Rev Esp Patol 1999; Vol. 32, Nº3: 271-282 © Prous Science, S.A. © Sociedad Española de Anatomia Patológica Symposium 2 © Sociedad Española de Citologia

New entities in pathology of soft tissue tumors Chairperson: C.D.M. Fletcher, USA. Co-chairpersons A P Del Tos Italy and T. Mentzel, Germany

Adipocytic tumors: eosinophilic chondroblast-like cells and vacuolated cells set in myxochondroid background. One of the most striking features is New entities and evolving concepts the presence of vacuolated cells that cannot be distinguished from ordinary lipoblasts. Immunohistochemically, S-100 protein deco- A.R Del Tos rates most neoplastic cells. The absence of a plexiform vascular network is helpful in the differential diagnosis with myxoid liposar- Regional Hospital of Treviso, Italy coma. Extraskeletal myxoid chondrosarcoma can be distinguished due to its a more pronounced lobular architecture associated with peripheral accentuation of cellularity, t also has to be stressed that Introduction despite popular belief, S-100 protein does not decorate more than Lipomatous tumors are the most common soft tissue lesions 20% of extraskeletal myxoid chondrosarcomas (7). encountered by practicing surgical pathologists. Diagnostic criteria for both typical lipoma and liposarcoma are well established (1-3); Spindle cell liposarcoma however, in recent years numerous variants have been reported, both in the benign and in the malignant category. Moreover, the Spindle cell liposarcoma was first described in 1994 (8, 9) and rep- resents an uncommon variant of well-differentiated liposarcoma. It integration of genetics and pathology have supported proposals for significant changes in classification schemes that deserve com- tends to occur in adults, and to involve relatively often the subcu- ment (Table 1). taneous soft tissue, at least in the first series. However, from the observation of a larger number of cases, the anatomic distribution of spindle cell liposarcoma seems to be comparable to that of the Table 1. Specific (primary) chromosome changes in adipocytic tumors. other well-differentiated liposarcoma subtypes. Spindle cell liposar- coma, whatever its location, tends to recur locally and may dedif- Ordinary lipoma t with 12q13-15 ferentiate. Morphologically, spindle cell liposarcoma is composed t with 6p21 -23 t with 11q13 of a fairly bland neural-like spindle cell proliferation set in a fibrous Rearrangementinvolving1p36.1-36.3 and/or myxoid background and is associated with an atypical lipo- Lipoblastoma t with 8q1 1-13 matous component. Main differential diagnoses include spindle cell Hibernoma t with 11q13,10q22 lipoma (composed of bland, sometimes palisading, CD34+ spindle Spindle cell and pleomorphic Loss of 16q13-qter cells, admixed with eosinophilic refractile collagen bundles); neu- lipoma Unbalanced aberration of 13q rofibroma (characterized by a less cellular S-i 00+ spindle cell pro- Atypicallipoma/+Ringorlongmarker(sequences well-differentiated liposarcoma 12q1 3-qi 5) liferation with wavy nuclei); dermatofibrosarcoma protuberans Myxoid and round cell t(12;16)(q13;p11) (cytologically bland CD34+ spindle cell proliferation organized in a liposarcoma t(12;22)(q13;q11) distinctive storiform growth pattern and characterized by its ten- Pleomorphic liposarcoma Complex rearrangements dency to infiltrate the surrounding fat in a peculiar honeycomb pat- tern); malignant peripheral nerve sheath tumor (generally highly cellular tumors composed of tapering or wavy spindle cells featur- Newly described adipocytic tumors ing perivascular accentuation of cellularity and focal S-100+ im- Myolipoma munoreactivity in about 50% of cases); and, well-differentiated scierosing liposarcoma (characterized by the presence of bizarre Myolipoma(orlipoleiomyoma)wasfirstreportedin1991(4)asa hyperchromatic stromal cells set in fibrillary collagen). The pres- deep-seated, usually large encapsulated benign lesion, arising in ence of an atypical lipomatous component permits distinction from the abdomen, retroperitoneum or abdominal wall of adults. low-grade fibromyxoid sarcoma (Evans’ tumor). Histologically, myolipoma is composed of mature adipocytic tissue The description of spindle cell liposarcoma has generated intermingled with bundles of differentiated smooth muscle. The some debate, which has been mostly focused upon an alleged sim- application of myoid differentiation markers confirms the presence ilarity with the so-called “fibroblastic liposarcoma”, as defined by Dr. of dual adipocytic and smooth muscle differentiation. Hajdu. Fibroblastic liposarcoma, where illustrated, appears as a lesion unrelated to spindle cell liposarcoma, while considerable mor- Chondroid lipoma phological overlap exists with myxofibrosarcoma. t is our opinion Chondroid lipoma is a rare benign fatty tumor first described under a that spindle cell liposarcoma represents a distinctive clinicopatholog- different name in 1986 (5) and fully categorized in 1993 (6). It usual- ic entity which is worthy of recognition, Interestingly, spindle cell ly presents as a well-defined, deep-seated lesion located in the liposarcoma exhibits chromosome changes (ring chromosomes and limbs, trunk and head and neck region of adult females. Microsco- giant marker chromosomes) identical to those observed in the well- pically it is composed by an admixture of mature adipocytes, differentiated liposarcoma/atypical lipoma group.

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Evolving concepts Cutaneous liposarcoma Atypical lipoma/well-differentiated liposarcoma Although any liposarcoma subtype occasionally arises in the sub- Well-differentiated liposarcoma represents a group of tumors fur- cutis, the dermis seems to represent an exceedingly rare site of occurrence. Nonetheless, it has been recently shown that liposarco- ther subclassified by the World Health Organization (WHO) into ma indeed can occur as a primary skin lesion (22). It often presents adipocytic (lipoma-like), scierosing and inflammatory subtypes. clinically as a dome-shaped or polypoid lesion which, histologically, Great debate has been generated by the introduction (pioneered most frequently shows high-grade morphological features. Primary by Evans in 1979) of the term atypical lipoma or atypical lipomatous cutaneous liposarcoma carries a comparatively good prognosis, tumors (10, ii) to underline the fact that well-differentiated liposar- although this needs to be confirmed by larger series. coma shows risk of local recurrence (about 30%) but no potential for metastasis. In our opinion, well-differentiated liposarcoma and Classification of liposarcoma atypical lipoma should be considered as synonyms that describe lesions identical both morphologically and kayotypically. Their use The latest edition of the WHO classification of soft tissue (2) rec- should depend on the degree of reciprocal comprehension ognized. five distinct subtypes of liposarcoma (well-differentiated, myxoid, round cell, dedifferentiated and pleomorphic). However, between the surgeon and the pathologist in order to prevent either inadequate or excessive treatment (12). during the last decade, the integration of morphology and genetics have greatly contributed to a more accurate classification of soft tis- sue neoplasms in general and of lipomatous tumor in particular. Dedifferentiated liposarcoma Considering currently available data, the most logical classification Dedifferentiated liposarcoma is considered by the WHO to be a dis- of liposarcoma is into the three following main groups: i) well-dif- tinct type of liposarcoma, in which transition from low-grade to high- ferentiated liposarcoma (including adipocytic, scierosing, inflam- grade nonlipogenic morphology within a well-differentiated liposar- matory, spindle cell and dedifferentiated variants), characterized by coma is observed. First described by Evans in 1979 (13), such a ring or long marker chromosomes derived from the long arm of phenomenon may occur either in the primary tumor (90%) or in chromosome 12; ii) myxoid and round cell (poorly differentiated recurrences (10%). The transition usually occur in an abrupt fash- myxoid) liposarcoma, characterized in most cases by a reciprocal ion, however in rare cases can be more gradual and, exceptional- translocation t(12;16)(q13;p11); and, ii) pleomorphic liposarcoma, ly, low grade and high grade areas appears to be intermingled. characterized by complex karyotypes. Rarely, liposarcoma may Recently it has also been proposed that dedifferentiated liposarco- combine features of different histological subtypes. ma should be further classified into low-grade and high-grade sub- types (14), but this remains rather controversial. Dedifferentiated References liposarcoma may exhibit heterologous (most often myoid) differen- 1. Enzinger RM, Weiss SW. (Eds.). Soft Tissue Tumors, 3rd Ed., Mosby, St. Louis tiation in about 5% of cases, which apparently does not affect the 1995. clinical outcome. Recently, a peculiar “neural-like whorling pattern” 2. Weiss SW. (Ed.). Histologic Typing of Soft Tissue Tumors. World Health Organization Histological Classification of Tumors. Springer, Berlin 1994. of dedifferentiation has been described, the line of differentiation of 3. Fletcher 0DM. Soft tissue tumors. In: Fletcher CDM. (Ed.). Diagnostic which still needs to be fully elucidated (15). Surprisingly, the clini- Histopathology of Tumors. Churchill-Livingstone, Edinburgh 1995; 1043-1096. cal outcome of dedifferentiated liposarcoma is less aggressive than 4. Meis JM, Enzinger FM. Myolipoma of soft tissue. Am J Surg Pathol 1991; 15: in other high-grade pleomorphic sarcomas (16). Interestingly, in 12 1-125. stark contrast with the complex karyotypic aberration observed in 5. Chan JKC, Lee KC, Saw D. Extraskeletal chondroma with lipoblast-like cells. Hum Pathol 1986; 17:1285-1287. pleomorphic sarcomas, dedifferentiated liposarcoma usually 6. Meis JM, Enzinger FM. Chondroid lipoma. A unique tumor simulafingliposar- exhibits the same basic cytogenetic anomalies as well-differentiat- coma and myxoid chondrosarcoma. Am J Surg Pathol 1993; 17: 1103-1112. ed liposarcoma (17). At the molecular level, overexpression of 7. Del Tos AP, Wadden K, Fletcher CDM. Extraskeletalmyxoid chondrosarcoma: MDM2 has been observed along with integrity of the p53 gene in An immunohistochemical reappraisal of 39 cases. Appl Immunohistochem the majority of cases. A significant increase in the level of both 1997; 5: 73-77. 