Superficial small round-cell tumors with special reference to the Ewing s sarcoma family of tumors and the spectrum of differential diagnosis

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1 Seminars in Diagnostic Pathology (2013) 30, Superficial small round-cell tumors with special reference to the Ewing s sarcoma family of tumors and the spectrum of differential diagnosis Isidro Machado, MD, PhD, a Victor Traves, MD, a Julia Cruz, MD, PhD, a Beatriz Llombart, MD, b Samuel Navarro, MD, PhD, c Antonio Llombart-Bosch, MD, PhD c From the a Department of Pathology, Instituto Valenciano de Oncología, Valencia, Spain; b Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain; and the c Department of Pathology, Valencia University, Valencia, Spain. KEYWORDS Superficial mesenchymal tumor; Ewing s sarcoma Superficial/cutaneous small round-cell tumors comprise a heterogeneous group of neoplasms including sarcoma, carcinoma, melanoma, and lymphomas. Among superficial sarcomas, the Ewing s sarcoma family of tumors (ESFT) represents a poorly understood rare variant, having a behavioral difference characterized by a relative favorable prognosis. Several problems are still to be resolved in superficial ESFT, including the differential diagnosis between ESFT of bone (intraosseous or periosteal) with superficial infiltration and superficial ESFT with bone infiltration, especially in the fingers. Our aim is to review the most common types of small round-cell tumors included in the differential diagnosis of superficial ESFT, analyzing the histopathology, phenotype, and molecular alterations of each entity Elsevier Inc. All rights reserved. Superficial/cutaneous small round-cell tumors (SRCT) comprise a heterogeneous group of neoplasms including sarcoma, carcinoma, melanoma, and lymphomas. 1-8 Sarcomas make up a high proportion of mesenchymal neoplasms with cutaneous involvement, being described in the literature as superficial soft tissue sarcomas (SSTS). 2,4-13 This type of neoplasm is defined by its location above the muscle fascia without invasion of the fascia. 5,6,14 The importance of tumor depth has been discussed in several studies and has been previously shown to be an independent prognostic factor. 5,6,14 Among the cutaneous mesenchymal neoplasms, superficial sarcomas represent an atypical category with a behavioral difference characterized by a reduced metastatic risk because of the lower incidence Address reprint requests and correspondence: Antonio Llombart- Bosch, MD, PhD, Department of Pathology, Valencia University, Avenida Blasco Ibáñez, 15, Valencia, Spain. address: antonio.llombart@uv.es. of high-grade tumors and the smaller tumor size. 1-7,11,14-19 In contrast, deep tumors are usually larger than superficial neoplasms, probably because they are discovered later, thus increasing the metastatic risk. 1-7,11,14-19 SSTS may present as primary lesions or skin metastases 4-6,12 ; however, postirradiation soft tissue sarcoma, including the Ewing s sarcoma family of tumors (ESFT), as a secondary cancer arising in the same area irradiated for treatment of Hodgkin lymphoma has been described. 20 The incidence of cutaneous sarcoma metastases is very low (1%-2.6%), and in several series, the vast majority of patients developed skin metastases distant to the site of primary origin. 12,13 In addition, most patients with sarcoma skin metastases had developed previous metastases elsewhere and had a well-established primary history, thus facilitating a definite diagnosis. 12,13 Nevertheless, a number of patients reveal skin sarcoma metastasis with unknown primary source complicating the final diagnosis. 12, /$ -see front matter 2013 Elsevier Inc. All rights reserved. doi: /j.semdp

