which may be a source of confusion if one is considering the possibility of leiomyosarcoma.2 The intramuscular myxoma typically occurs in middle-aged to elderly patients, and is extremely rare in childhood. These lesions present as a painless, palpable fluctuant mass within the deep soft tissues of the thigh, shoulder, buttocks or upper arm, although virtually any site may be involved.3 In addition, lesions with similar histology can occur in a cutaneous and juxta-articular location. Although usually solitary, multiple intramuscular myxomas have been found to be associated with fibrous dysplasia, and generally occur in the same anatomic region as the bony abnormalities.4 Rare patients also display melanotic pigmentation of the skin and endocrine abnormalities (Albright's syndrome). Myxomas occurring in a cutaneous location may be sporadic or associated with Carney's complex, characterized by an association with endocrine abnormalities, spotty pigmentation, cardiac myxomas, and psammomatous melanotic schwannomas, inherited in an autosomal dominant manner.5 The juxta-articular myxoma is another variant of myxoma, most commonly found in the area of the knee (90%).6 Males are affected significantly more commonly than females, typically between the third and seventh decades of life. In the series by Meis and Enzinger, 34% of the cases recurred, sometimes with
multiple recurrences. Despite the tendency for these lesions to recur, these are best treated conservatively by local excision. Grossly, the intramuscular myxoma appears to be well-circumscribed, although a true fibrous capsule is not present. Histologically, these lesions characteristically are of low cellularity, composed of bland spindled or stellate cells with cytoplasmic processes. The cells tend not to touch one another, but rather are separated by abundant myxoid stroma composed of hyaluronic acid. Although some cells with vacuolated cytoplasm may be present and may resemble lipoblasts, these are macrophages that have imbibed products of the myxoid stroma resulting in cytoplasmic vacuolization. In addition, although grossly well circumscribed, there is often some infiltration into the surrounding skeletal muscle, with entrapment of atrophic skeletal muscle fibers. Although scattered blood vessels may be present, there is relatively little vascularity, and the vascularity lacks the organization of many myxoid sarcomas. These lesions are essentially cured by local excision, and have little tendency to recur, even if incompletely excised. Angiomyxoma (aggressive angiomyxoma) typically occurs as a large, ill-defined mass within the pelvis, perineum, or genital tract in women.7,8 Rare cases have also been reported in men.9 Histologically, the lesion is composed of spindled or stellate cells that generally do not touch one another, and are separated by an abundant myxoid stroma composed primarily of hyaluronic acid. The cells lack nuclear atypia, and mitotic figures are difficult to identify. Mast cells are frequently prominent. In addition, these lesions are characterized by a prominent vascularity with vessels of different caliber, including thin-walled vessels and thick hyalinized vessels. Although histologically bland, these lesions are characterized by a high rate of local recurrence; metastases have not been reported. Myxoid liposarcoma is the most common subtype of liposarcoma.10 This is a tumor of adult life and typically occurs in the deep soft tissues of the extremity, especially the thigh and popliteal region. At low power, the most striking feature is the very characteristic delicate plexiform capillary pattern that is found throughout the neoplasm. The spindled cells between the capillaries are primitive mesenchymal cells, and vary little from one another, without significant nuclear pleomorphism. The cells are evenly distributed, and typically do not touch one another. Interspersed between the primitive mesenchymal cells are the diagnostic lipoblasts, which occur in varying numbers. By definition, a lipoblast is characterized by a sharply defined lipid droplet
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that usually pushes the nucleus to a peripheral location and indents or scallops the nucleus. Vacuolated cells indistinguishable from lipoblasts may be found in a variety of benign and malignant lesions. Therefore, an appropriate histologic background must be present in order to establish that cell as a true lipoblast. Unless there is a significant round cell component, myxoid liposarcomas are generally considered to be low-grade sarcomas. Round cell liposarcoma is considered to be a poorly differentiated form of myxoid liposarcoma for several reasons. First, it is not uncommon to see mixtures of both myxoid and round cell liposarcoma within the same tumor. Furthermore, the characteristic translocation found in myxoid liposarcoma, t(12;16)(q13;p11), is also present in round cell liposarcoma,11,12 and can be detected by either fluorescence in-situ hybridization13,14 or polymerase chain reaction.15 At the molecular level, this translocation results in fusion of the DDIT3 (CHOP) gene on 12q13 with the FUS gene on 16p11.16-18 Rarely, the DDIT3 gene is fused to the N-terminal portion of the EWS gene.19,20 It has been suggested that tumors that have hypercellular or round cell areas within an otherwise typical myxoid liposarcoma pursue a more aggressive clinical course.21-24 However, it is difficult to know where on the spectrum of cellularity these cases actually lie. Furthermore, it is unknown whether there is a critical amount of these round cell areas that are predictive of a worse prognosis. Smith et al studied 29 cases of myxoid/round cell liposarcoma of the extremities and found that those patients whose tumors had greater than 5% round cell component were more likely to develop metastases or die from their disease.25 Round cell areas were defined as those areas with a marked increase in cellularity in which the cells were round and separated by little or no myxoid stroma. In these areas, the mitotic index was generally increased, and a plexiform vascular pattern was difficult to recognize secondary to the overgrowth of primitive round cells. In addition, transitional areas, defined as areas of increased cellularity compared to typical myxoid liposarcoma, but in which the cells remained spindled, did not have overlapping nuclear borders, and retained an easily discernible plexiform vascular pattern, were not found to worsen clinical outcome in the absence of a round cell component. Kilpatrick et al. found similar findings, although they found a cut-off point of 25% round cell component to be prognostically important by multivariate analysis.26 The myxoid variant of MFH was first characterized by Weiss and Enzinger in 1977, and was defined as an MFH that has at least 50% of the tumor cells deposited in a hyaluronic acid-rich
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myxoid stroma.27 However, it is apparent that there is a wide spectrum of lesions ranging from superficially located, hypocellular, low-grade myxoid lesions (low-grade myxofibrosarcoma) to those that are more deeply located, of higher stage and more biologically aggressive. Mentzel et al. recently evaluated the clinicopathologic features of 75 cases of so-called myxofibrosarcoma,28 now the preferred term for this entity. Almost 70% of their cases were superficially located, either in the dermis or subcutaneous tissues, usually on the upper or lower extremities, and characterized by a nodular growth pattern, a myxoid matrix containing elongated, curvilinear capillaries and spindled or stellate-shaped tumor cells with hyperchromatic atypical nuclei. These superficially located low-grade lesions are the lesions that are most likely to be confused with benign myxoid lesions. Some of the cases were more deeply located and showed areas of increased cellularity and cytologic atypia, more typical of the classic myxoid MFH described by Weiss and Enzinger. The latter group of lesions was characterized by moderate cellularity in which the cells showed significant nuclear pleomorphism and hyperchromatism, with easily identified mitotic figures. Similar to myxoid liposarcoma, a characteristic vasculature was present throughout the neoplasm, although these blood vessels tended to be more coarse than those seen in myxoid liposarcoma. Frequently, the atypical cells condensed along the periphery of the blood vessels. Although the depth of the primary lesion did not influence the incidence of local recurrence, only those neoplasms of intermediate or high-grade metastasized. In addition, some cases of low-grade myxofibrosarcoma progressed to higher-grade lesions in recurrences. In 1987, Evans described a tumor that typically presents as a large, well-circumscribed mass in the deep soft tissues, most commonly in the shoulder, thigh and inguinal region, which he termed low-grade fibromyxoid sarcoma.29 Histologically, this lesion is composed of bland spindled cells of low to moderate cellularity deposited in a fibrous and myxoid stroma. The cells often have a swirling growth pattern and occasionally condense in a perivascular location. Cytologically, there is little nuclear pleomorphism, and mitotic figures are difficult to identify. Similar to other myxoid sarcomas, low-grade fibromyxoid sarcoma often has a rich, regular vascular network that is useful in its distinction from a benign lesion. Also, despite the gross circumscription, there is microscopic infiltration of the surrounding tissues. Of the twelve patients described in Evans 1993 paper, nine had local recurrences, seven had evidence of distant metastasis, and four died of disease.30 Some authors have also reported histologic progression to a higher-grade lesion in recurrences.31 Low-grade fibromyxoid sarcoma (and the related hyalinizing spindle cell tumor with giant rosettes) is characterized by a t(7;16) with fusion of the
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CREB3L2 gene on chromosome 12 with the FUS gene on chromosome 16.32 Mertens and colleagues reported the presence of CREB3L2-FUS fusion in 22 of 23 (96%) cases of low-grade fibromyxoid sarcoma,33 and we utilize paraffin-embedded tissue for FISH, probing with a FUS breakapart probe to confirm this difficult diagnosis. Similar to myxoid liposarcoma, extraskeletal myxoid chondrosarcoma also occurs primarily in the deep soft tissues of the extremities.34 Macroscopically, the neoplasm occurs as a multinodular, well-circumscribed mass, which frequently shows large areas of hemorrhage. Histologically, this is a lesion of moderate cellularity in which the cells tend to touch one another and are arranged in small cords or strands. These cells show little nuclear pleomorphism, low mitotic activity, and have a moderate amount of eosinophilic cytoplasm. The vascularity is not prominent, in contrast to myxoid liposarcoma and myxofibrosarcoma. The myxoid matrix in this case is composed of chondroitin sulfate. Immunohistochemically, these cells may be S-100 protein positive, although Dei Tos et al found that only 7 of 39 cases (18%) stained for this antigen,35 although it is usually unnecessary to perform immunostains. In addition, this tumor has been found to harbor a characteristic translocation, t(9;22)(q22;q12), which involves a rearrangement of the EWS gene on 22q12 with the NR4A3 gene (formerly known was CHN or TEC).36 The resultant NR3A3-EWS fusion transcript can be detected by RT-PCR or FISH.37 In the series by Meis-Kindblom et al, older patient age, larger tumor size and tumor location in the proximal extremity or limb girdle were adverse prognostic factors identified by multivariate analysis.38 Local recurrences and metastases were noted in 48% and 46% of patients, respectively. Some patients had prolonged survival even after the development of metastasis, although many of these patients eventually died as a result of tumor. Interestingly, this study did not identify a relationship between tumor cellularity and prognosis. In conclusion, despite the fact that numerous benign and malignant soft tissue lesions may have a myxoid stroma, these lesions can be reliably separated from one another through the systematic evaluation of certain parameters, in conjunction with clinical features including age, site and rate of growth of the neoplasm, with little need for ancillary studies. However, molecular testing for translocations has become increasingly important.