8. Del Tos AP, Mentzel T. Newman PL et al. Spindle cell liposarcoma: A hitherto MDM2 overexpression and amplification in the high-grade areas unrecognized variant of well-differentiated liposarcoma: Analysis ofsix cases. has been observed which may account for the tumor progression Am J Surg Pathol 1994; 18: 913-921. in this subset of sarcomas (18). 9. Nascimento AG. Spindle cell liposarcoma (Commentary). Adv Anat Pathol 1995; 2: 320-325. Myxoid and round cell liposarcoma 10. Evans HL, Souls EH, Winkelmann RK. Atypical lipoma, atypical intramuscular lipoma, and well differentiated retroperitonealliposarcoma. A reappraisalof 30 Myxoid and round cell liposarcoma, even if still classified by the cases formerly classifiedas well-differentiated liposarcoma. Cancer 1979; 43: WHO as two distinct subtypes, share both clinical and morphological 574-584. features. Lesions combining both patterns are very frequent and 11. Evans HL. Liposarcoma and atypical lipomatous tumors: A study of 66 cases followedfor a minimum of 10 years. Surg Pathol 19881; 43: 41-54. wide agreement exists in considering round cell liposarcoma as the 12. Mentzel T, Fletcher 0DM. Lipomatous tumours of soft tissue: An update. high-grade counterpart of myxoid liposarcoma. Furthermore, myxoid Virchows Arch 1995; 427: 353-363. and round cell liposarcoma share the same characteristic chromo- 13. Evans HL. Liposarcoma. A study of 55 cases with a reassessment of its clas- some change, t(12;16) (19, 20), which, at the molecular level, fuses sification. Am J Surg Pathol 1979; 3: 507-523. the CHOP gene on 12q13 with the FUS (or TLS) gene on 16p11 or 14. Henricks WH, Chu YC, Goldblum JR etal. Dedifferentiatedliposarcoma: A clin- icopathologic analysis of 155 cases withproposal foran expanded definition of with EWS on 22q1 2. Lesions showing more than 10% of round cell dedifferentiation. Am J Surg Pathol 1997; 21: 271-281. 58. (orhypercellular) areas should be classified as high grade (21), how- 15. Nascimento AG, Kurtin PJ, Guillou L et al. Dedifferentiated liposarcoma. A ever, the prognostic meaning of a more limited round cell change report ofninecases with a peculiarneural-like whorling pattem associated with remains to be elucidated. metaplastic bone formation. Am J Surg Pathol 1998; 22: 945-955.

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16. McCormick 0, Mentzel T, Beham A et al. Dedifferentiated liposarcoma. The overall recurrence rate is about 80% at 10 years (10). Since Clinicopathologic analysis of 32 cases suggesting a batter prognostic sub- conservative procedures are associated with an increased recur- group among pleomorphic sarcomas. Am J Surg Pathol 1994; 18:1213-1223. rence rate and reduced survival (9,11), radical surgery (i.e., ampu- 17. Fletcher CDM, Akerman M, Dal Cin P et al. Correlation between clinicopatho- tation) is advocated as the primary treatment of epithelioid sarco- logical features and karyotype in lipomatous tumors. Am J Pathol 1996; 148: ma. Adverse prognostic factors in epithelioid sarcoma include male 623-630. 18. Dei Tos AP, Doglioni C, Piccinin S et al. Molecular abnormalities of the p53 sex (2), advanced age at diagnosis, large tumor size (>5 cm) (8), pathway indedifferentiated liposarcoma. J Pathol 1997; 181: 8-13. deep location (9), presence of tumor necrosis (9), nuclear pleo- 19. Knight JC, Renwick PJ, Dal Cin P et al. Translocation t(12;16)(q13:p11) inmyx- morphism, high mitotic activity, presence of vascular and/or nerve oidliposarcoma and round cell liposarcoma: Molecular and cytogeneticanaly- invasion (12), multiple recurrences and presence or absence of sis. Cancer Res 1995; 55: 24-27. regional lymph node metastases (12). 20. 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: Recently, a special type of aggressive malignant soft tissue Clinicopathologic features. J Pathol 1997; 182: 437-441 . neoplasm thought to represent a “proximal” variant of epithelioid 21. Kilpatrick SE, Doyon J, Choong PFM et al. The clinicopathologic spectrum of sarcoma has been described (13). In this variant, the tumors devel- myxoid and round cell liposarcoma. A study of 95 cases. Cancer 1996; 77: op predominantly in the pelvis, perineum and genital tract (pubis, 1450-1458. vulva, penis). Most of them are deep seated and they tend to occur 22. Dei Toa AP, Mentzel T, Fletcher CDM, Primary liposarcoma of the skin: A are in older adults more frequently than the “distal” conventional vari- neoplasm with unusual high grade features. Am J Dermatopathol 1998; 20: 332-338. ant of epithelioid sarcoma. Microscopically, “proximal-type” epithelioid sarcoma which often shows a multinodular pattern of growth is made of large epithelioid carcinoma-like cells with marked cytologic atypia, vesicular nuclei and prominent nucleoli. Rhabdoid features are also frequently ob- Tumors of uncertain histogenesis served and may even predominate in some lesions. Tumor necro- sis, a common finding, seldom results in a granuloma-like pattern L. Guillou contrasting with that observed in the classical form of epithelioid sarcoma. University Institute Df Pathology, Lausanne, Switzerland. Immunohistochemically, tumor cells show reactivity for keratin and EMA, singly or in combination, together with vimentin. About half of the cases are also positive for CD34, an antigen which is “Proximal-type” epithelioid sarcoma rarely expressed by carcinomas. Ultrastructural features of epithe- lial differentiation (tonofilaments and/or desmosomes) are also com- Epithelioid sarcoma was recognized as a distinctive entity in 1970 when Enzinger (1) reported 62 cases of this unusual type of neo- monly observed. Proximal-type epithelioid sarcoma involves a diagnosis of plasm. In its classical presentation, epithelioid sarcoma appears in exclusion. Many entities have to be considered in the differential the distal extremities (hand, wrist, forearm) of young adults as firm, slowly growing nodules of the subcutis, tendons and/or fascia. diagnosis including carcinoma, melanoma, epithelioid malignant peripheral nerve shealth tumor, smooth and striated muscle Ulceration of the skin may occur. A history of trauma is reported in up to 20% of the cases (2). sarcomas, epithelioid angiosarcoma, rhabdoid tumor, as well as ana- On microscopic examination, the conventional “distal” form of plastic lymphoma. Immunohistochemistry and/or electron micro- epithelioid sarcoma exhibits slight nuclear atypia, vesicular nuclei scopy are of paramount importance in this regard. and small nucleoli. It is now admitted that, outside the kidney, the term rhabdoid Transition between the two cell types is gradual and intercellu- tumor does not refer to an entity but rather to a distinctive pheno- lar collagen deposition is usually marked. Frequently, the tumor type shared by many tumors such as melanoma, carcinoma, nodules undergo central necrosis resulting in a pseudogranuloma- mesothelioma and a large variety of sarcomas including both “dis- tous appearance simulating a benign necrobiotic process, such as tal” and “proximal” variants of epithelioid sarcoma (14-17). On a rheumatoid nodule or a granuloma annulare. Pseudoangiosarco- occasion, the latter contains rhabdoid cells in such a quantity that matous features due to cell disaggregation, dystrophic calcifications, distinction from an extrarenal rhabdoid tumor becomes almost bone formation, and accompanying chronic inflammation are also impossible (18-20). Recent cytogenetic data showing chromosome potential additional features (2). 22q abnormalities in both tumor types would also support a close Immunohistochemically, epithelioid sarcoma is characteristical- relationship between epithelioid sarcoma and rabdoid tumor (21, ly immunoreactive for vimentin and epithelial markers (keratin 22). Renal rhabdoid tumors are known to be highly malignant and/or epithelial membrane antigen; EMA) (3-5). Half of the cases tumors with poor prognosis. Accumulated data also indicate that are also positive for 0D34 (6) and occasional reactivity for smooth rhabdoid features in extrarenal malignant tumors correlate with muscle actin has also been reported. Ultrastructurally, epithelioid aggressive behavior, multimodal therapy resistance, and a rapidly sarcoma shows features of fibroblastic/myofibroblastic and epithe- fatal outcome. In keeping with the latter observation, “proximal- lial (desmosome-like intercellular junctions, microvilli, tonofila- type” epithelioid sarcoma seems also to be associated with a more ments) differentiation (7). aggressive clinical course and earlier tumor-related deaths as com- Epithelioid sarcoma is characterized by a protracted clinical pared with the more indolent behavior of conventional epithelioid course. Metastases which develop in about 40% of the patients, sarcoma (2, 5,13). However, it is not clear yet whether this dismal usually following repeated recurrences, involve primarily regional behavior is related to the prominent rhabdoid phenotype or merely lymph nodes but also lungs, bone, and scalp (2, 8). Five- and 10- to classical prognostic factors such as tumor size, depth, proxi- year overall survival rates range between 50% (2, 8) and 80% (9). mal/axial location, resectability, vascular invasion, etc.