2 86 Seminars in Diagnostic Pathology, Vol 30, No 1, February 2013 Table 1 Small round cell tumour with cutaneous involvement Small round cell tumour (SRCT)/sarcomas with superficial involvement Ewing s sarcoma family of tumors Other round-cell sarcomas with superficial metastases: PDSS, round-cell MPNST, RMS, and epithelioid sarcoma Pediatric tumors with skin metastases (round-cell morphology) Malignant rhabdoid tumors (MRT) Neuroblastoma Other blastomas Round-cell carcinomas with cutaneous involvement, with or without EWSR1 rearrangement Merkel cell carcinoma (MCC) Round-cell myoepithelial carcinoma Neuroendocrine carcinoma Undifferentiated carcinoma Other round-cell tumors with superficial/skin infiltration Round-cell melanoma PDSS, poorly differentiated synovial sarcoma; MPNST, malignant peripheral nerve sheath tumor; RMS, rhabdomyosarcoma. The list of SRCT with superficial/cutaneous involvement comprises different categories (Table 1), as detailed in the following text. Superficial ESFT Although superficial location in Ewing s sarcoma seems to offer a better prognosis as reported by Collier et al, 14 the prognosis and evolution of superficial ESFT is still under debate. 1,3-8,12-14,17-28 Sporadic cases with superficial genetically confirmed ESFT and poor prognosis have also been reported. 6,8,27 In a review article, Collier et al 14 reported that ESFT are almost always localized, and of 78 patients already described in the literature, only 1 presented with distant metastatic disease and 1 with local node involvement at diagnosis. 14 In addition, the relapse rate for patients with cutaneous ESFT was approximately 15% compared with 30% for nonmetastatic bone and other soft tissue ESFT. Furthermore, 62 of the 78 patients (88.5%) remained alive with no evidence of disease; however, for bone and other soft tissue nonmetastatic ESFT, the overall survival rate was 72% with an event-free survival of 69% (14). Although these survival rates are not directly comparable, cutaneous ESFT seems to be less aggressive compared with deepseated ESFT. 7,8,14,27 It should be noted that the previously described review article is somewhat limited, as all the articles reviewed were case reports or small series. In addition, there were no clinical trials that analyzed the clinical aspect of superficial ESFT, and the treatment regimens were quite different on comparing all the series or cases reports. 14 Indeed, almost all the articles published on superficial ESFT appear convincing regarding the clinically favorable subtype of this aggressive neoplasm; however, no definitive conclusion can be proposed about their behavior. 7,8,14,18,19,27 In addition, Machado et al 27 recently described a series of superficial ESFT in which 3 cases evolved poorly, with death from disease and multiple metastases at 1 month, 5 month, and 2 years after the diagnosis. Of these 3 cases with poor outcome, 2 were located superficially in fingers and 1 was located in the thigh. Finger location can suggest a possible origin in bone in these cases and could explain the poor outcome; however, only 1 patient with finger location and poor outcome had osteolytic bone lesion. Furthermore, 1 patient with superficial finger tumor location and osteolytic lesion demonstrated by radiology remained without evidence of disease after 8 years (favorable evolution). 27 Considering the data available in the literature, several problems remain unresolved in superficial ESFT. These difficulties include the differential diagnosis between ESFT of bone (intraosseous or periosteal) with superficial infiltration and superficial ESFT with bone infiltration, especially in the fingers, as well as between deep-seated extraskeletal ESFT with cutaneous infiltration and cutaneous ESFT with deep-seated infiltration. 27 In particular, finger location in superficial ESFT represents a puzzling problem not discussed in the previous series of superficial ESFT, and it has been shown that radiology can offer additional clues regarding the probable tumor origin. Osteolytic bone lesions in fingers affected by superficial ESFT favor the possible origin in bone, although the possibility of superficial ESFT with bone infiltration cannot be excluded. In these cases the prognosis for ESFT of superficial origin (extraosseous) is generally favorable, unlike its counterpart originating in bone with secondary superficial/dermal infiltration. 