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References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Bernstein KE, Lattes R. Nodular (pseudosarcomatous) fasciitis, a nonrecurrent lesion: Clinicopathologic study of 134 cases. Cancer 1982; 49:1668-1675. Montgomery EA, Meis JM. Nodular fasciitis. Its morphologic spectrum and immunohistochemical profile. Am J Surg Pathol 1991; 15:942-948. Kindblom LG, Stener B, Angervall L. Intramuscular myxoma. Cancer 1974; 34;17341744. Ireland DCR, Soule EH, Ivins JC. Myxoma of somatic soft tissues. A report of 58 patients, three with multiple tumors and fibrous dysplasia of bone. Mayo Clin Proc 1973; 48:401-410. Carney JA, Headington JT, Su WPD. Cutaneous myxomas. A major component of the complex of myxomas, spotty pigmentation, and endocrine overactivity. Arch Dermatol 1986; 122:790-798. Meis JM, Enzinger FM. Juxta-articular myxoma. A clinical and pathological study of 65 cases. Hum Pathol 1992; 23:639-646. Steeper TA, Rosai J. Aggressive angiomyxoma of the female pelvis and perineum. Report of nine cases of a distinctive type of gynecologic soft tissue neoplasm. Am J Surg Pathol 1983; 7:463-475. Begin LR, Clement PB, Kirk ME, Jothy S, McCaughey WTE, Ferenczy A. Aggressive angiomyxoma of pelvic soft parts: A clinicopathologic study of nine cases. Hum Pathol 1985; 16:621-628. Tsang WYW, Chan JKC, Lee KC, Fisher C, Fletcher CDM. Aggressive angiomyxoma. A report of four cases occurring in men. Am J Surg Pathol 1992; 16:1059-1065. Weiss SW, Goldblum JR. Myxoid variant of liposarcoma. In: Soft Tissue Tumors, 4th Edition, CV Mosby, St. Louis, MO, 2001. Gibas Z, Miettinen M, Limon J, et al. Cytogenetic and immunohistochemical profile of myxoid liposarcoma. Am J Clin Pathol 1995;103:20-26. Tallini G, Akerman M, Del Cin P, et al. Combined morphologic and karyotypic study of 28 myxoid liposarcomas. Implications for a revised morphologic typing (a report from the CHAMP group). Am J Surg Pathol 1996;20:1047-1055. Mezzelani A, Sozzi G, Pierotti MA, Pilotti S. Rapid differential diagnosis of myxoid liposarcoma by fluorescence in-situ hybridization on cytological preparations. J Clin Pathol 1996;49:308-309. Aoki T, Hisaoka M, Kouho H, Hashimoto H, Nakata H. Interphase cytogenetic analysis of myxoid soft tissue by fluorescence in-situ hybridization and DNA flow cytometry using paraffin-embedded tissue. Cancer 1997;79:284-293. Kuroda M, Ishida T, Horiuchi H, et al. Chimeric TLS/FUS-CHOP gene expression and the heterogeneity of its junction in human myxoid and round cell liposarcoma. Am J Pathol 1995;147:1221-1227. Aman P, Ron D, Mandahl N, et al. Rearrangement of the transcription factor gene CHOP in myxoid liposarcomas with t(12;16)(q13;p11). Genes Chromosomes Cancer 1992;5:278-285. Crozat A, Aman P, Mandahl N, Ron D. Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 1993;363:640-644. Rabbitts T, Forster A, Larson R, Nathan P. Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma. Nature Genet 1993;4:175-280. Panagopoulos I, Hoglund M, Mertens F, et al. Fusion of the EWS and CHOP genes in myxoid liposarcoma. Oncogene 1996;12:489-494.
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20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38.
Dal Cin P, Sciot R, Panagopoulos I, et al. Additional evidence of a variant translocation t(12;22) with EWS/CHOP fusion in myxoid liposarcoma: clinicopathological features. J Pathol 1997;182:437-441. Azumi N, Curtis J, Kempson RL, Hendrickson MR. Atypical and malignant neoplasms showing lipomatous differentiation: A study of 111 cases. Am J Surg Pathol 1987;11(3):161-183. Enzinger FM, Winslow DJ. Liposarcoma: A study of 103 cases. Virch Arch Pathol Anat 1962;335:367-388. Evans HL. Liposarcoma: A study of 55 cases with a re-assessment of its classification. Am J Surg Pathol 1979;3(6):507-523. Evans HL. Liposarcomas and atypical lipomatous tumors: A study of 66 cases followed for a minimum of 10 years. Surg Pathol 1988;1(1):41-54. Smith TA, Easley KA, Goldblum JR. Myxoid/round cell liposarcoma of the extremities: A clinicopathologic study of 29 cases with particular attention to extent of round cell liposarcoma. Am J Surg Pathol 1996;20(2):171-180. Kilpatrick SE, Doyon J, Choong PFM, Sim FH, Nascimento AG. The clinicopathologic spectrum of myxoid and round cell lipoma. A study of 95 cases. Cancer 1996;77:14501458. Weiss SW, Enzinger FM. Myxoid variant of malignant fibrous histiocytoma. Cancer 1977; 39;1672-1689. Mentzel T, Calonje E, Wadden C, et al. Myxofibrosarcoma: Clinicopathologic analysis of 75 cases with emphasis on the low-grade variant. Am J Surg Pathol 1996;20(4):391405. 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. Evans HL. Low-grade fibromyxoid sarcoma: A report of twelve cases. Am J Surg Pathol 1993; 17(6):595-600. Goodlad JR, Mentzel T, Fletcher CDM. Low-grade fibromyxoid sarcoma: Clinicopathological analysis of 11 new cases in support of a distinct entity. Histopathology 1995;26:229-237. Panagopoulos I, Storlazzi CT, Fletcher CD, et al. The chimeric FUS/CREB3L2 gene is specific for low-grade fibromyxoid sarcoma. Genes Chromosomes Cancer 2004;40:218228. Mertens F, Fletcher CD, Antonescu CR, et al. Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma and cloning of a novel FUS/CREB3L1 fusion gene. Lab Invest 2005;85:408-415. Enzinger FM, Shiraki M. Extraskeletal myxoid chondrosarcoma: An analysis of 34 cases. Hum Pathol 1972;3:421-435. Dei Tos AP, Wadden C, Fletcher CDM. Extraskeletal myxoid chondrosarcoma: An immunohistochemical reappraisal of 39 cases. Appl Immunohistochem 1997;5(2):73-77. Hinrichs SH, Jaramillo MA, Gumerlock PH, et al. Myxoid chondrosarcoma with a translocation involving chromosomes 9 and 22. Cancer Genet Cytogenet 1985;14:219226. Brody, RI, Ueda T, Hamelin A, et al. Molecular analysis of the fusion of EWS to an orphan nuclear receptor gene in extraskeletal myxoid chondrosarcoma. Am J Pathol 1997;150:1049-1058. Meis-Kindblom JM, Bergh P, Gunterberg B, Kindblom L-G. Extraskeletal myxoid chondrosacroma. A reappraisal of its morphologic spectrum and prognostic factors based on 117 cases. Am J Surg Pathol 1999;23:636-650.
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Fibrosarcoma-Like Pattern
Highly cellular spindled mesenchymal neoplasms arranged into a fascicular growth pattern are not uncommonly encountered in the deep soft tissues, mediastinum or retroperitoneum. When presented with such a lesion, the most common differential diagnosis usually includes cellular schwannoma, MPNST, leiomyosarcoma, monophasic synovial sarcoma and fibrosarcoma. Through a combination of light microscopy and immunohistochemistry, one can usually detect a specific line of cellular differentiation in such tumors. As a matter of fact, a diagnosis of fibrosarcoma, once a very common diagnosis to make in the realm of soft tissue pathology, has become a diagnostic rarity.
Cellular Schwannoma
Cellular schwannoma is one of several variants of schwannoma that may cause diagnostic confusion, in this case because of its high cellularity, mitotic activity, and presence of bony destruction. These lesions typically occur in middle-aged patients (although the age range is broad), with a slight female predilection. They are most commonly found within the paravertebral region of the posterior mediastinum, retroperitoneum, and pelvis. A small number of patients have been found to have neurofibromatosis. Grossly, these lesions are typically encapsulated, and may or may not be associated with an identifiable nerve, either grossly or microscopically. Degenerative changes, including cyst formation, hemorrhage and necrosis may be seen. Histologically, the neoplasm is composed of slender, elongated spindled cells with wavy contours that may be arranged in short intersecting fascicles, or in longer sweeping fascicles reminiscent of the herringbone pattern seen in fibrosarcoma. By definition, the lesion is composed almost entirely of Antoni A areas, and although abortive nuclear palisades may be seen, true Verocay bodies are not formed. Although at first glance this lesion may be difficult to differentiate from other spindle cell sarcomas, a variety of histologic features may serve as useful diagnostic clues. This lesion typically has cellularity that is disproportionate to the degree of mitotic activity and cytologic atypia that is present. It should be noted that the cellular schwannoma can have some mitotic activity, although it is typically less than that seen in MPNSTs (<4 MF/10 HPF). Similarly, focal cytologic atypia has been identified in a small percentage of cellular schwannomas, but is typically not to
16
the degree both in quality and quantity as is seen in MPNSTs. Other useful features to recognize this lesion include (1) the presence of paracapsular and/or perivascular lymphoid aggregates; (2) the focal presence of Antoni B areas; (3) prominent perivascular hyalinization and, very importantly (4) diffuse and strong immunoreactivity for S-100 protein. It is critical to distinguish the cellular schwannoma from a MPNST, given the differences in both therapy and prognosis. Tumor cellularity is not useful in that both of these lesions are highly cellular. As mentioned previously, although nuclear pleomorphism and mitotic activity may be seen in cellular schwannoma, MPNSTs typically have more extensive nuclear pleomorphism and mitotic figures, including atypical mitoses. Divergent differentiation, often in the form of rhabdomyoblasts, is found in approximately 10% of MPNSTs1, but is not seen in cellular schwannomas. Finally, S-100 protein immunoreactivity is a useful adjunct in this differential diagnosis, as cellular schwannomas show diffuse and strong S-100 protein positivity, whereas only about 60% of MPNSTs show S-100 protein positivity, typically in a focal distribution.2 Four large studies of cellular schwannoma with significant follow-up (total of 119 cases) have been published.3-6 Although up to 5% of tumors have locally recurred, none of the patients have developed metastatic disease or died due to their tumor. Importantly, erosion of adjacent bone has been noted in approximately 13% of the patients in these series, and may contribute to the erroneous diagnosis of a sarcoma. Ultrastructurally, these cells have been found to have the characteristic features of schwann cells, with elongated bipolar cytoplasmic extensions, interdigitating cytoplasmic processes, and multilayering of basal lamina.7
Other Variants of Schwannoma Ancient Schwannoma