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The histogenesis of epithelioid sarcoma is stilla matter of con- ly, attention has been drawn to the possible occurrence of mixed troversy. Although proximal-type epithelioid sarcoma shows strik- tumors and/or myoepitheliomas in the subcutis and deep soft tis- ing resemblance to a carcinoma with regard to its morphology and sues (27, 28). Based on the study of Kilpatrick et al. (27), who immunohistochemical profile, it differs from the latter in its lack of reported on 19 cases of such lesions, mixed tumors and myo- connection with detectable epithelial structures and its 0034 epitheliomas of soft tissues would originate predominantly in limbs immunoreactivity (in at least in 50% of the cases). The recent (hand, forearm, ankle, foot) and limb girdles (shoulder, thigh, demonstration of V-cadherin rather than C-cadherin expression in inguinal region) of middle-aged adults with a male sex predomi- epithelioid sarcoma militates also against the carcinoma hypothe- nance. Trunk and head and neck regions are less frequently sis and gives support to the mesenchymal derivation of such a involved, The lesions are located within the subcutis in their great tumor (23). majority, encroaching occasionally upon dermis; a minority of them may be found in deep subtascial soft tissues. Mixed tumors and Pleomorphic hyalinizing angiectatic tumor of soft parts myoepitheliomas of soft tissue behave as benign lesions in most Recently characterized (24), the pleomorphic hyalinizing angiectat- cases. A minority of patients, however, develop local recurrence or metastases. No specific pathological feature, including the mitotic ic tumor (PHAT) is a nonencapsulated mesenchymal lesion that rate, seems to correlate reliably with relapse. With regard to recur- occurs mostly in lower extremity subcutaneous tissues of middle- rences (two patients out of 10 in the series by Kilpatrick et al.; 27), aged patients with no sex predilection. Clinically, it may resemble a it is likely that they have more to do with an insufficient surgical pro- hematoma or Kaposi’s sarcoma. In the original series, tour tumors cedure rather than with intrinsic tumor biological properties. Hence, out of eight (50%) with available follow-up recurred but none of complete excision with a clear margin seems to be the treatment of them metastasized. Grossly, most PHAT show infiltrative margins; a minority of choice for those lesions. Macroscopically, most mixed tumors of soft tissue are predom- lesions being well circumscribed. Histologically, this lesion presents inantly well circumscribed and lobulated, measuring usually less as a proliferation of spindle and/or pleomorphic cells in which one than 5 cm in maximal diameter. Histologically, they are character- can find clusters of ectatic thin-walled vessels surrounded by promi- ized by the presence of cords and strands and/or ductules of nent fibrin/collagen deposition. Most often, the lesion has infiltrative epithelioid cells and/or nests of spindle cells within a hyalinized to borders; intratumoral hemosiderin deposits may be prominent and chondromyxoid stroma. In rare cases, some tumors may predomi- organized intravascular thrombi are commonly observed. The spin- nantly be composed of myoepithelial spindle cells. Epithelioid cells dle and pleomorphic cells possess hyperchromatic, pleomorphic nuclei with frequent prominent intranuclear pseudoinclusions. are often large and round with abundant, clear to eosinophilic cyto- plasm. Occasionally, they may have a plasmacytoid appearance Mitosis are very rare (less than 1 per 50 high-power fields). Chronic and/or may contain prominent cytoplasmic hyaline inclusions. inflammatory cells can be found in or surrounding the lesion as well Myoepithelial cells show either a round/ovoid or spindle cell cyto- as intratumoral mast cell collections. The spindle/pleomorphic cells morphology, Epithelioid and myoepithelial cells coexist in varying in PHAT are negative for S100 protein and vascular markers (0031, proportions in the same tumor. Nuclear atypia is minimal and mitot- factor VIII) but half of the tumors in the original series and in a sub- ic figures are rare even in those tumors which proved to metasta- sequent report (25) were CD34 positive. Reactivity for factor XIIIa size. The cartilaginous component which fails to show any features has also been observed (25). of malignancy may be mature and/or myxoid. Predominantly myx- Because of the cellular pleomorphism, the hemorrhagic old lesions should be differentiated from an extraskeletal myxoid changes, and the occasional presence of prominent cytoplasmic chondrosarcoma, which is the main differential diagnosis. Foci of intranuclear inclusions, the lesion may be confused with a high grade squamous differentiation, osteoid and cartilage production as well storiform/pleomorphic variant of malignant fibrous histiocytoma or a as the presence of an adipocytic component are potential addition- vascular variant of this, although one should be struck bythe contrast al morphological features. between the low mitotic rate and the marked cellularity and pleomor- Most epithelial and myoepithelial cells in mixed tumors and phism of the lesion. The peculiar clustered arrangement of vessels myoepitheliomas of soft tissue express cytokeratin and S100 pro- with heavy perivascular fibrin deposition is another clue to the diag- tein, respectively. In addition, some myoepithelial cells may also nosis. PHAT of soft tissues is more likely to be confused with a express smooth muscle actin, muscle-specific actin and, more benign lesion, especially an ancient schwannoma, and perhaps a rarely, desmin and glial fibrillary acid protein (GEAP). EMA reactiv- melanotic schwannoma in cases with heavy intratumoral hemo- ity is generally restricted to ductules structures. siderin and/or calcitication deposition or an ancient hemangioma (so- In the subcutis, mixed tumors and myoepitheliomas of soft tissue called symplastic hemangioma) (26). The lack of immunoreactivity should be differentiated from chondroid syringoma. The latter (also for S100 protein and vascular markers allows distinction from those called pleomorphic adenoma or mixed tumor of the skin) presents latter entities but it should be noted that 50% of the tumors are CD34 generally as a small (often less than 2 cm), well-circumscribed positive (24, 25), a reactivity usually not observed in malignant benign lesion of the head and neck (as opposed to mixed tumors of fibrous histiocytoma but common in neurilemoma. soft tissue which predominate in limbs), located in the dermis or in the very superficial portion of the hypodermis. Microscopically, Mixed tumors and myoepitheliomas of soft tissue myoepithelial differentiation is usually less pronounced in chondroid Mixed tumors in the salivary glands (pleomorphic adenoma) and syringoma than in mixed tumors/myoepitheliomas of soft tissue. In the skin (chondroid syringoma) are well-known entities. deep soft tissues, mixed tumors/myoepitheliomas should be differ- Microscopically, these tumors are made of a varying admixture of entiated from extraskeletal myxoid chondrosarcomas. Epithelioid epithelial and myoepithelial elements within a hyalinized to chon- cellreactivity for epithelial markers and myoepithelial cell positivity dromyxoid stroma, the term myoepithelioma being restricted to for smooth muscle actin and/or GFAP are crucial in making the dis- those tumors composed exclusively of myoepithelial cells. Recent- tinction. S100 protein is not a discriminating marker since it may

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also be positive in myxoid chondrosarcoma (29). Tumors predomi- 25. Silverman JS, Dana MM. Pleomorphic hyalinizing angiectatic tumor of soft nantly made of myoepithelial cells that display a marked plasma- parts: Immunohistochemical case study shows cellular composition by CD34+ fibroblasts and factorXIIIa+. dendrophages. J Cutan Pathol 1997; 24: 377-383. cytoid and/or rhabdoid appearance are prone to be confused with 26. Tsang WYW, Chan JKC, Fletcher CDM at al. Symplastic hemangioma: A dis- a carcinoma, a melanoma or an epithelioid-appearing sarcoma. tinctive vascular neoplasm featuring bizarre stromal cells. Int J Surg Pathol Parachordoma, another Si00 positive lesion of the extremities, 1994; 1: 202 (Abstract). also enters the differential. As opposed to mixed tumors of soft tis- 27. Kilpatrick SE, Hitchcock MO, Kraus MD at al. Mixed tumors and myoepithe- sue, parachordoma is negative for epithelial markers. liomas ofsoft tissue. A clinicopathologic study of 19 cases with a unitying con- cept. Am J Surg Pathol 1997; 21: 13-22. 28. Burke T, Sahin A, Johnson DE, Ordoñez NO at al. Myoepithelioma of the References retroperitoneum. ultrastruct Pathol 1995; 19: 269-274. 1. Enzinger FM. Epithelioid sarcoma. A sarcoma simulating a granuloma ora car- 29. Dei Tos AP, Wadden C, Fletcher COM. Extraskeletal myxoid chondrosarcoma: cinoma. Cancer 1970; 26: 1029-1041. An immunohistochemical reappraisal of 39 cases. Appl Immunohistochem 2. Chase DR, Enzinger FM. Epithelioid sarcoma: Diagnosis, prognostic indicators 1997; 5: 73-77. and treatment. Am J Surg Pathol 1985; 9: 241-263. 