6-8,13,14,19,20,27,28 Equivalent circumstances occur in deep-seated extraskeletal ESFT with cutaneous infiltration and cutaneous ESFT with deep-seated infiltration. 6-8,13,14,19,20,27,28 The histopathology of superficial ESFT is identical to its deep-seated counterpart and includes the conventional primitive neuroectodermal tumors (PNET) and atypical variants. 6-8,13,14,19,20,27,28 Conventional (Figures 1A and B) and PNET subtypes do not usually offer any problem in the differential diagnosis with other small round-cell sarcomas. Nevertheless, the increased incidence of the atypical variant complicates the differential diagnosis with several SRCT including Merkel cell carcinoma (MCC)/neuroendocrine carcinomas, lymphomas, myoepithelial carcinoma, round-cell melanomas, and other small round-cell sarcomas (undifferentiated synovial sarcoma and rhabdomyosarcoma [RMS]) and pediatric tumors (malignant rhabdoid tumors [MRT] and neuroblastoma). 1,3,6-8,10,13,14,18-20,27-37 In atypical ESFT, vascular-like areas have been reported (hemangioendothelial variant), and abundant hemosiderin deposits can be misinterpreted clinically as melanic pigment. 27,28 Moreover, the atypical vascular variant of ESFT can mimic a superficial vascular tumor, for instance angiosarcoma or angiomatoid fibrous histiocytoma. The immunohistochemical and ultrastructural studies provide additional and sometimes significant clues in the differential

3 Machado et al Spectrum of Differential Diagnosis 87 Figure 1 (A) Superficial Ewing s sarcoma family of tumors (ESFT) 20. (B) Conventional Ewing s sarcoma with skin infiltration 40. (C) CD99 strong membranous staining in tumor cells, negative staining in epidermis 20. (D) Caveolin-1 strong membranous and cytoplasmic staining in ESFT 20. (E) Fluorescent in situ hybridization analysis with EWSR1-positive translocation. diagnosis of superficial ESFT, mainly in cases with unusual morphology. 23,24,27,28,33,37 The immunoexpression of CD99, FLI-1, HNK-1, and caveolin-1 (CAV-1) seems to be very suggestive of ESFT as recently reported in a large series of ESFT 23 (Figures 1C and D). Furthermore, genetically confirmed Ewing s tumors with negative CD99 frequently reveal positive CAV-1 expression. 23 It is important to remark that several small round-cell sarcomas, for example undifferentiated synovial sarcoma or neural sarcoma, can reveal strong CD99 immunoexpression. 12,23,27,28,35-38 However, the staining pattern is usually cytoplasmic/diffuse and, to a lesser extent, strong membranous as seen in ESFT. Neuroendocrine immunomarkers (neuron-specific enolase [NSE], chromogranin-a, synaptophysin, or CD56) can be positive in ESFT, thus complicating the differential diagnosis with superficial primary or metastatic neuroendocrine carcinoma including MCC, especially when taking into account that MCC can reveal a high proportion of CD99 expression, and sporadic neuroendocrine tumor can harbor the EWSR1 rearrangement. 3,12,14,19,23,27,28,34-38 In contrast, MCC displays strong CK20 paranuclear staining, and practically, all ESFT so far reported fail to express CK20. 27,28,37 Epithelial differentiation (pan-ck expression) is detected in 20% of ESFT, particularly the atypical variant, which shows a high proportion of epithelial differentiation, mainly confirmed by immunohistochemistry (IHC) studies. 27,28,37 Thus, the differential diagnosis with other superficial SRCT with CK immunoexpression, for instance MCC/neuroendocrine carcinomas, undifferentiated carcinoma, synovial sarcoma, RMS, epithelioid sarcoma, cutaneous disseminated malignant rhabdoid tumor, and myoepithelial carcinoma, becomes complicated. 27,28,33,35,37 In addition, ESFT can also reveal epithelial membrane antigen (EMA) and carcinoembrionary antigen (CEA) expression; therefore, epithelial differentiation does not exclude the possibility of ESFT when dealing with superficial SRCT. EMA expression in ESFT is less frequent when compared with pan-ck expression; thus in superficial SRCT suggestive of ESFT with strong EMA expression, alternative diagnoses such as neuroendocrine carcinoma, undifferentiated carcinoma, myoepithelial carcinoma, plasmablastic lymphoma, or round-cell synovial sarcoma should be excluded. 