Ancient schwannomas are recognized by their extensive degenerative changes, which include cyst formation, hemorrhage, hyalinization and calcification. Significant nuclear atypia may also be noted, but importantly, the degree of mitotic activity is not proportionate to the degree of nuclear atypia that is present, suggesting a degenerative phenomenon.8 These degenerative findings typically occur in lesions that have been present for a long duration, and thus are more commonly found in more deeply situated tumors.
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Plexiform Schwannoma
Rare schwannomas may also be arranged in a plexiform architecture, reminiscent of what one encounters in the plexiform neurofibroma. Frequently, the individual nodules closely resemble those seen in the cellular schwannoma. It is important to distinguish these lesions from plexiform neurofibroma, as they lack an association with neurofibromatosis type I, and also are not known to undergo malignant transformation.9,10
Glandular Schwannoma
Rare peripheral nerve sheath tumors also contain clear-cut epithelial differentiation in the form of glands. Although most of these lesions have been described in patients with neurofibromatosis type I and presumably have arisen from neurofibromas, there have been several reports of glandular differentiation in schwannomas.11,12 However, the existence of this entity has been disputed, as some authors believe that these reports represent schwannomas containing entrapped skin adnexal structures.13 Woodruff and Christensen identified 11 cases of glandular peripheral nerve sheath tumors and found that 92% of the tumors were histologically malignant and 74% of the patients had neurofibromatosis type I. The authors did not identify any cases of glandular schwannoma.13
Multiple Schwannomas (schwannomatosis)