3. Daimaru Y, Hashimoto H, Tsuneyoshi M et al. Epithelial profile of epithelioid sarcoma: An immunohistochemical analysis of eightcases. Cancer 1987; 59: 134-141. 4. Manivel JC, Wick MR, Dehner LP et al. Epithelioid sarcoma: An immunohisto- chemical study Am J Clin Pathol 1987; 87: 319-326. Small round cell tumors of childhood 5. Meis JM, Mackay B, Ordoñez NG. Epithelioid sarcoma: An immunohistochemi- cal and ultrastructural study. Surg Pathol 1988; 1: 13-31. 6. van de Rijn M, Rouse RV. CD34: A review Appi Immunohistochem 1994; 2: E. de Álava 71-80. 7. Fisher C. Epithelioidsarcoma. the spectrum ofultrastructural differentiation in Clínica Universitaria de Navarra, Pamplona. Spain. seven immunohistochemicaldefined cases. Hum Pathol 1988; 19: 265-275. 8. Evans H, Baer S. Epithelioid sarcoma: A clinicopathologic and prognostic study of26 cases. Semin Diagn Pathol 1993; 10: 286-291 . Introduction 9. Boa GD, Pritchard DJ, Reiman HM, Dobyns JH, Ilstrup DM, Landon GC. Epithelioidsarcoma. An analysis of51 cases. J Bone Joint Surg 1988; 70:862- “Small round cell tumor” is the traditional generic name given to a 870. group of undifferentiated tumors occurring with predilection in chil- 10. Chase DR. Do “rhabdoid features” impart a poorer prognosis to proximal-type dren and young adults in which light microscopy alone is not epithelioid sarcoma. Adv Anat Pathol 1997; 4: 293-299. 11. Steinberg BD, Gelberman RH, Mankin HJ et al. Epithelioid sarcoma in the always Sufficient to give an accurate diagnosis. The new immuno- upper extremity J Bone Joint Surg 1992; 74: 28-35. histochemical and molecular techniques have had a deep impact 12. Prat J, Woodruft JM, Marcove RC. Epithelioid sarcoma. An analysis of 22 on the diagnosis and classification of tumors of this group, and sev- cases indicating the prognostic significance of vascular invasion and regional eral new entities have been delineated over the last few years. This lymph node metastasis. Cancer 1978; 41:1472-1487. review is mainly focused on rhabdomyosarcomas and desmoplas- 13. Guillou L, Wadden C, Coindre JM et al. “Proximal-type” epithelioid sarcoma, a tic small round cell tumor. distinctive aggressive neoplasm showing rhabdoid features. Clinicopathologic, immunohistochemical, and ultrastructural study ofa series. Am J Surg Pathol Rhabdomyosarcoma is the most common Soft tissue sarcoma 1997; 21: 130-146. in childhood. The traditional classification scheme included the four 14. Wick MR, Ritter JH, Dehner LR Malignant rhabdoid tumors: A clinicopatholog- following histological subtypes: embryonal, botryoid, alveolar and ic review and conceptual discussion. Semin Diagn Pathol 1995; 12: 233-248. pleomorphic. The first two are associated with a good prognosis, and 15. Parham DM, Weeks DA, Beckwith JB. The clinicopathologic spectrum ofputa- the latter twowith a poor outcome. Pleomorphic rhabdomyosarcoma tive extrarenal rhabdoid tumors. An analysis of 42 cases studied with immuno- is virtually never seen in childhood. During the last few years two histochemistry or electronmicroscopy Am J Surg Pathol 1994; 18:1010-1029. 16. Tsuneyoshi M, Daimaru Y, Hashimoto H et al. Malignant soft tissue neoplasms new subtypes of rhabdomyosarcoma have been recognized, one as with the histologic features of renal rhabdoid tumors: An ultrastructural and a variant of the embryonal type with a particularly good prognosis, immunohistochemical study Human Pathol 1985; 16: 1235-1242. and the other as a subtype of alveolar rhabdomyosarcoma, which 17. Tsuneyoshi M. Daimaru Y, Hashimoto H et al. The existence of rhabdoid cells can be easily confused with the former and is accompanied by a in specified soft tissue sarcomas. Histopathological, ultrastructural and challenging differential diagnosis. immunohistochemical evidence. Virchows Arch A 1987; 411: 509-514. 18. Molenaar WM, DeJong B. Dam-Meiring A at al. Epithelioid sarcoma or malig- nant rhabdoid tumor ofsoft tissue. Epithelioid immunophenotypeand rhabdoid Embryonal rhabdomyosarcoma, spindle cell variant karyotype. Hum Pathol 1989; 20: 347-351 . It was originally reported by Cavazzana et al. in 1992 (1) as a prog- 19. Perrone T, Swanson PE, Twigga Let al. Malignant rhabdoid tumorofthe vulva: nostically favorable variant of rhabdomyosarcoma, and is charac- is distinction from epithelioid sarcoma possible. Am J Surg Pathol, 1989; 13: 848-858. terized histologically by elongated fusiform cells. It usually appears 20. Chase DR. Rhabdoid versus epithelioid sarcoma. Am J Surg Pathol 1990; 14: in male children (mean age, 6; M/F ratio, 6), the most frequent loca- 792-794. tion being the paratesticular area, followed by the head and neck 21. Schofield DE, Beckwith JB, Sklar J. Loss of heterozygosity at chromosome region. Microscopically the tumor is arranged in well-circumscribed regions22q11-12 and lIp15.5 in renal rhabdoid tumors. Genes Chromosomes nodules of spindle cells, similarto fetal myotubes at a late stage of Cancer 1996; 15:10-17. 22. Quezado MM, Middleton LP, Bryant B at al. Allelic loss on chromosome 22q in differentiation. Two different histological patterns can be seen. The epithelioid sarcomas. Hum Pathol 1998; 29: 604-608. most usual form corresponds to long fascicles similarto those seen 23. Smith MEF, Brown JI, Fisher C. Epithelioid sarcoma: Presence of vascular- in fibrosarcoma or smooth muscle tumors. In the other type, the endothelial cadherin and lack of epithelial cadherin. Histopathology 1998; 33: cells are arranged in whorls or short fascicles embedded in a high- 425431. ly collagenized stroma. Vimentin, actin, desmin and myoglobin are 24. Smith MEF, Fisher C, Weiss SW. Pleomorphic hyalinizing angiectatic tumor of more frequently expressed than in classical embryonal rhab- soft parts. A low-grade neoplasm resembling neurilemoma. Am J Surg Pathol 1996; 20: 21-29. domyosarcoma, which is consistent with a higher degree of skele-

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A prominent vascular hyperplasia can be sometimes seen in the tal muscle differentiation, also evident at the ultrastructural level. stroma, as well as some foci of epithelial differentiation in the form The better prognosis of the spindle cell variant compared with clas- of glands, rosettes, or trabecular arrangements. Although cells are sical embryonal rhabdomyosarcoma (1), was confirmed in a further usually small, foci of pleomorphic cells can also be seen. The clinicopathological study carried out on paratesticular rhab- immunohistochemical profile of DSRCTconsistently includes reac- domyosarcoma (2). The 5-year survival rate was 88% for the spin- dle cell variant, and 66% for the classical variant. Interestingly, sev- tivity to keratins, desmin, neuron-specific enolase (NSE), vimentin, and epithelial membrane antigen (EMA) in various combinations. In eral cases have recently been reported in adults (3) and have shown similar pathological features but are associated with a less contrast, muscle common actin or myogenin are not detected, favorable outcome. which could be of help in the differential diagnosis with rhab- domyosarcomas. Reactivity for MIC2 (013) is seen in 19% of cases (7), but it shows a cytoplasmic staining in contrast with the Alveolar rhabdomyosarcoma. solid variant membranous pattern displayed by Ewing’s sarcoma cells. This entity wasdescribed early this decade when subsets of patients The EWS-WT1 chimeric transcript has been found in 97% of diagnosed with embryonal rhabdomyosarcoma were reported to studied cases. This consistency is useful for the molecular differ- have tumors with compact small round cell histology, with the unfa- ential diagnosis among small round cell tumors, many of them also vorable prognosis of alveolar rhabdomyosarcoma but lacking an having specific chimerical transcripts (Ewing’s/PNET, alveolar evident alveolar pattern (4). They usually arise as alveolar rhab- rhabdomyosarcoma) (9). This consistent presence of the fusion domyosarcoma in the sott tissues of the trunk and extremities of gene also suggests that this genetic event is of importance in the adolescents or older boys. Light microscopy shows a solid pattern development of DSRCT. In fact, the fusion protein functions as an of growth, sometimes with a small amount of intervening stroma aberrant transcription factor, modulating the expression of genes that delineates tumor cell nests. Actually a closer look reveals that that overlap with those normally regulated by WT1 . Interestingly, their cytology, with a coarse chromatin pattern and nucleoli, is simi- one of those genes is PDGFA, a potent fibroblast growth factor that lar to that of alveolar rhabdomyosarcoma. Muscle differentiation is contributes to the characteristic reactive fibrosis associated with this evident when antibodies for MyoD1, desmin or actin are used, unique tumor. Furthermore, the serosal lining of the body cavities, although myoglobin reactivity is seldom found. Z-bands or other the most usual site for DSRCT, is a structure that has an intense tran- ultrastructural signs of rhabdomyoblastic differentiation can be sient fetal expression of the WT1 gene. This gene could then be found in about 60% of cases. Interestingly, solid alveolar rhab- related to the normal development of specific mesodermal tissues domyosarcoma display the same molecular features of