27,28,37 Desmin expression is exceptional in ESFT, and its presence practically excludes the possibility of ESFT in superficial SRCT and suggests the possibility of a tumor with myogenic differentiation (RMS cutaneous metastasis). 36,38 Although histopathology, IHC, and ultrastructural studies provide significant clues in the diagnosis of superficial SRCT, additional studies are pivotal for achieving a definitive diagnosis. Indeed, in doubtful cases, final diagnosis is only possible through molecular confirmation (fluorescent in situ hybridization [FISH] and/or reverse transcription polymerase chain reaction) of the translocation specific to the sarcoma in question (Figure 1E). It is important to note that the list of neoplasms with EWSR1 rearrangement has increased in recent years, and this theoretically specific genetic alteration frequently observed in ESFT can also be detected in other sarcomas (clear-cell sarcoma, myxoid chondrosarcoma, round-cell liposarcoma, desmoplastic SRCT, angiomatoid fibrous histiocytoma, and small-cell osteosarcoma) 14,19,24,33-36,38,39 as well as carcinomas (myoepithelial carcinoma and neuroendocrine

4 88 Seminars in Diagnostic Pathology, Vol 30, No 1, February 2013 Figure 2 (A) Poorly differentiated synovial sarcoma with skin metastasis H/E 10. (B) Tumor nodule with small round-cell mimics atypical ESFT H/E 20. (C) High-grade small round-cell neoplasm with high mitotic index, poorly differentiated synovial sarcoma H/E 40. (D) Pan-CK (AE1/AE3) strong membranous staining in neoplastic cells of synovial sarcoma 20. (E) EMA positivity in synovial sarcoma. (F) Bcl-2 strong cytoplasmic and membranous staining in synovial sarcoma 10. (G) Fluorescent in situ hybridization analysis shows SYT rearrangement. Specific gene fusion detection provides very useful information in questionable cases. 14,19,24,33-36,38,39 Moreover, sporadic cases with morphological, IHC, and clinical characteristics very suggestive of ESFT fail to detect the EWSR1 rearrangement or specific gene fusion described in this type of tumors. The existence of negativetranslocation ESFT tumors has been demonstrated; thus suggesting that final diagnosis requires the integration of clinical, morphological, immunohistochemical, and molecular findings. 24,27,28,37,40 The differential diagnosis of superficial ESFT includes varying types of neoplastic lesions, as listed in Table 1. carcinoma). 14,19,24,33-36,38,39 Poorly differentiated synovial sarcoma (PDSS) with cutaneous infiltration PDSS frequently reveals morphological features very suggestive of ESFT. In addition, CD99, FLI-1, and CAV-1 can be positive in this type of neoplasm. 12,27,28,35-37,39 CK and/or EMA expression does not offer a definitive clue in the differential diagnosis with ESFT because epithelial differentiation is observed in Ewing s tumors, especially the atypical variant. Bcl-2 and SOX9 can be positive in synovial sarcoma, and TLE1 is also positive in the majority of synovial sarcomas. 35 In most cases, the genetic analysis reveals an SYT rearrangement; however, as far as we know, the SYT translocation has been not reported in ESFT. 35,36 Parallel to negative-translocation ESFT, a low percentage of synovial sarcomas also fail to demonstrate the SYT translocation; therefore, the existence of translocation-negative synovial sarcoma complicates the differential diagnosis; thus, the nomenclature undifferentiated small round cell sarcoma may be an appropriate one for these uncategorized tumors. Figure 2 shows a metastatic poorly differentiated monophasic synovial sarcoma to skin with unknown primary tumor in a young man (23 years old), where the immunohistochemical profile and FISH analysis supported the final diagnosis of synovial sarcoma. Round-cell malignant peripheral nerve sheath tumor (MPNST) Cutaneous metastases of MPNST are rare. The tumor nodules are usually composed of uniform epithelioid and/ or round cells with S100 immunoexpression. 12,30,35,41,42