Rarely, schwannomas may occur multifocally, either in the form of multiple cutaneous schwannomas coursing along a nerve14 or occurring in multiple different sites and often associated with intracranial tumors.15,16 While some authors believe that this entity (schwannomatosis) is distinct from neurofibromatosis type II (NF-2), others believe that this might represent an unusual variant of NF-2.17
18
Neuroblastoma-like Schwannoma
Another rare variant of schwannoma is one in which the cells have a rounded morphology and are often centered around a collagen core forming rosette-like structures, giving a superficial resemblance to neuroblastoma.18 However, both ultrastructural and immunohistochemical examination reveal that these cells have the characteristic features of schwann cells, and this is supported by the benign clinical outcome in all cases.
Melanotic Schwannoma
Another rare form of schwannoma has been variably referred to as the melanocytic schwannoma19 or the psammomatous melanotic schwannoma.20 Interestingly, over 50% of the patients with this unusual tumor have evidence of Carney's syndrome (myxomas in a variety of sites, spotty pigmentation and endocrine overactivity).20 The most striking histologic features are the heavy pigment deposits which stain positively for Fontana's stain and negatively for iron, as well as the presence of psammoma bodies, which may be extensive in some cases. Immunohistochemically, the cells strongly express S-100 protein and HMB-45. Ultrastructurally, the cells resemble typical schwann cells, except for the presence of premelanosomes and melanosomes. Although most of these tumors act in a benign fashion, rare cases may metastasize.20 Finally, the issue of malignant transformation in a schwannoma is an interesting one, as Woodruff et al could only find 9 acceptable cases reported in the literature.21 None of the patients had evidence of neurofibromatosis type I, and the majority of the patients died of their disease. Histologically, the benign component in these tumors was classical schwannoma, whereas the malignant component consisted of an epithelioid malignant peripheral nerve sheath tumor in 7 cases, and showed evidence of neuroepithelial differentiation in 2 cases. Thus, although exceedingly rare, schwannomas do have the capacity to undergo malignant transformation.
Synovial Sarcoma
Synovial sarcoma is the third most common type of sarcoma (after so-called MFH and liposarcoma), and typically affects adolescents and young adults (most common between 15-40
19
years).22 By far the most common location is the extremities, particularly in proximity to large joints (especially the knees), but distal extremity synovial sarcomas are not uncommon. These tumors can also occur on the upper extremities, head and neck region and the trunk. Although these tumors are often intimately related to tendons, tendon sheaths and bursal structures, they are exceedingly rare within joint cavities. Histologically, synovial sarcomas are composed of variable mixtures of epithelial cells, spindled cells and cells that have features intermediate between these two (transitional cells). Thus, the classic biphasic synovial sarcoma is fairly easily recognized, as it is composed of a distinct population of these three cell types. However, when the epithelial elements are predominant (epithelial type of synovial sarcoma), these lesions may be extremely difficult to recognize and separate from carcinomas, melanomas or mesotheliomas. At the other extreme, when the epithelial elements are difficult to identify or completely absent (monophasic fibrous type of synovial sarcoma), then this lesion becomes difficult to differentiate from other highly cellular spindle cell sarcomas. The monophasic fibrous type of synovial sarcoma is probably the most common subtype and can usually be recognized through a combination of histologic and immunohistochemical features. At low magnification, one is often impressed with a marbled appearance that is due to alternating areas of low and high cellularity. The spindled cells are often arranged into irregular fascicles, but typically lack the regular herringbone pattern seen in fibrosarcoma. Although the cells are generally spindled, some may have more of an ovoid appearance. Nuclear pleomorphism is typically minimal, and mitotic figures can be identified fairly easily. Other features that should suggest a diagnosis of monophasic fibrous type of synovial sarcoma include the presence of calcification or ossification, a conspicuous mast cell infiltrate, and a hemangiopericytomatous vasculature. Immunohistochemistry is extremely useful in arriving at this diagnosis. Virtually all monophasic synovial sarcomas stain for cytokeratins, epithelial membrane antigen, or both.23-26 Guillou et al.26 found that all but one of 100 cases of synovial sarcoma stained for at least one of these epithelial markers. In their hands, a significantly greater percentage of cases stained for EMA, although in our laboratory, we have found AE1/AE3 or CAM 5.2 to be more consistently positive. In addition, Guillou et al. noted the relative frequent S-100 protein immunoreactivity in all subtypes of synovial sarcoma. Thus, not all spindle cell sarcomas that stain for S-100 protein
20
are necessarily malignant peripheral nerve sheath tumors. Given the fact that rare cases of MPNST stain for cytokeratins (and in fact may be S-100 protein negative), we have found cytokeratin subsets useful in this regard. Smith et al.27 found that virtually all monophasic synovial sarcomas stained for cytokeratins 7, 19, or both, whereas staining for either of these antigens is extremely rare in cases of MPNST. More recently, gene expression profiling of synovial sarcomas revealed consistent expression of the TLE1 gene.28 Subsequently, an antibody to TLE1 was developed which, according to Terry et al, shows a high degree of sensitivity and specificity for synovial sarcoma.29 In our experience, this antibody is exceedingly useful in confirming a diagnosis of synovial sarcoma, and it is very easy to interpret, since, in my experience, virtually all cells in every synovial sarcoma I have tested shows strong nuclear immunoreactivity. Finally, it must be kept in mind that a significant percentage of synovial sarcomas (including poorly differentiated synovial sarcomas) show membranous immunoreactivity for CD99, a feature which can cause confusion with the Ewing's family of tumors.30 A consistent, specific translocation, most commonly a balanced reciprocal translocation, t(X;18) (p11;q11), is found in virtually all synovial sarcomas, regardless of subtype.31 This translocation involves the fusion of the SYT gene (also known as SS18) on chromosome 18 with either the SSX1 or SSX2 gene on the X chromosome (both at Xp11) or very rarely with SSX4 (also Xp11).32-34 This fusion can be detected by RT-PCR or FISH. In our practice, we utilize an SYT breakapart probe utilizing paraffin-embedded tissue, an ancillary test used in virtually any case in which we suspect a diagnosis of synovial sarcoma. Synovial sarcoma is generally viewed and treated as a high-grade sarcoma. However, in a large series of cases reported by Bergh et al, the authors identified features that could place patients in either low or high-risk groups.35 Adverse prognostic factors with regard to metastasis and survival included older age, larger tumor size, the presence of poorly differentiated areas, high Ki-67 values, the presence of necrosis, vascular invasion and prior local recurrence.
Malignant Peripheral Nerve Sheath Tumor