alveolar close to the serosal lining. Inappropriate activation of WT1-respon- rhabdomyosarcoma [t(2;13),t(1 ;13), and their related gene fusions, sive genes due to the EWS-WT1 fusion protein could explain why namely PAX3-FKHR, and PAX7-FKHR]. In contrast, it lacks the DSRCT commonly arises in the coelomic cavities. genetic loss at 11 p15, a characteristic feature of embryonal rhab- Although DSRCT is associated with a poor prognosis, multi- domyosarcoma. The differential diagnosis includes lymphoma, modal therapy, including debulking surgery, chemo- and radiother- neuroblastoma, and, most importantly, extraskeletal Ewing’s sarco- apy, suggest that long-term survival is possible when aggressive ma/primitive neuroectodermal tumors (PNET). The presence of therapy is instituted. PAX3/7-FKHR fusion transcripts, readily detectable by RT-POR or FISH, along with an appropriate immunohistochemical panel are of Isolated case reports on other polyphenotypic tumors have been recently published. These tumors shared similar morphologi- help for the differential diagnosis. cal features with DSRCT, but showed different chimerical tran- Desmoplastic small round cell tumor scripts (EWS-FLI1 and EWS-ERG) characteristic of Ewing’s sarco- ma/PNET (10, 11, Gerald W., personal communication). These The first reported series of desmoplastic small round cell tumor findings suggest that classification of this group of primitive tumors (DSRCT) (5) describes a distinct undifferentiated neoplasm that is not yet fully established, and new entities could be described in usually affects male adolescents, and presents clinically with wide- the years to come. spread abdominal serosal involvement. Histologically, small round tumor cells are arranged in nests or trabeculae and embedded in a References desmoplastic stroma, and immunohistochemically display a char- 1. Cavazzana AO, Schmidt D, Ninfo v et al. Spindle cell rhabdomyosarcoma. A acteristic polyphenotypia. Subsequent cytogenetic and molecular 1 3;ql 2) resulting in a EWS- prognostically favorable variant of rhabdomyosarcoma. Am J Surg Pathol studies reported a consistentt(1 1 ;22)(p WT1 gene fusion, whose products can be detected at the RNA and 1992; 16: 229-235. 2. Leuschner I, Newton WA, Schmidt D et al. Spindle cell variants of embryonal protein levels (6). This tumor is being diagnosed with increased fre- rhabdomyosarcoma in the paratesticular region. A report of the Intergroup quency, and although the presence of the translocation and fusion Rhabdomyosarcoma Study Am J Surg Pathol 1993; 17: 221-230. of EWS and WT1 genes are consistent features (7), there is a 3. Rubin BP, Hasserjian RP, Singer Set al. Spindle cell rhabdomyosarcoma (so- greater degree of clinical, pathological, and molecular variation called) in adults, Report of two cases with emphasis on differential diagnosis. than originally reported. Am J Surg Pathol 1998; 22: 459-464. There is a striking predominance of male patients (5/1), with a 4. Tsokos M. The diagnosis and classification of childhood rhabdomyosarcoma. mean age of 22 years (range 6-49). The overwhelming majority of Sam Diagn Pathol 1994; 11: 26-38. tumors (95%) are intraabdominal, although four cases have been 5. Gerald WL, Miller HK, Battifora H et al. Intra-abdominal desmoplastic small described in the pleural cavity, one in the posterior cranial fossa, round-cell tumor. Report of 19 cases of a distinctive type of high-grade polyphenotypic malignancy affecting young individuals. Am J Surg Pathol and one in the hand (8). Typical histology, as described above, is 1991; 15: 499-513. seen in most cases, although considerable histological variation is 6. Gerald WL, Rosai J, Ladanyi M. Characterization of the genomic breakpoint reported in other cases (7). The size of the tumor nests varies, from and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small smallclusters to large solid areas, with or without central necrosis. round cell tumor Proc NaIl Acad Sci USA 1995; 14; 92: 1028-1032.

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7. Gerald WL, Ladanyi M, de Álava E at al. Clinical, Pathologic and molecular diagnoses include rare tufted hemangioma and “targetoid hemo- spectrum of tumors associated with t(11;22)(p13;q12): Desmoplastic small siderotic hemangioma” (see below). round cell tumorand its variants.J Olin Oncol 1998; 16: 3028-3036. 8. Antoneacu CR, Gerald WL, Magid MS at al. Molecular variants of the EWS- Hobnail hemangioma WT1 gene fusion in desmoplastic small round cell tumor. Diagn Mol Pathol 1998; 7: 24-28. (“targetoid hemosiderotic hemangioma” 9. de Álava E, Ladanyi M, Rosai J, Gerald WL, Detection ofchimeric transcripts Hobnail hemangioma is a further recently recognized benign vas- in desmoplastic small round cell tumor and related developmental tumors by cular lesion. The original term “targetoid hemosiderotic heman- reverse transcriptase polymerase chain reaction. A specific diagnostic assay gioma” resulted from the characteristic targetoid clinical appear- Am J Pathol 1995; 147: 1584-1591. 10. Katz RL, Quezado M, Senderowicz AM et al. Anintra-abdominalsmall round cell ance (4). Further expanded clinicopathological studies have shown neoplasm with features of primitive neuroectodermal and desmoplastic round clearly that most vascular lesions showing histological features of cell tumorand a EWS/FLI-1 fusion transcript Hum Pathol 1997; 28: 502-509. this distinctive neoplasm lack this clinical appearance, which is also 11. Ordi J, de Álava E, Tome A at al. lntraabdominal desmoplastic small round cell evident in other conditions (5, 6). In order to emphasize the inde- tumorwith EWS/ERG fusion transcript. Am J Surg Pathol 1998; 22:1026-1032. pendent diagnostic hobnail cytomorphology it the targetoid appear- ance is evident, the alternative term of hobnail hemangioma was proposed (5, 7). Hobnail hemangioma represents a superficially located lesion in which a broad spectrum of diagnoses is suggest- Vascular tumors ed clinically, ranging from dermal melanocytic nevus and heman- gioma to fibrous histiocytoma (6). It affects mainly adults with a T. Mentzel slight male predominance; most common anatomic locations are the extremities and the trunk (6), and rare cases were reported in the Dept. of Pathology University of Jena, Germany head and neck region (5, 8). Diagnostic criteria of hobnail heman- gioma are a biphasic growth pattern (dilated vascular spaces on the surface and more narrow vascular spaces infiltrating deeper Introduction parts of the dermis) and a hobnail cytomorphology of neoplastic endothelial cells (plump and prominent cells with scanty, ill-defined Vascular tumors are a large and heterogeneous group of mes- cytoplasm and large, mostly hyperchromatic nuclei). Further fea- enchymal lesions and Span a broad spectrum of morphology and tures include an associated lymphocytic infiltrate, fibrosis of the clinical behavior. Despite recent developments, the exact classifi- dermal collagen and hemosiderin deposits. These morphological cation of vascular tumors is still problematic because conceptual features vary according to the age of the neoplasm. More mature confusion persists in the distinction between vascular malforma- examples are composed predominantly of narrow vascular struc- tions, reactive and truly neoplastic endothelial lesions. In addition, tures, and in few cases overlapping features to retiform heman- there exists an expanding group of vascular neoplasms in which morphological features do not predict reliably the clinical behavior, gloendothelioma (see below) were noted (5). In contrast, “early” examples of hobnail hemangioma are mainly composed of dilated as well as benign vascular neoplasms that closely mimic more vascular structures in the upper dermis resembling features of aggressive lesions (i.e., angiosarcoma, Kaposi’s sarcoma) (1). In this review, recently characterized vascular tumors of skin and soft early Kaposi’s sarcoma and lymphangioma (4, 6). Immunohisto- tissues are briefly discussed, including benign and low-grade chemically, endothelial cells stain positively for CD31, whereas malignant lesions which simulate early forms of Kaposi’s sarcoma CD34 stains only a minority of cases (6). In contrast to other benign and aggressive angiosarcoma. neoplasms of blood vessels, neoplastic vascular structures are not surrounded by a complete layer of actin-positive pericytes (5, 6). Microvenular hemangioma Furthermore, a limited number of cases stained positively for vas- cular endothelial growth factor receptor (VEGFR-3) (6), a recently Microvenular hemangioma is a distinctive vascular proliferation in described marker of lymphatic endothelial cells. These results and the spectrum ofcapillary hemangiomas which is easily mistaken for early Kaposi’s sarcoma or cutaneous angiosarcoma. Clinically, the evidence ot associated lymphocytes and the described mor- most cases present as a small, enlarging papule on the limbs of phological features suggest a lymphatic line of differentiation of young to middle-aged adults (2). Histologically, a proliferation of neoplastic cells in hobnail hemangioma (6). Despite the bland clin- irregularly branching, thin-walled venules is seen, which infiltrate ical picture, hobnail hemangioma may show worrisome