5 Machado et al Spectrum of Differential Diagnosis 89 Figure 3 (A) Tumor nodule with dermal and subcutaneous tissue infiltration H/E 10. (B) Epithelioid and round-cell tumor with skin infiltration H/E 20. (C) Epithelioid and round-cell tumor with skin infiltration associated with lymphoid proliferation (epithelioid sarcoma) H/E 40. (D) Vimentin strong cytoplasmic staining in tumor cells and peritumoral normal tissue 40. (E) CEA positivity in tumor cells 40. (F) EMA strong immunoexpression in epithelioid sarcoma 40. MPNST can reveal CD99 positivity and sporadic epithelial marker expression (CK and EMA) similar to ESFT. 12,30,35,41,42 MPNST may reveal loss of INI1 staining, a finding which is very unusual in ESFT. Molecular analysis may be required in doubtful cases; nevertheless, the EWSR1/FLI-1 gene fusion has been described in sporadic MPNST complicating the differential diagnosis with ESFT. In fact, EWSR1 translocation by FISH has not been detected in such cases; thus, making the existence of true EWSR1/ FLI-1 gene fusion in sporadic cases of MPNST doubtful. Skin metastases RMS Aggressive pediatric RMS can reveal cutaneous metastasis, and the morphology can mimic other pediatric SRCT, mainly ESFT and MRT. 12,28,33,35,38,39,43 Most tumors display diffuse cytoplasmic staining for desmin, nuclear staining for myogenin and PAX5 immunopositivity. CD99, CD56, and CK can be positive in some cases, making the differential diagnosis with ESFT difficult; however, myogenic differentiation in Ewing s tumor is exceptional, with such cases being named biphenotypic sarcomas. 12,28,33,35,38,39,43 Heterologous rhabdomyoblastic differentiation in some tumors, for instance MCC, complicates the differential diagnosis with RMS. Epithelioid RMS is a novel morphologically distinct variant of RMS that closely mimics carcinoma, melanoma, or atypical ESFT. 43 In complex cases, molecular analysis can detect PAX3/FOXO1 or PAX7/FOXO1 fusion genes, particularly in alveolar RMS. Cutaneous epithelioid sarcoma Epithelioid sarcoma as a superficial nodule may be clinically misinterpreted as a chronic ulcer, and the very unusual round-cell morphology can resemble superficial atypical ESFT. CK, VIM, EMA, CD34, and calponin are frequently positive in epithelioid sarcoma, and most tumors reveal INI1/BAF-47 negative immunostaining. 12,34,35,44-48 CD34 expression in ESFT is exceptional, and so far, there are no Ewing tumors with loss of INI1. Figure 3 shows a cutaneous metastasis of round/epithelioid tumor in a young patient (20-year-old man) with a previous history of epithelioid sarcoma. Superficial/skin metastases malignant rhabdoid tumor Malignant rhabdoid tumor can reveal PNET-like areas mimicking ESFT (Figures 4A-C). Also, the tumor shows overlapping morphological and immunohistochemical features with other pediatric and nonpediatric SRCT because tumor

6 90 Seminars in Diagnostic Pathology, Vol 30, No 1, February 2013 Figure 4 (A) Tumor nodule with subcutaneous tissue infiltration in disseminated malignant rhabdoid tumor (MRT) H/E 10. (B) Epithelioid and round-cell tumor subcutaneous infiltration H/E 20. (C) Tumor cells in MRT with abundant cytoplasm and focal rhabdoid morphology H/E 100. (D) Absent INI1 immunoexpression in MRT 40. (E) Tumor nodule with subcutaneous tissue infiltration in neuroblastoma H/E 10. (F) Undifferentiated neuroblastoma with subcutaneous infiltration H/E 20. cells can show a polyphenotypic pattern with CD99, epithelial markers (CK and EMA), neural markers (S100, NSE, synaptophysin, GFAP), myogenic (SMA and desmin), and frequent claudin-1 immunoexpression. 