Another lesion that frequently enters into the differential diagnosis is malignant peripheral nerve sheath tumor (MPNST). Unless this lesion clearly arises from a nerve trunk, a neurofibroma, or occurs in a patient with von Recklinghausen's disease, it may be extremely difficult to recognize
21
and differentiate from these other lesions. At low magnification, similar to the appearance of monophasic synovial sarcoma and cellular schwannoma, there are alternating hypo- and hypercellular regions resulting in a marbled appearance. The spindled cells are arranged into an irregular fascicular pattern, similar to that seen in fibrosarcoma, but other architectural patterns may be present, including areas of nuclear palisading, myxoid zones, and a perivascular targetoid growth pattern. The tumor cells are wavy or angulated, but show more nuclear pleomorphism than that seen in cellular schwannoma. Mitotic figures are usually numerous (>4 MF/10 HPF). Immunohistochemically, about 60% of MPNSTs stain for S-100 protein, typically with only focal positivity.
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References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. Ducatman BS, Scheithauer BW. Malignant peripheral nerve sheath tumors with divergent differentiation. Cancer 1984;54:1049-1057. Weiss SW, Langloss JM, Enzinger FM. Value of S-100 protein in the diagnosis of soft tissue tumors with particular reference to benign and malignant schwann cell tumors. Lab Invest 1983;49:299-308. Lodding P, Kindblom LG, Angervall L, Stenman G. Cellular schwannoma: A clinicopathologic study of 29 cases. Virch Arch Pathol Anat 1990; 416:237-248. White W, Shiu MH, Rosenblum MK, Erlandson RA, Woodruff JM. Cellular schwannoma: A clinicopathologic study of 57 patients and 58 tumors. Cancer 1990; 66:1266-1275. Fletcher CDM, Davies SE, McKee PH. Cellular schwannoma: A distinct pseudosarcomatous entity. Histopathology 1987; 11:21-35. Woodruff JM, Godwin TA, Erlandson RA, Susin M, Martini N. Cellular schwannoma: A variety of schwannoma sometimes mistaken for a malignant tumor. Am J Surg Pathol 1981; 5:733-744. Woodruff JM. Cellular schwannoma. Bone and Soft Tissue Specialty Conference, Case 1. USCAP Meeting, Toronto, Canada, 1995. Dahl I. Ancient neurilemmoma (schwannoma). Acta Pathol Microbiol Scand 1977;85(6):812-818. Fletcher CDM, Davies SE. Benign plexiform (multinodular) schwannoma: A rare tumor unassociated with neurofibromatosis. Histopathology 1986;19:971-980. Hirose T, Scheithauer BW, Sano T. Giant plexiform schwannoma: A report of two cases with soft tissue and visceral involvement. Mod Pathol 1997;10:1075-1081. Brooks JJ, Draffen RM. Benign glandular schwannoma. Arch Pathol Lab Med 1992;116:192-195. Fletcher CDM, Madziwa D, Heyderman E, et al. Benign dermal schwannoma with glandular elements - true heterology or a local organizer effect? Clin Exp Dermatol 1986;11:475-485. Woodruff JM, Christensen WN. Glandular peripheral nerve sheath tumors. Cancer 1993;72:3618-3628. Buenger KM, Porter NC, Dozier SE, Wagner RF. Localized multiple neurilemmomas of the lower extremity. Cutis 1993;51:36-38. Purcell SM, Dixon SL. Schwannomatosis: An unusual variant of neurofibromatosis or a distinct clinical entity? Arch Dermatol 1989;125:390-393. Shishibo T, Niimura M, Ohtsuka F, Tsuru N. Multiple cutaneous neurilemmomas as a skin manifestation of neurilemmomatosis. J Am Acad Dermatol 1984;10:744-754. Reith JR, Goldblum JR. Multiple cutaneous plexiform schwannomas: Report of a case and review of the literature with particular reference to the association with types 1 and 2 neurofibromatosis and schwannomatosis. Arch Pathol Lab Med 1996;120:399-401. Goldblum JR, Beals TF, Weiss SW. Neuroblastoma-like neurilemmoma. Am J Surg Pathol 1994;18:266-273. Fu YS, Kaye GI, Lattes R. Primary malignant melanocytic tumors of the sympathetic ganglia with an ultrastructural study of one. Cancer 1975;36:2029-2041. Carney JA. Psammomatous melanotic schwannoma: A distinctive heritable tumor with special associations including cardiac myxoma and the Cushing syndrome. Am J Surg Pathol 1990;14:206-222. Woodruff RM, Selig AM, Crowley K, Allen PW. Schwannoma with malignant transformation. A rare, distinctive peripheral nerve tumor. Am J Surg Pathol 1994;18(9):882-895.
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22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35.
Weiss SW, Goldblum JR. Synovial sarcoma. In: Enzinger and Weiss's Soft Tissue Tumors, 5th Ed. Elsevier, New York 2008. Ordonez NG, Mahfouz SM, Mackay B. Synovial sarcoma. An immunohistochemical and ultrastructural study. Hum Pathol 1990;21:733-749. Schmidt D, Thum P, Med C, Harms D, Treuner J. Synovial sarcoma in children and adolescents. A report from the Kiel Pediatric Tumor Registry. Cancer 1991;67:16671672. Fetsch JF, Meis JM. Synovial sarcoma of the abdominal wall. Cancer 1993;72:469-477. Guillou L, Wadden C, Kraus MD, Dei Tos AP, Fletcher CDM. S-100 protein reactivity in synovial sarcomas - A potentially frequent diagnostic pitfall. Immunohistochemical analysis of 100 cases. Appl Immunohistochem 1996;4(3):167-175. Smith TA, Machen SK, Fisher C, Goldblum JR. Utility of cytokeratin subsets in distinguishing monophasic synovial sarcoma from malignant peripheral nerve sheath tumor. Am J Clin Pathol 1999;112:641-648. Nielsen TO, West RB, Linn SC, et al. Molecular characterization of soft tissue tumours: a gene expression study. Lancet 2002;359:1301-1307. Terry J, Saito T, Subramanian S, et al. TLE1 as a diagnostic immunohistochemical marker for synovial sarcoma emerging from gene expression profiling studies. Am J Surg Pathol 2007;31:240-246. Folpe AL, Schmidt RA, Chapman D, Gown AM. Poorly differentiated synovial sarcoma: immunohistochemical distinction from primitive neuroectodermal tumors and high-grade malignant peripheral nerve sheath tumors. Am J Surg Pathol 1998;22:673-682. Dal Cin P, Rao U. Jani-Sait S, Karasousis C, Sandberg AA. Chromosomes in the diagnosis of soft tissue tumors. I. Synovial sarcoma. Mod Pathol 1992;5:357-362. de Leeuw B, Balemans M, Olde Weghuis D, Geurts van Kessel A. Identification of two alternative fusion genes, SYT-SSX1 and SYT-SSX2, in t(x;18)(p11.2;q11.2)-positive synovial sarcomas. Hum Mol Genet 1995;4:1097-1099. Fligman I, Lonardo F, Jhanwar SC, Gerald WL, Woodruff J, Ladayni M. Molecular diagnosis of synovial sarcoma and characterization of a variant SYT-SSX2 fusion transcript. Am J Pathol 1995;147:1592-1599. Argani P, Zakowski MF, Klimstra DS, Rosai J, Ladanyi M. Detection of the SYT-SSX chimeric RNA of synovial sarcoma in paraffin-embedded tissue and its application in problematic cases. Mod Pathol 1998;11;65-71. Bergh P, Meis-Kindblom JM, Gherlinzoni F, et al. Synovial sarcoma: identification of low and high-risk groups. Cancer 1999;85:2596-2602.
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Round Cell Tumor Pattern