histological the sclerotic dermal collagen. These narrow neoplastic vascular features and the diagnosis ofpatch- or lymphangioma-like Kaposi’s structures are lined by inconspicuous, sometimes plump endothe- sarcoma, well-differentiated angiosarcoma, and retiform heman- lial cells surrounded by actin-positive pericytes. No prominent gloendothelioma is suspected. In addition to different clinical fea- inflammatory infiltrate or hemosiderin deposits are noted. The evi- tures of evolving Kaposi’s sarcoma, hobnail hemangioma is char- dence of lobular aggregates of small capillaries in deeper parts of acterized by a biphasic growth pattern and hemosiderin deposits. some lesions suggests a close relationship to ordinary capillary Early examples of Kaposi’s sarcoma are seen in the reticular but hemangioma (3). The main differential diagnosis of microvenular not in the papillary dermis, show an adnexocentric growth and fre- hemangioma is patch-stage Kaposi’s sarcoma. However, the lack quently contain plasma cells. Cutaneous angiosarcoma occurs irregular anastomosing vascular spaces, plasma cells and hyaline mainly in the head and neck region of elderly patients, and is char- globules is of help in the distinction of microvenular hemangioma. acterized morphologically by anastomosing vascular structures Anastomosing neoplastic vascular structures in aggressive cuta- lined by atypical and proliferative active endothelial cells. Low- neous angiosarcoma are lined by atypical endothelial cells. In addi- grade malignant retiform hemangioendothelioma presents clinically tion, no biphasic proliferation of CD31+ endothelial cells and actin- usually as an exophytic or plaque-like vascular tumor and is charac- positive pericytes is evident in angiosarcoma. Further differential terized by a high rate of often repeated local recurrences (7). The

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small size ofcircumscribed hobnail hemangioma is ofhelp in the dis- Within the lobules, short cellular fascicles of spindle-shaped cells tinction of both entities, however, there are rare neoplasms showing are intertwined with slit-like vascular spaces reminiscent of those overlapping morphological features between both entities (5). seen in Kaposi’s sarcoma. Ectatic capillaries lined by flat endothe- lial cells containing frequently hyaline thrombi are found in the Retiform hemangioendothelioma periphery of some tumor lobules. Occasionally, small nests of Retiform hemangioendothelioma (RHE) is a distinctive vascular polygonal epithelioid cells are scattered throughout the neoplasms neoplasm that arises mainly in the distal extremities of young (15). Immunohistochemical markers confirm the endothelial nature adults. Occasionally, it is seen on the trunk, penis, orscalp (7), and of the elongated cells that line the narrow vascular spaces, and rare cases of multicentric lesions were reported (9). Clinically, RHE intralesional pericytes that stain positively for smooth muscle actin is characterized by an infiltrative growth pattern and a high rate of are also seen; spindle cells may be positive for 0D34 focally. In local recurrences, but metastasis to a lymph node has only been adults, KHE has to be distinguished from nodular Kaposi’s sarco- seen in one patient so far (7). The morphologic hallmark of RHE is ma. The lack of a lobulargrowth pattern and dilated capillaries with long, arborizing, thin-walled vascular spaces that infiltrate in a reti- hyaline thrombi in Kaposi’s sarcoma, which is often associated with form pattern reminiscent of the normal rete testis. The neoplastic chronic inflammatory infiltrate, is of help. In addition, tumor cells in vascular spaces are lined by a single layer of monomorphic hobnail Kaposi’s sarcoma stain constantly positive for 0D34 and are actin endothelial cells without prominent atypia and increased mitotic negative. Spindle cell hemangioma (“spindle cell hemangioen- activity. Solid areas composed of plump oval or polygonal neoplas- dothelioma”) is seen mainly in the distal extremities, and shows his- tic cells are often present in deeper parts of lesions, whereas tologically a biphasic pattern of cavernous vascular structures and superficially, dilated vascular structures with intraluminal papillary ramifying vascular spaces associated with bland spindle cells and projections are infrequently evident. Neoplastic cells are positive scattered epithelioid endothelial cells. In a superficial location KHE for endothelial markers, but surrounding actin-positive pericytes must be distinguished also from tufted hemangioma. Tufted are not evident. A prominent lymphocytic infiltrate composed of hemangioma is characterized by an irregular, cannon-ball distribu- mature B and T lymphocytes is present in at least 50% of cases. tion of vascular tufts and lacks lymphangiomatous changes (16). The most important differential diagnosis of RHEis aggressive cuta-

neous angiosarcoma, which may show focally, retiform features as Polymorphou s hemangioendothelioma well. However, cutaneous angiosarcoma occurs primarily in the head Polymorphous hemangioendothelioma (PHE) is an exceedingly and neck region of elderly patients and is characterized by anasto- rare neoplasm that was first described in lymph nodes (17) and mosing and dissecting vascular spaces lined by atypical endothelial subsequently in extranodal soft tissue (18). In one of the four cells that are often arranged in layers and tufts. Malignant endovas- patients with follow-up information, local recurrence and pulmonary cular papillary angioendothelioma (Dabska tumor) is a further rare metastasis developed, and the patient died. At the moment, PHE vascular neoplasm composed of hobnail endothelial cells. Although should be best regarded as a vascular tumor of low-grade malig- described almost 30 years ago (10), it still represents a vascular lesion which is poorly understood and in which it is difficult to repro- nancy. Histologically, PHE is characterized by solid zones of poly- duce diagnostic criteria. In contrast to the original description, it has gonal tumorcells admixed with an angiomatous component showing clefts and groups of ectatic vascular spaces lined by plump hobnail also been reported in adult patients, and a rather benign clinical behavior has recently been proposed (11). At the moment it seems endothelial cells without striking afypia and proliferative activity. that Dabska tumor comprises a morphological spectrum of lesions The polygonal cells contain scant cytoplasm and uniform oval or showing overlap with retiform hemangioendothelioma (12) and other round nuclei. Neoplastic cells are positive variably for different vascular entities. endothelial markers. In contrast to spindle cell hemangioma, PHE does not contain spindle cell fascicles but solid tumor areas. The Kaposiform hemangioendothelioma absence of epithelioid endothelial cells with characteristic cytoplas- micvacuoles as well as the lack of myxohyaline stroma are of help Kaposiform hemangioendothelioma (KHE) is a recently recog- in distinguishing PHE from epithelioid hemangioendothelioma. nized, uncommon vascular neoplasm that occurs most frequently Most importantly, PHE must be separated from angiosarcoma and in neonates and young children and appears as a solitary lesion in metastatic carcinoma. Angiosarcoma shows dissecting and anas- deep soft tissues of the retroperitoneum, chest wall, upper extrem- tomosing vascular channels lined by atypical endothelial cells. ities, and head and neck region (13, 14). More recently, KHE has Special stains and immunohistochemical markers enable the also been found in dermal and subcutaneous tissue of adult exclusion of metastatic carcinoma. patients (15). KHE is sometimes associated with intestinal obstruc- tion, jaundice or Kasabach-Merritt syndrome, and in rare cases References features of lymphangiomatosis are seen. KHE was regarded as a 1. Fletcher 0DM. Vascular tumors: An update with emphasis on the diagnosis of low-grade malignant vascular neoplasm because it sometimes pur- angiosarcoma and borderline vascular neoplasms. In: Weiss SW, Brooks JSJ. sues an aggressive clinical course. Although KHE is associated (Eds.). Soft Tissue Tumors. Willliams & Wilkins, Baltimore, 1996; 181-206. with a relatively high mortality rate, deaths are almost always relat- 2. Hunt SJ, Santa Cruz DJ, Barr RJ. Microvenular hemangioma. J Cutan Pathol ed to locally invasive effects or as a result of bleeding and con- 1991; 18: 235-240. sumption coagulopathy. To date, no metastasis of KHE has been 3. Aloi F, Tomasini C, Pippione M. Microvenular hemangioma. Am J recorded, and small and superficially located lesions amenable to Dermatopathol 1993; 15: 534-538. 4. Santa Cruz DJ, Aronberg J. Targetoid hemosiderotic hemangioma. J Am Acad complete surgical excision are characterized by a favorable clinical Dermatol 1988; 19: 550-558. course. It seems best to classify KHE as a locally aggressive but 5. Guillou L, Calonie E, Speight P et al. Hobnail hemangioma: A benign vascular nonmetastasizing vascular neoplasm. KHE is characterized by cel- lesion mimicking patch stage Kaposi’s sarcoma and retiform hemangioen- lular lobules of neoplastic cells that are separated by fibrous septa. dothelioma. Am J Surg Pathol 1999.