33,47 Although ESFT can reveal a polyphenotypic profile, INI-1 is characteristically positive in this family of tumors and regularly negative in MRT (Figure 4D). An aggressive congenital form of MRT has been recognized, which is often disseminated with superficial infiltration as described by Machado et al. 33 Neuroblastoma and other blastomas with skin metastases Neuroblastomas and other blastomas, for instance Wilms tumor, can be recognized not only by their clinical presentation (pediatric patients, intra-abdominal tumor, or adrenal neoplasm), but also by their expression of NB84, tyrosine hydroxylase, NSE, CD56, and neurofilament proteins Although cutaneous involvement by pediatric blastomas is an infrequent event, the tumor nodules can resemble cutaneous infiltration by ESFT (Figures 4E and F). Neuroblastomas are usually negative for CD99 and lack epithelial and/or myogenic differentiation. Merkel cell carcinoma The superficial location of the tumor and the round-cell morphology complicate the differential diagnosis between ESFT (mostly the atypical variant) and MCC. In addition, the epithelial differentiation in ESFT and CD99 expression in 30% of MCC make the differential diagnosis difficult in some cases. 27,28,37,55,56 Fortunately, CK20 immunoreactivity is expected in MCC and practically absent in ESFT (Figure 5). Neuroendocrine differentiation can be present in both tumors; therefore, this finding does not contribute toward the differential diagnosis. Neuroendocrine carcinoma/small cell carcinoma with skin metastasis The histopathology of neuroendocrine carcinoma is characteristic in most cases; however, the poorly differentiated variant can resemble several SRCT, including atypical ESFT. The differential diagnosis between cutaneous atypical ESFT and skin metastasis of neuroendocrine carcinoma has been further complicated by the recent publication of one case diagnosed as neuroendocrine tumor and showing

7 Machado et al Spectrum of Differential Diagnosis 91 Figure 5 (A) Merkel cell carcinoma (MCC) with superficial dermal infiltration H/E 10. (B) Tumor nodules with small round-cell morphology and dermal infiltration H/E 20. (C) MCC with small round-cell morphology H/E 40. (D) Dot-like CK20 expression in MCC 20. (E) Strong CK20 immunoexpression with paranuclear accentuation 40. the EWSR1 translocation detected by FISH. 57 Although, a gene fusion study was not performed in this case, a molecular analysis in neuroendocrine carcinoma would probably fail to detect any of the gene fusions already described in ESFT. Furthermore, both ESFT and neuroendocrine tumor can reveal synaptophysin, chromogranin-a, and CK positivity, and although EMA is more frequently expressed in neuroendocrine carcinoma, up to 6% of ESFT can show EMA expression, albeit less intense. 27,28,37,57 Generally, the clinical history and a serologic study of neuroendocrine markers can offer additional information to reach the final diagnosis. Although small-cell carcinoma can also reveal positive CD99 staining, the clinical context and the histopathology are usually different when compared with ESFT (nonpediatric patient, previous lung neoplasm). In addition, positive TTF-1 nuclear immunoexpression is consistent with cutaneous metastasis of small-cell carcinoma Cutaneous myoepithelial carcinoma Atypical ESFT, particularly with adamantinoma-like pattern, can resemble myoepithelial carcinoma. 27,28,37 Myoepithelial carcinomas express epithelial markers (CK and EMA), S100, GFAP, or calponin, and they frequently lack myogenic markers CD99-positive expression can be present in myoepithelial carcinoma, and along with neuroendocrine carcinoma, myoepithelial carcinoma can also reveal the EWSR1 rearrangement that causes difficulties in the differential diagnosis with atypical ESFT. 64 Although ESFT and myoepithelial carcinoma show overlapping histologic, immunophenotypic, and FISH features, they have different gene fusions at molecular level by reverse transcription polymerase chain reaction study, 27,28,37 and molecular analysis is able to detect a specific gene fusion for either ESFT or myoepithelial carcinoma in most of the tumors. Undifferentiated carcinoma Skin infiltration by undifferentiated round-cell tumor with epithelial differentiation and without neuroendocrine, myogenic, melanic, or any other type of differentiation at histopathological and immunohistochemical level is highly indicative of undifferentiated carcinoma Undifferentiated carcinoma can reveal CD99 expression as shown in Figure 6, and the differential diagnosis with translocationnegative atypical ESFT is complex, especially in a confused clinical setting. In superficial tumors with undifferentiated round-cell morphology and EMA expression without CK expression, the possibility of plasmablastic lymphoma should be excluded through additional staining for CD138, CD38, CD30, and MUM