The differential diagnosis of small round cell tumors is broad. On occasion, one can encounter a benign round cell tumor (e.g. glomus tumor, giant cell tumor of tendon sheath, cutaneous adnexal tumors of various types), which can be mistaken for a high-grade round cell sarcoma. However, most of the time when one encounters a round cell pattern, the differential diagnosis includes a broad group of malignant round cell tumors which includes the Ewing's family of tumors (EFT), alveolar rhabdomyosarcoma, neuroblastoma, lymphoblastic lymphoma, Merkel cell carcinoma, small cell carcinoma, poorly differentiated synovial sarcoma, mesenchymal chondrosarcoma, round cell liposarcoma, desmoplastic small round cell tumor, small cell osteosarcoma and others. Although the light microscopic features are useful in narrowing this differential diagnosis, in virtually every case, ancillary studies including immunohistochemistry and molecular genetic studies are required in order to more precisely classify the round cell tumor. Given that this has important therapeutic and prognostic implications, simply designating a given tumor as a round cell tumor, not otherwise specified, is not acceptable in most cases. However, there are rare cases that cannot be precisely classified.
Ewings/Peripheral Neuroectodermal Tumor (Ewing's Family of Tumors or EFT)

A review of the literature over the past twenty years reveals a remarkable evolution in the concepts regarding classic osseous and extra-osseous Ewing's sarcoma. Through an accumulation of data, it has become apparent there is a spectrum of tumors that ranges from classic Ewing's sarcoma to classic peripheral neuroectodermal tumor (PNET). Since its initial description by James Ewing in 1921, Ewing's sarcoma was felt to arise only in bone, and it was not until 1975 when Angervall and Enzinger described the first cases of extra-osseous Ewing's sarcoma.1 PNET, since its initial description by Arthur Purdy Stout in 1918 as a round cell tumor of the ulnar nerve,2 has been documented in soft tissue unassociated with nerve,3 as well as within bone.4 As discussed below, these entities have histologic, immunohistochemical, ultrastructural, cytogenetic and molecular genetic features that are overlapping, supporting the histogenetic relationship among these neoplasms.
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EFT: Clinical Features Most patients with EFT are adolescents or young adults, the majority of whom are less than 30 years of age.5 Although the mean age for PNET is similar to that of ES, there tends to be a broad age range for the former, with a significant number of patients over the age of 40 years. In contrast, patients with classic extraskeletal ES are rarely over 40 years of age. Both tumors are slightly more common in males than in females. PNET most commonly arises in the extremities. In my experience, the most common anatomic sites are the upper thigh and buttock, followed by the upper arm and shoulder. Tumors intimately attached to a major nerve may give rise to signs and symptoms related to diminished neurologic function. The principal sites of classic extraskeletal ES are the paravertebral region and chest wall, generally in close association with the vertebrae or the ribs. These tumors may also arise in the soft tissues of the lower extremities and rare in the pelvic and hip regions, the retroperitoneum and the upper extremities. However, it is important to note that virtually every anatomic site has been documented to be involved by this family of tumors. In general, the tumor presents as a rapidly growing, deeply situated mass measuring between 5 and 10 cm. Superficially located cases do occur but are quite rare. EFT: Pathologic Findings Classic ES is composed of solidly packed uniform small cells arranged in a lobular pattern separated by dense fibrous septa. At low magnification, there is nuclear uniformity, and nucleoli are inconspicuous, as are mitotic figures. The nuclear chromatin is fine and powdery, and there is a thin rim of pale cytoplasm often filled with glycogen. Hemorrhage and necrosis are prominent features. On the other end of the spectrum, classic PNET is characterized by more irregularity in nuclear size and shape, as well as a coarsening of the chromatin, more prominent nucleoli and increased mitotic figures. In addition, rosettes of varying types, including Homer Wright, Flexner-Wintersteiner and perivascular rosettes are typically seen. However, in between these ends of the spectrum is a variety of architectural and cytologic features in which it is unclear whether the lesion is best classified as a classic ES or PNET. The entity of "atypical Ewing's sarcoma" has been proposed to include some of these cases between the two ends of the histologic spectrum.6 However, the cut-off between ES and atypical ES, and between ES and PNET, is unclear and arbitrary. Fortunately, however, this distinction is not necessary since
26
a number of more recent studies have shown that there is no significant difference in prognosis based upon where a given tumor lies on this morphologic spectrum.7 Ultrastructurally, typical ES is a primitive neoplasm composed of uniform round cells devoid of specific features and characterized by abundant deposits of cytoplasmic glycogen. On the other hand, PNET shows ultrastructural evidence of some degree of neural differentiation, including rare dense core granules, neuritic cell processes, neurofilaments and neural tubules. Similar to that seen histologically, there is a spectrum of ultrastructural features between the two extremes that can be seen. EFT: Immunohistochemical Features For many years, a diagnosis of either ES or PNET was essentially an immunohistochemical diagnosis of exclusion. However, it is clear that the product of the MIC2 gene (CD99) is the most sensitive marker on this family of tumors.8 The MIC2 gene is a pseudoautosomal gene located on the short arms of the sex chromosomes, and its product is a membranous glycoprotein that can be detected immunohistochemically using a variety of differenti antibodies (including 12E7 and O13). Although initially believed to be highly specific for the EFT, it is apparent that virtually all other round cell tumors in the differential diagnosis, on rare occasion, show membranous immunoreactivity for the MIC2 gene product, including lymphomas, particular T-lymphoblastic lymphoma and precursor B-lymphoblastic lymphoma, Merkel cell carcinoma, small cell carcinoma, alveolar rhabdomyosarcoma, small cell osteosarcoma, desmoplastic small round cell tumor and mesenchymal chondrosarcoma.9-12 Notably, however, childhood neuroblastomas have not been reported to stain for this antigen. Thus, although immunostains for CD99 are highly sensitive for recognizing the EFT, this marker should be used as part of a panel of immunostains, given the lack of complete specificity. There are a few other notable immunohistochemical findings that one should be aware of for EFT. For example, up to 20% of tumors have focal immunoreactivity for low-molecular-weight cytokeratins,13 although these tumors do not express cytokeratins 7 or 19, a useful finding for distinguishing EFT from poorly differentiated synovial sarcoma.14 Desmin may also rarely be found in EFT, but there is no ultrastructural evidence of skeletal muscle differentiation in these tumors.15
27
Cytogenetic and Molecular Genetic Findings Approximately 90-95% of EFT are characterized by rearrangements of the EWS gene on 22q12 and ETS-related oncogenes, most commonly FLI-1 on 11q24.16 Less commonly, the EWS gene is fused with other ETS-related genes, including ERG on 21q22,17 ETV-1 on 7p22,18 E1AF on 17q1219 or FEV on 2q33.20 The translocation breakpoints are restricted to introns 7-10 of the EWS gene and introns 3-9 on the ETS-related gene, with the most common fusion being between exon 7 of EWS and exons 5 or 6 of FLI-1.21 These translocations result in a novel chimeric gene that encodes for a chimeric transcript in protein, the function of which is largely unknown. Given the limitations of traditional cytogenetic techniques for detecting these translocations, the ability to detect fusion transcripts by molecular genetic techniques (including RT-PCR and FISH) using fixed, paraffin-embedded tissues has greatly facilitated the diagnosis of these tumors. In our practice, we utilize an EWSR1 breakapart probe as a routine part of the work-up for a suspected EFT.
Alveolar Rhabdomyosarcoma
Alveolar rhabdomyosarcoma (ARMS) is another important lesion to distinguish from EFET, given the different therapeutic modalities used to treat these tumors. Although there may be some overlap in the age distribution, ARMS often occurs in patients younger than seen in EFT. This tumor has a predilection for the deep soft tissues of the extremities, although it may arise in many other sites, including the head and neck, trunk, perineum, pelvis and retroperitoneum. Histologically, ARMS is composed largely of ill-defined aggregates of poorly differentiated round or oval tumors cells that frequently show central loss of cellular cohesion and formation if irregular "alveolar" spaces. The individual cellular aggregates are separated and surrounded by a framework of dense, frequently hyalinized fibrous septa that surround dilated vascular channels. The cells at the periphery of the alveolar spaces are well preserved and adhere in a single layer to the fibrous septa, whereas those in the center of the alveolar spaces tend to be more loosely arranged or freely floating. These centrally located cells are often poorly preserved and show evidence of degeneration and necrosis. There are also "solid" forms of ARMS that lack an alveolar growth pattern entirely and are composed of densely packed groups of tumor cells resembling the round cell areas of EFT. These solidly cellular areas are more commonly encountered at the periphery of the tumor and probably represent the most active and most
28
cellular stage of growth. However, even in these solid areas, there is a regular arrangement of fibrous septa that surround the primitive round cells. Rhabdomyoblasts may be found, but in some cases, they may be extremely difficult to identify. Immunohistochemistry is extremely useful in making the diagnosis of ARMS. Although it is true that most of these tumors do express desmin and muscle-specific actin (HHF-35), there are some ARMS that do not express either of these antigens. In my experience, myogenin is the best marker in recognizing ARMS. Both MyoD1 and myogenin are members of the MyoD family of genes, which encode a series of DNA binding proteins that are involved in the initiation of myogenic differentiation.22 These genes are expressed at the earliest stages of commitment of a mesenchymal cell to striated muscle, and antibodies to these genes appear to be the most sensitive markers of skeletal muscle differentiation.23 Although myogenin is expressed by virtually all subtypes of rhabdomyosarcoma, it is clear that ARMS tends to express this antigen more diffusely and strongly than the other subtypes of rhabdomyosarcoma. It is also important to recognize that some examples of ARMS may show membranous immunoreactivity for CD99. Again, cytogenetic and molecular genetic features of ARMS may be extremely useful in confirming this diagnosis. The most common translocation is a t(2;13)(q35;q14), resulting in the fusion of the PAX3 gene on chromosome 2 with FOXO1a (formerly known as FKHR) gene on chromosome 13.24 Less commonly, ARMS may show a t(1;13), resulting in a PAX7-FOXO1a fusion. In our practice, we utilize a FOXO1a breakapart probe on fixed, paraffin-embedded tissues to detect this translocation. However, it must be kept in mind that only about 75% of ARMS have either a t(2;13) or t(1;13), and 25% of ARMS lack either of these translocations. Once a diagnosis of rhabdomyosarcoma is established, it is important to properly subtype the tumor, given the significant prognostic implications. However, pathologists are not particularly good at subclassifying rhabdomyosarcomas, as there is a high degree of inter- and intraobserver variation in classifying these tumors.25 The Intergroup Rhabdomyosarcoma Study (IRS) has proposed the International Classification of Rhabdomyosarcoma (ICR), which seems to be the most reproducible classification scheme as well as the scheme which predicts prognosis best.26 Tumors having a superior prognosis include botryoid and spindle cell variants of embryonal rhabdomyosarcoma. The usual type of embryonal rhabdomyosarcoma has an intermediate prognosis, whereas ARMS has a poor prognosis.
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Desmoplastic Small Round Cell Tumor (DSRCT)