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6. Mentzel T, Kutzner, K. Hobnail hemangioma (“targetoid hemosiderotic hae- Collagenous fibroma (desmoplastic fibroblastoma mangioma”): Clinicopathologic and immunohistochemical analysis of 62 cases. J Cutan Pathol (submitted). Desmoplastic fibroblastoma was first described by Evans (1) and 7. Calonje E, Fletcher CDM, Wilson-Jones E et al. Retiform hemangioendothe- has subsequently been renamed “collagenous fibroma” for fairly lioma. A distinctive form oflow-grade angiosarcoma delineated in a series of sound linguistic reasons (2, 3). Collagenous fibroma affects mainly 15 cases. Am J Surg Pathol 1994; 18:115-125. adults (most often over the age of 40) with a male predominance 8. Santonja C, Torrelo A. Hobnail hemangioma. Dermatology 1995; 191: 154- and presents usually as a painless, slowly growing subcutaneous 156. mass, most often less than 4 cmin diameter (although larger lesions g. Duke D, Dvorak AM, Harris TJ et al. Multiple retiform hemangioendotheliomas. A low-grade angiosarcoma. Am J Dermatopathol 1996; 18: 606-610. do occur). The anatomical distribution is wide, with some predilection 10. Dabska M. Malignant endovascularpapillary angioendothelioma of the skin in for the upper limb and shoulder regions and occasional cases are childhood. Clinicopathologic study of 6 cases. Cancer 1969; 24: 503-510. intramuscular. These lesions seem not to recur locally, 11. Fanburg-Smith JC, Michal M, Miettinen M. Dabska tumor(malignant endovas- Grossly collagenous fibromas appear fusiform or ovoid, firm and cular papillary angioendothelioma), Study of 10 cases. Archives D’Anatomie et rubbery and well circumscribed but, histologically, most cases have de Cytologie Pathologiques. Clin Exp Pathol 1998; 46: 1 7A. infiltrative margins with entrapment of fat or skeletal muscle. They 12. Sanz-Trelles A, Rodrigo Fernández I, Ayala-Carbonero A et pal. Retiform hemangioendothelioma. A new case in a child with diffuse endovascular pap- are often centered on fascial or aponeurotic tissue and are com- illary endothelial proliferation. J Cutan Pathol 1997; 24: 440-444. posed of spindle-shaped or stellate fibroblasts, sparsely and hap- 13. Tsang WYW, Chan JKC. Kaposi-like infantile hemangioendothelioma. A dis- hazardly distributed in a copious collagenous or focally myxoid tinctive vascular tumor of the retroperitoneum. Am J Surg Pathol 1991; 15: matrix containing very few blood vessels, Tumor cell nuclei are main- 982-989. ly ovoid with small nucleoli and mitoses are generally absent or very 14. Zukerberg LR, Nicoloff BJ, Weiss SW. Kaposiform hemangioendothelioma of hard to find. Necrosis and cytologic atypia are not seen. infancy and childhood. An aggressive neoplasm associated with Kasabach- Immunohistochemistry shows focal actin (smooth muscle actin or Merrill syndrome and lymphangiomatosis. Am J Surg Pathol 1993; 17: 321- 328. HHF35) positivity in many cases and, as with other lesions having a 15. Mentzel T, Mazzoleni G, Del Tos AP et al. Kaposiform hemangioendothelioma myofibroblastic component, rare keratin-positive cells may be seen. in adults. Clinicopathologic and immunohistochemcialanalysis of three cases. Differential diagnosis includes principally nodular fasciitis, Am J Clin Pathol 1997; 108: 450-455. which generally affects younger patients, is both more cellular and 16. Wilson-Jones E, Orkin M. Tuftedangioma (angioblastoma): A benign progres- more vascular and often shows microcystic and inflammatory com- sive angioma not to be confused with Kaposi’s sarcoma orlow-grade angiosar- ponents; fibroma of tendon sheath, which generally arises in the coma. JAm Acad Dermatol 1989; 20: 214-225. hands or feet, is better circumscribed, often more cellular and con- 17. Chan JKC, Frizzera G, Fletcher CDM et pal. Primary vascular tumors of lymph nodes other than Kaposi’s sarcoma, Analysis of 3g cases and delineation of tains slit-like vascular channels; and desmoid fibromatosis, which two new entities. Am J Surg Pathol 1992; 16: 335-350. is usually deep-seated, more cellular and has a consistently fasci- 18. Nascimento AG, Keeney GL, Sciot R et al. Polymorphous hemangioendothe- cular growth pattern. lioma. A report of two cases, one affecting extranodal soft tissues, and review of the literature, Am J Surg Pathol 1997; 21: 1083-1089. Giant cell angiofibroma Giant cell angiofibroma is an uncommon fibroblastic neoplasm which was first described in the orbital region (4). It has subse- quently become clear that giant cell angiofibroma may also occur outside the orbital region (5) and cases may even occur on the Fibrous and myofibroblastic tumors trunk and the extremities (personal unpublished observations). Nevertheless, based on our experience of more than 30 cases, most C.D.M. Fletcher examples of giant cell angiofibroma occur in the head and neck region of adults with a slight predilection for males. Occasional cases Dept. of Pathology Harvard Medical SChool and Brigham and recur locally in a nondestructive fashion but I have not to date Women’s Hospital, Boston, Massachusetts, USA. encountered a case which metastasized, Giant cell angiofibromas are relatively circumscribed neo- plasms characterized by a rather patternless growth of round or Introduction plump spindled tumor cells admixed with multinucleate giant cells, set in a collagenized or myxoid matrix with a prominent network of In the past, a very wide variety of tumorS were labelled as “fibroma” small blood vessels. Hyalinization of vessel walls may be promi- or “fibrosarcoma” without further qualification. With time, these nent. Tumor cells of giant cell angiofibroma have ill-defined palely generic terms have been shown to subsume a spectrum of numer- eosinophilic cytoplasm and plump nuclei which often show irregu- ous reactive and neoplastic lesions with striking clinicopathological lar folding and pseudoinclusions. In most cases irregularly shaped differences and often different therapeutic implications, With the pseudovascular spaces are noted, and these are lined by mononu- advent of electron microscopy and immunohistochemistry it has clear and multinucleate tumor cells. Mitotic figures are very rare. become clear that many so-called fibrous lesions show, in varying Immunohistochemically, tumor cells are strongly positive for CD34, degree, both fjbroblastic and myofibroblastic differentiation (the whereas myogenic and epithelial markers as well as S-100 protein fibromatoses and fasciitis family being prime examples). It remains and CD31 are negative. a matter of controversy whether these are functional variants of a In contrast to giant cell angiofibroma, giant cell fibroblastoma single cell type or whether there exist primarily myofibroblastic occurs mainly in early childhood and is characterized by a diffusely lesions. By necessity, this brief overview focuses only on some of infiltrative growth and a high rate of local recurrence. Morpholo- the lesions which have been characterized (or more clearly under- gically, giant cell fibroblastoma lacks the prominent vascular pattern stood) in the past 5 years. characteristic of giant cell angiofibroma. More complicated seems

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the distinction of giant cell angiofibroma from solitary fibrous tumor plasia and one case was reported to show transition to a more cellu- (SFT) and it is arguable that the giant cells and pseudovascular larfibrosarcoma-like pattem (8). Immunostains very often show pos- spaces in giant cell angiofibroma represent degenerative features in itivity for variably specific neural crest antigens (S-100 protein, Leu7, SFT. However, tumor cells in SFT tend to have more elongated wavy neuron-specific enolase) but this has been claimed to be more strik- nuclei, and stromal keloid-like or stellate hyalinization is seen. The ing in the rosette-like foci rather than the spindle cell fascicles. vascular pattern in SET is most often thin-walled and pericytoma- The original authors proposed that this was a variant of low- like. grade fibromyxoid sarcoma, differing only in the presence of the giant rosettes, and predicted an indolent, potentially metastatic Cellular angiofibroma course. My personal experience has been that the spindle cell Cellular angiofibroma is a recently described benign vulval neo- areas are usually S-100 protein positive and, while accepting that plasm which clinically is often mistaken for a Bartholin gland cyst these lesions bear no resemblance to schwannoma or neurofibro- (6). It occurs mainly in middle-aged women but comparable lesions ma, I wonder if they might represent a form of low grade malignant have been described in male patients (7). Thus far, in our experi- peripheral nerve sheath tumor. Certainly similar rosettes can be ence, no case has either recurred locally or metastasized. seen in a variety of tumor types and future electron microscopic Morphologically, cellular angiofibroma is generally a circum- studies may help to better resolve the nature of these tumors. scribed neoplasm composed of uniform spindle cells arranged in short, irregularly intersecting fascicles with wispy stromal collagen Inflammatory myofibroblastic tumor bundles, numerous smallto medium sized blood vessels which often (inflammatory tibrosarcoma show prominent hyalinization of their walls, and a varying proportion The concept of reactive “tumorous” proliferations composed of of mature adipocytes. The tumor cells have ill-defined cell borders, fibroblasts, myofibroblasts and chronic inflammatory cells grew in pale cytoplasm and oval or fusiform, bland nuclei, thus closely popularity following Bahadori and Liebow’s seminal paper on plas- resembling tumor cells of spindle cell lipoma. They stain positively ma cell granuloma of the lung (11). Subsequently, such lesions for vimentin and, in a few cases, for 0D34 as well. Generally, these were more often referred to as inflammatory pseudotumors or, neoplasms are cellular and show quite frequent mitoses, but pleo- more recently, as inflammatory myofibroblastic tumors to empha- morphism and tumor necrosis are absent. Stromal mast cells are size their major cellular constituent and, increasingly, to imply that common. such proliferations may represent benign neoplasms. They have Because of the brisk mitotic activity, examples of cellular angio- been described in virtually all organs including the mesentery and fibroma may be mislabeled as sarcoma, especially as leiomyosar- retroperitoneum (12). In 1991, Meis and Enzinger (13) proposed coma. However, smooth muscle tumors of the external genitalia that, especially in children, at least some of the intraabdominal have abundant eosinophilic cytoplasm and cigar-shaped nuclei, lesions previously designated as inflammatory pseudotumor actu- and they stain positively for myogenic markers. Because of its loca- ally represent a true sarcoma which they called inflammatory tion, cellular angiofibroma has also to be distinguished from anglo- fibrosarcoma. It is my experience that there is sufficient clinico- myofibroblastoma, which is much less cellular and composed of pathological evidence to justify such a designation for at least a rather rounded myoid tumor cells which stain positively for desmin. small minority of these lesions, but this is a controversial topic. In contrast to cellular angiofibroma, spindle cell lipoma is more The originally published clinical data in Meis and Enzinger’s common in male patients and shows a predilection for the neck and series described 38 cases. These arose predominantly in the upper back region, It typically contains ropey refractile collagen mesentery and retroperitoneum