8 92 Seminars in Diagnostic Pathology, Vol 30, No 1, February 2013 Figure 6 (A) Small round-cell tumor (undifferentiated carcinoma) with skin infiltration H/E 10. (B) Tumor cells mimics superficial atypical ESFT or MCC H/E 20. (C) Tumor cells with high apoptotic index resembling high-grade lymphoma H/E 40. (D) CK (AE1/AE3) strong cytoplasmic and membranous staining in undifferentiated carcinoma. (E) EMA positivity in undifferentiated carcinoma. (F) CD99 focal positivity in large tumor cells. Round-cell melanoma Round-cell melanoma represents a very unusual variant compared with other melanoma variants. 73 In superficial tumors with abundant hemosiderin pigment deposition, the clinical differential diagnosis between vascular/hemangioendothelial ESFT and melanoma is particularly complicated, whereas the histopathology and IHC can usually offer additional clues for the differential diagnosis. 27 Melanic markers (HMB-45 and Melan-A) are consistently negative in ESFT and positive in almost all melanomas. 27,28 References 1. Sexton CW, White WL: Primary cutaneous Ewing s family sarcoma. Report of a case with immunostaining for glycoprotein p30/32 mic2. Am J Dermatopathol 18: , Brooks AD, Heslin MJ, Leung DH, et al: Superficial extremity soft tissue sarcoma: an analysis of prognostic factors. Ann Surg Oncol 5:41-47, Hasegawa SL, Davison JM, Rutten A, et al: Primary cutaneous Ewing s sarcoma: immunophenotypic and molecular cytogenetic evaluation of five cases. Am J Surg Pathol 22: , Mentzel T: Cutaneous mesenchymal neoplasms versus mesenchymal neoplasms of subcutaneous and deep soft tissue. Similarities and differences. [Article in German] Pathologe 23:97-106, Lachenmayer A, Yang Q, Eisenberger CF, et al: Superficial soft tissue sarcomas of the extremities and trunk. World J Surg 33: , Salas S, Stoeckle E, Collin F, et al: Superficial soft tissue sarcomas (S-STS): a study of 367 patients from the French Sarcoma Group (FSG) database. Eur J Cancer 45: , Shingde MV, Buckland M, Busam KJ, et al: Primary cutaneous Ewing sarcoma/primitive neuroectodermal tumour: a clinicopathological analysis of seven cases highlighting diagnostic pitfalls and the role of FISH testing in diagnosis. J Clin Pathol 62: , Terrier-Lacombe MJ, Guillou L, Chibon F, et al: Superficial primitive Ewing s sarcoma: a clinicopathologic and molecular cytogenetic analysis of 14 cases. Mod Pathol 22:87-94, Fisher C: Pathology of soft tissue sarcomas. Cancer Treat Res 44:1-21, Fisher C: Soft tissue sarcomas: diagnosis, classification and prognostic factors. Br J Plast Surg 49:27-33, Orbach D, Rey A, Oberlin O, et al: Soft tissue sarcoma or malignant mesenchymal tumors in the first year of life: experience of the International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Committee. J Clin Oncol 23: , Mentzel T: Sarcomas of the skin in the elderly. Clin Dermatol 29:80-90, Wang WL, Bones-Valentin RA, Prieto VG, et al: Sarcoma metastases to the skin: a clinicopathologic study of 65 patients. Cancer; in press 14. Collier AB 3rd, Simpson L, Monteleone P: Cutaneous Ewing sarcoma: report of 2 cases and literature review of presentation, treatment, and outcome of 76 other reported cases. J Pediatr Hematol Oncol 33: , ten Harkel AD, Hogendoorn PC, Beckers RC, et al: Skin metastases of osteogenic sarcoma: a case report with review of the literature. J Pediatr Hematol Oncol 19: , Mentzel T, Requena L, Kaddu S, et al: Cutaneous myoepithelial neoplasms: clinicopathologic and immunohistochemical study of 20 cases suggesting a continuous spectrum ranging from benign mixed

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