DSRCT is a relatively uncommon entity that typically involves the abdominal or pelvic peritoneum of young males and pursues an aggressive clinica course. Most patients with this tumor are 15 to35 years of age, although patients younger and older than this classic age range have also been reported. In a study of 109 patients with this tumor by Gerald et al,27 the patients ranged in age from 6 to 49 years, with a mean age of 22 years. Males far outnumber females at a ratio of approximately 4:1. Most patients present with a large abdominal and/or pelvic mass with extensive peritoneal involvement, usually without an identifiable visceral site of origin. However, this tumor has been noted to arise in virtually every other anatomic location and does not necessarily arise in association with a mesothelial-lined surface. Although there was some speculation that this lesion could be related to a mesothelial neoplasm (mesothelial blastoma), given the fact that these tumors can arise in non-mesothelial locations and given the absence of convincing immunohistochemical or ultrastructural evidence of mesothelial differentiation, the histogenesis of this unusual tumors remains unknown. Histologically, the neoplasm is composed of sharply outlined islands of tumor cells that are separated by a desmoplastic stroma containing myofibroblasts and prominent vascularity. There is often a suggestion of peripheral palisading, occasionally with central necrosis. The individual cells are relatively uniform, small and round to oval with hyperchromatic nuclei, inconspicuous nucleoli and scanty cytoplasm. Mitotic figures are easily identified. Rarely, cells with peripherally located nuclei and increased eosinophilic cytoplasm with a perinuclear clear zone (rhabdoid morphology) are seen. Despite this classic histology, the morphologic profile of this tumor continues to expand, as Ordonez noted that up to one-third of these tumors have atypical histologic features.28 Immunohistochemically, these lesions have a characteristic polyphenotypic profile with coexpression of cytokeratins, vimentin, desmin and NSE. The pattern of desmin immunoreactivity is quite unique with a characteristic perinuclear globular pattern of staining. An antibody that recognizes the carboxyl terminus portion of the WT1 gene product has also been developed and is highly sensitive and reasonably specific in recognizing this tumor.29 It is also important to note that up to 20% of DSRCT do stain for CD99. Interestingly, a characteristic
30
cytogenetic aberration has been associated with this neoplasm, t(11;22)(p13;q12), involving the Wilms' tumor gene on chromosome 11 and the EWS gene on chromosome 22. In virtually all suspected cases, we utilize an EWSR1 breakapart probe in an attempt to detect this translocation.
Neuroblastoma
Neuroblastoma may also be difficult to differentiate from some of these other round cell tumors. Patients with neuroblastoma are typically younger than those with the other tumors, as 90% of patients are diagnosed before the age of 5 years. Neuroblastoma is exceedingly rare in adolescents and adults. These patients often have elevated catecholamine metabolite levels in their urine. Neuroblastomas arise from either the adrenal gland or extra-adrenal sympathetic ganglia, although metastases may be seen in virtually any location. Histologically, neuroblastomas are composed virtually entirely of small round undifferentiated cells, typically with dark nuclei and clumped chromatin, inconspicuous nucleoli and scanty cytoplasm. The tumor cells are divided into small lobules by fibrovascular septa. Typically, some cells with peripherally located larger nuclei with vesicular chromatin and increased eosinophilic cytoplasm (representing immature ganglion cells) are seen. Neuroblastomas are characterized by rosettes of various types, including Homer Wright rosettes, with the cells deposited in a fibrillary background. Calcifications are often seen, and mature ganglion cells may be present. Immunohistochemically, neuroblastomas do not stain for CD99, actin, desmin or myogenin. Although the vast majority of neuroblastomas do stain for neural markers, particularly NSE, the expression of these neural markers is not specific. Miettinen et al reported a high degree of sensitivity of the monoclonal antibody NB84 in recognizing neuroblastoma,30 but we have had no experience utilizing this antibody in our clinical practice. Neuroblastomas are characterized by a consistent cytogenetic abnormality with deletion of the short arm of chromosome 1 (1p-).31 Amplification of the N-myc gene is frequently seen in neuroblastoma and is of important prognostic value.32
Mesenchymal Chondrosarcoma
31
Mesenchymal chondrosarcoma is a rare neoplasm that typically occurs in young adults with a peak age in the second to third decade of life. Approximately 20% of these neoplasms arise in an extraosseous location and are most common in the cranial or spinal meninges, orbit and soft tissues of the thigh.33 Histologically, Histologically, the neoplasm is characterized by a biphasic appearance of small nests or nodules of well-differentiated cartilage intimately admixed with undifferentiated round or slightly spindled cells with hyperchromatic nuclei and scanty cytoplasm. Frequently, a hemangiopericytoma-like vascular pattern is present. Although the biphasic appearance is characteristic, this may not be appreciated on a small biopsy, making distinction from other round cell tumors difficult. Immunohistochemically, mesenchymal chondrosarcomas do not express cytokeratins or myogenic markers, but variably express neural markers, including S100 protein. Membranous CD99 immunoreactivity is found in the majority of these tumors.34 In addition, there have been rare reports of mesenchymal chondrosarcoma with the identical t(11;22) identified in the EFT, raising the possibility that these tumors are histogenetically related.35
Round Cell Liposarcoma

Round cell liposarcoma is a poorly differentiated form of myxoid liposarcoma and typically behaves as a high-grade sarcoma. Histologically, the cells are relatively uniform, small and round with vesicular nuclei. The fine plexiform vascular pattern that is so characteristic of myxoid liposarcoma is inconspicuous in the round cell areas. This neoplasm may be very difficult to recognize, particularly on a needle biopsy, without a component of myxoid liposarcoma. In such cases, the application of FISH can be extremely useful, since (like myxoid liposarcoma) round cell liposarcoma is characterized most commonly by a t(12;16) involving the DDIT3 gene on chromosome 12 and the FUS gene of chromosome 16, for which breakapart probes are commercially available. Like myxoid liposarcoma, some cases of round cell liposarcoma may also harbor a t(12;22), and in such cases, using an EWSR1 probe can be useful.
Poorly Differentiated Synovial Sarcoma