of children (median aged 8.5 years), bundles and lacks numerous blood vessels with hyalinized vessel although comparable lesions in adults also occur. Over one-third of walls; tumor cells in spindle cell lipoma stain consistently for CD34. patients had multiple tumors. Among 27 patients with follow-up, 10 developed local recurrence (3 repeatedly) and 3 developed metas- Hyalinizing spindle cell tumor with giant rosettes tases. Overall, 6 patients died of their tumor, although interestingly Hyalinizing spindle cell tumor with giant rosettes is a rather enig- most were adults. Microscopically, these lesions displayed a spec- matic lesion, first described by Weiss and coworkers in late 1997 trum of histological appearances which incorporated two major (8), which has been said to resemble low grade fibromyxoid sarco- components; plump spindle cells arranged in cellular fascicles or ma. The original report included 19 cases and, since that time, whorls and a prominent infiltrate of plasma cells and some lym- there have been just occasional case reports (9,10), one of which phocytes. The spindle cells showed features of fibroblastic and described possible primary lung involvement (10). These lesions myofibroblastic differentiation and, invariably, at least some affect mainly young to middle-aged adults and present as a deep- showed nuclear irregularity and contained very large nucleoli. A seated slowly growing mass with predilection for the limbs. Most variable number of ganglion-like cells were present. In common examples have measured less than 10 cm in diameter and, although with inflammatory pseudotumor, some cases showed areas of myx- follow-up data are limited so far, only one tumor has recurred locally old change and/or marked hyalinization of collagen. and none has metastasized. It soon became clear, however, that a significant number of Grossly these are well-circumscribed, pale firm tumors but histo- pathologists felt uncomfortable with the designation of sarcoma for logically they have infiltrative margins. They consist principally ofuni- these lesions. Such concerns were based upon the fact that some form spindle cells with fibroblastic or neural-like morphology examples were histologically indistinguishable from the reactive arranged in fascicles in a collagenous or myxoid matrix. Large zones process, long known as inflammatory pseudotumor, and upon the of hyalinization are generally present and characteristically these possibility that so-called metastasis in fact represented multicen- may form nodules, surrounded in rosette-like fashion by more round- tricity. This alternative point of view was supported by a large study ed or ovoid tumor cells in axial array. Pleomorphism is minimal and of 84 cases from Coffin et al. (14). These authors again noted the mitoses are scarce. Some cases show osseous or chondroid meta- predilection for children and location within the abdomen, although

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they described cases at a wide variety of sites and occurring up to of inflammation and very rarely has such plump nuclei with promi- the age of 46 years. Frequently associated anemia was noted, as nent nucleoli. Deep benign fibrous histiocytoma is an uncommon was the occasional presence of other systemic features such as lesion and is especially rare in the abdomen or in children. It has a elevated erythrocyte sedimentation rate or unexplained fever. storiform rather than fascicular pattern and usually consists of a From the histologic point of view, Coffin et al. (14) described highly cellular admixture of short fibroblast-like cells and plumper the three following principal patterns which were commonly inter- histiocyte-like cells. Chronic inflammatory cells are relatively mixed: i) a myxoid fasciitis-like pattern with mixed inflammatory sparse. Inflammatory leiomyosarcoma is more cellular and more cells; ii) a more cellular pattern resembling fibromatosis or fibrous cytologically atypical than inflammatory myofibroblastic tumor and histiocytoma but with numerous admixed plasma cells; and ii) a generally shows much more extensive actin immunostaining. hypocellular fibrous pattern resembling scar tissue, in which there Lymphocytes typically predominate in the inflammatory infiltrate. were scattered chronic inflammatory cells and sometimes foci of calcification. Because some cases were multinodular, hard to erad- Low-grade myofibroblastic sarcoma icate and sometimes recurrent (approximately 25%), Coffin et al. For many years, the existence of myofibroblastic neoplasms (and further reaffirmed their preference for the designation “inflammato- especially myofibroblastic sarcomas) has been disputed, principal- ry myofibroblastic tumor”. They also noted four patients whose ly because the scientists who described this cell type felt strongly tumors regressed spontaneously and two patients who died of that this was not possible (19). Yet one of the prototypical myofi- uncontrollable local disease. Importantly, they made no mention of broblastic lesions, desmoid fibromatosis, is now known to be a nuclear or cytologic atypia in any of their primary lesions and none clonal proliferation and a wide variety of benign neoplasms have of their patients developed metastatic disease. They did, however, been shown to have a myofibroblastic phenotype at the immuno- describe two cases in which local recurrence was associated with histochemical and ultrastructural levels (e.g., infantile digital fibro- the development of areas having histological features of a histiocy- matosis, intranodal myofibroblastoma, mammary myofibroblas- told malignant neoplasm. This phenomenon had been described toma and angiomyofibroblastoma). It has also become evident that previously in lung lesions by Spencer and conceptually is quite dif- a variety of more aggressive lesions show myofibroblastic differen- ficult to reconcile with an intrinsically reactive process. tiation, including inflammatory myofibroblastic tumor (also known My personal experience of more than 50 cases, based largely as inflammatory fibrosarcoma), infantile fibrosarcoma and some on consultation material with no pediatric bias, has revealed the cases of so-called “MFH” (20). To this list has been added more same predilection for anatomic site and an age distribution of 2 recently a distinctive group of lesions which we have designated as months to 79 years, with 40% of cases occurring in patients older low-grade myofibroblastic sarcoma (21). than 18. It has seemed to me that at least a minority of cases do Low-grade myofibroblastic sarcoma (21) affects adults of either show the nuclear atypia described by Meis and Enzinger — and sex over a wide age range, with a peak incidence between the when this is combined with high cellularity, this inevitably raises ages of 20 and 50. Overall anatomic distribution is wide but, strik- concern for malignancy. This concern has been substantiated by ingly, around 25% of cases occur in the oral cavity (especially the the development of liver metastases (by all usual criteria) in at least tongue). Most cases present as slowly growing perifascial or deep- two patients (both children) and I am aware of other convincing seated masses which generally measure less than 5 cm(with larg- clinically malignant cases in other people’s practices. Admittedly, er exceptions). Although follow-up data are limited at present, local this is a very small number of “malignant” examples and the major- recurrence is a feature of 20-30% of cases (usually due to margin- ity of other cases are cytologically bland, more closely resembling al or incomplete excision), and occasional patients develop indo- either fasciitis or the old-fashioned inflammatory pseudotumor. lent metastases. Given this premise, are there any reliable histological features Grossly, most lesions are firm, pale and fibrous with infiltrative which allow accurate recognition of inflammatory fibrosarcoma margins, reminiscent of desmoid fibromatosis. Generally there is from among the group of inflammatory myofibroblastic lesions as a no hemorrhage or necrosis. Most cases are hypercellular through- whole? The major discriminant feature employed by Meis and out, usually being more cellular than a fibromatosis and, distinc- Enzinger was that of nuclear atypia. In my experience, focally, tively, these lesions typically show a diffusely infiltrative growth pat- there may also be very cellular, fascicular areas. Undoubtedly, reli- tern within skeletal muscle (producing a pattern rather reminiscent able distinction (in prognostically useful terms) is very difficult but of proliferative myositis). Focal stromal hyalinization is common. consideration of the nuclear detail of such tumors perhaps allows Tumor cells show usual myofibroblastic features, with variably recognition of a more aggressive subset. Limited available cytoge- wavy/tapering or plump/vesicular nuclei, and typically are arranged netic data have revealed a variety of clonal aberrations in lesions in a fascicular pattern. When compared to a fibromatosis there is of this type (15, 16), supporting their neoplastic nature, and the distinctly more nuclear atypia, even if only mild and focal in extent. original protagonists in the dispute concerning the nature of these Scattered multinucleate tumor giant cells are occasionally seen lesions have very recently moved towards a consensus viewpoint and, in most cases, the mitotic rate does not exceed 5 per 10 high- that they should all be regarded as low-grade sarcomas (17, 18). power fields. Immunohistochemically around 65% of cases show Principal considerations in the differential diagnosis include diffuse desmin immunopositivity and a similar proportion of cases fasciitis-like proliferations, fibromatosis, deep fibrous histiocytoma (although not necessarily the same ones) are smooth muscle actin and inflammatory leiomyosarcoma. Some of the fasciitis-like lesions positive. Electron microscopy shows typical myofibroblastic fea- reported at visceral locations may in fact belong in the inflammatory tures. myofibroblastic tumor category — but most cases show much less Low-grade myofibroblastic sarcoma should be distinguished pronounced inflammation, a more tissue culture-like cytomorphology from fibromatosis, myofibromatosis, solitary fibrous tumor, other and they are generally smaller in terms of lesional size. Fibromatosis types of myofibroblastic sarcoma, fibrosarcoma and leiomyosarco- is more uniformly fascicular, generally lacks any significant degree ma. The fairly consistent hypercellularity and at least focal nuclear

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Mikami Y, Shimizu M, Hirokawa M et al. Extraorbital giant cell angiofibromas. Mod usually has more circumscribed margins, more eosinophilic cyto- Pathol 1997; 10: 1082-1087. plasm and more cigar-shaped nuclei. 8. Nucci MR, Granter SR, Fletcher CDM. Cellularangiofibroma: A benign neoplasm die- tinctfrom angiomyofibroblastoma and spindle cell lipoma. Am J Surg Pathol 1997; 21: Sclerosing epithelioid fibrosarcoma 838-844. 7. Laskin WB, Fetsch JF, Mostofi FK. Angiomyofibroblastoma-like tumor of the male Sclerosing epithelioid fibrosarcoma, first described by Meis- genital tract, Analysis of 11 cases with comparison to female angiomyofibroblastoma. Kindblom and colleagues from AFIP in 1995 (22), is an uncommon Am J Surg Pathol 1998; 22: 8-16. and probably poorly recognized type of sarcoma which has only 8. Lane KL, Shannon RJ, Weiss SW. Hyalinizing spindle cell tumor with giant rosettes. slowly gained acceptance as a distinct entity. 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