Poorly differentiated synovial sarcoma is composed of small round cells with little cytoplasm, often separated by a hemangiopericytoma-like vascular pattern. Unless one identifies other areas of classic biphasic or monophasic synovial sarcoma of lower grade, this lesion may be
32
extremely difficult to separate from some of the other round cell sarcomas. In addition, the poorly differentiated form of synovial sarcoma is less likely to express cytokeratins.36 Further adding to the difficulty, some cases of poorly differentiated synovial sarcoma express membranous CD99 immunoreactivity, making distinction from EFT difficult.37 We have found the use to cytokeratin subsets useful in this regard, as a substantial portion of poorly differentiated synovial sarcomas stain for CK7 and 19, while EFT rarely, if ever, stains for the antigens.14 Detection of the t(X;18) using either RT-PCR or FISH (for the SYT gene) may be exceedingly useful in recognizing this tumor.38
33
References 1. Angervall L, Enzinger FM. Extraskeletal neoplasm resembling Ewing's sarcoma. Cancer 1975;36:240-251. 2. Stout AP. A tumor of the ulnar nerve. Proc NY Pathol Soc 1918;1:2-12. 3. Seemayer TA, Thelmo WL, Bolande RP, Wigglesworth FW. Peripheral neuroectodermal tumors. Perspect Pediatr Pathol 1975;2:151-172. 4. Jaffe R, Santamaria M, Yunis EJ, et al. The neuroectodermal tumor of bone. Am J Surg Pathol 1984;8:885-898. 5. Dehner LP. Primitive neuroectodermal tumor and Ewing's sarcoma. Am J Surg Pathol 1993;17(1):1-13. 6. Navarro S, Cavazzana AO, Llombart-Bosch A, Triche TJ. Comparison of Ewing's sarcoma of bone and peripheral neuroepithelioma: An immunocytochemical and ultrastructural analysis of 2 primitive neuroectodermal neoplasms. Arch Pathol Lab Med 1994;118:608-615. 7. Terrier P, Henry-Amar M, Trich TJ, et al. Is neuroectodermal differentiation of Ewings sarcoma of bone associated with an unfavorable prognosis? Eur J Cancer 1995;31:307314. 8. Stevenson AJ, Chatten J, Bertoni F, Miettinen M. CD99 (P30/32MIC2) neuroectodermal/Ewing's sarcoma antigen as an immunohistochemical marker: Review of more than 600 tumors and the literature experience. Appl Immunohistochem 1994;2(4):231-240. 9. Riopel M, Dickman PS, Link MP, Pearlman EJ. MIC-2 analysis in pediatric lymphomas and leukemias. Hum Pathol 1994;25:396-399. 10. Lumadue JA, Askin FB, Perlman EJ. MIC-2 analysis of small cell carcinoma. Am J Clin Pathol 1994;102:692-694. 11. Weidner N, Tjoe J. Immunohistochemical profile of monoclonal antibody O13: Antibody that recognizes glycoprotein p30/32MIC-2 and is useful in diagnosing Ewing's sarcoma and peripheral neuroepithelioma. Am J Surg Pathol 1994;18(5):486-494. 12. Perlman EJ, Dickman PS, Askin FB, et al. Ewing's sarcoma: Routine diagnostic utilization of MIC-2 analysis. Hum Pathol 1994;25:303-307. 13. Gu M, Antonescu CR, Guiter G, et al. Cytokeratin immunoreactivity in Ewings sarcoma. Prevalence in 50 cases confirmed by molecular diagnostic studies. Am J Surg Pathol 2000;24:410-416. 14. Machen SK, Fisher C, Gautam RS, Tubbs RR, Goldblum JR. Utility of cytokeratin subsets for distinguishing poorly differentiated synovial sarcoma from peripheral primitive neuroectodermal tumour. Histopathology 1998;33:501-507. 15. Parham DM, Dias P, Kelly DR, Rutledge JC, Houghton P. Desmin positivity in primitive neuroectodermal tumors of childhood. Am J Surg Pathol 1992;16(5):483-492. 16. Delattre O, Zucman J, Melot T, et al. The Ewing family of tumors - a subgroup of small round cell tumors defined by specific chimeric transcripts. N Engl J Med 1994;331:294299. 17. Sorensen PHB, Lessnick SL, Lopez-Terrada D, et al. A second Ewings sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nature Genet 1994;6:146-151. 18. Jeon I-S, Davis JN, Braun BS, et al. A variant Ewings sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV-1. Oncogene 1995;10:1229-1234. 19. Kaneko Y, Yoshida K, Handa M, et al. Fusion of the ETS-family gene E1AF to EWS by t(17;22)(q12;q12) chromosome translocation in an undifferentiated sarcoma of infancy. Genes Chromosomes Cancer 1996;15:115-121. 20. Peter M, Couturier J, Pacquement H, et al. A new member of ETS family fused to EWS in Ewing tumors. Oncogene 1997;14:1159-1164.
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de Alava E, Kawai A, Healey JH, et al. EWS-FLI-1 fusion transcript structure is an independent determinant of prognosis in Ewings sarcoma. J Clin Oncol 1998;16:12481255. Weintraub H, Davis R, Tapscott S, et al. The MyoD gene family: Nodal point during specification of the muscle cell lineage. Science 1991;251:761-766. Wang NP, Marx J, McNutt MA, et al. Expression of myogenic regulatory proteins (myogenin and MyoD1) in small blue round cell tumors of childhood. Am J Pathol 1995;147:1799-1810. Shapiro DN, Sublett JE, Li B, Downing JR, Maeve CW. Fusion of PAX 3 to a member of the forkhead family of transcription factors in human alveolar rhabdomyosarcoma. Cancer Res 1993;53:5108-5112. Asmar L, Gehan E, Newton WA, et al. Agreement among and within groups of pathologists in the classification of rhabdomyosarcoma and related childhood sarcomas: Report of an international study of four pathology classifications. Cancer 1994;74:25792588. Newton WA, Gehan EA, Webber BL, et al. Classification of rhabdomyosarcomas and related sarcomas: Pathologic aspects and proposal for a new classification - an Intergroup Rhabdomyosarcoma Study. Cancer 1995;76:1073-1085. Gerald WL, Ladanyi M, de Alava E, et al. Clinical, pathologic and molecular spectrum of tumors associated with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants. J Clin Oncol 1998;16:3028-3036. Ordonez NG. Desmoplastic small round cell tumor. I: a histopathologic study of 39 cases with emphasis on unusual histological patterns. Am J Surg Pathol 1998;22:1303-1313. Barnoud R, Sabourin J-C, Pasquier D, et al. Immunohistochemical expression of WT1 by desmoplastic small round cell tumor: a comparative study with other small round cell tumors. Am J Surg Pathol 2000;24:830-836. Miettinen M, Chatten J, Paetau A, Stevenson A. Monoclonal antibody NB84 in the differential diagnosis of neuroblastoma and other small round cell tumors. Am J Surg Pathol 1998;22:327-332. Brodeur GM, Green AA, Hayes FA, Williams KJ, Williams DL, Tsiatis AA. Cytogenetic features of human neuroblastomas and cell lines. Cancer Res 1981;41:4678-4686. Brodeur GM, Seeger RC, Schwab M, et al. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 1984;224:1121-1124. Nakashima Y, Unni KK, Shives TS, Swee RG, Dahlin DC. Mesenchymal chondrosarcoma of bone and soft tissue: a review of 111 cases. Cancer 1986;57:24442453. Granter SR, Renshaw AA, Fletcher CDM, Bhan AK, Rosenberg AE. CD99 reactivity in mesenchymal chondrosarcoma. Hum Pathol 1996;27:1273-1276. Sainati L, Scapinello A, Montaldi A, et al. A mesenchymal chondrosarcoma of a child with the reciprocal translocation (11;22)(q24;q12). Cancer Genet Cytogenet 1993;71:144-147. Folpe AL, Schmidt RA, Chapman D, Gown AM. Poorly differentiated synovial sarcoma: immunohistochemical distinction from primitive neuroectodermal tumors and high-grade malignant peripheral nerve sheath tumors. Am J Surg Pathol 1998;22:673-682. Dei Tos AP, Wadden C, Calonje E, et al. Immunohistochemical demonstration of glycoprotein P30/32MIC2 (CD99) in synovial sarcoma. A potential cause of diagnostic confusion. Appl Immunohistochem 1995;3(3):168-173. Shipley J, Crew J, Birdsall S, et al. Interphase fluorescence in-situ hybridization and reverse transcription polymerase chain reaction as a diagnostic aide for synovial sarcoma. Am J Pathol 1996;148:559-567.
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COMMON MORPHOLOGIC PATTERNS IN SOFT TISSUE TUMORS WITH AN EMPHASIS ON USEFUL ANCILLARY DIAGNOSTIC TECHNIQUES

John R. Goldblum, M.D.

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Myxoid Soft Tissue Tumors and Tumor-Like Lesions

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Other Variants of Schwannoma Ancient Schwannoma

Common Morphologic Patterns in Soft Tissue Tumors

Multiple Schwannomas (schwannomatosis)

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Malignant Peripheral Nerve Sheath Tumor

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Round Cell Tumor Pattern

Ewings/Peripheral Neuroectodermal Tumor (Ewing's Family of Tumors or EFT)

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Desmoplastic Small Round Cell Tumor (DSRCT)

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Round Cell Liposarcoma

Poorly Differentiated Synovial Sarcoma

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

Common Morphologic Patterns in Soft Tissue Tumors

21. 22. 23. 24. 25.

Common Morphologic Patterns in Soft Tissue Tumors

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