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Rhabdomyosarcomas in adults: classification and differential diagnosis
Mini-symposium: soft tissue tumour pathology
Rhabdomyosarcomas in adults: classification and differential diagnosis
Recognition of the correct diagnosis and histological subtype of RMS is of critical importance in the therapy of this disease. Treatment of RMS in adults is largely based on the North American and European Cooperative Groups for the treatment of children with RMS, and requires a multimodality approach that includes surgery, radiotherapy and chemotherapeutic regimens, often comprising a combination of drugs such as vincristine and dactinomycin with either cyclophosphamide or isophosphamide.3 Additionally, RMS may be present as a component of heterologous differentiation in other soft tissue sarcomas, such as dedifferentiated liposarcoma and malignant peripheral nerve sheath tumour (also known as malignant Triton tumour). Much less commonly, this form of heterologous differentiation is also present in other non-mesenchymal neoplasms, such as poorly differentiated carcinomas and germ cell tumours. This article will briefly review paediatric RMS, as context to discuss the clinicopathological characteristics of RMS in adults, the different histological variants, heterologous rhabdomyoblastic differentiation in other tumours and the approach to differential diagnosis.
Alessandra F Nascimento
Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. In contrast, RMS is rare in adults, accounting for <1% of all malignancies. It is subdivided into three main subtypes, namely embryonal, alveolar and pleomorphic RMS. Embryonal and alveolar RMS are nearly exclusive to the paediatric population, whereas pleomorphic RMS generally affects older adults. In recent years, spindle cell and sclerosing variants of RMS have also been recognized in adults. The diagnosis of RMS depends on the confirmatory detection of skeletal muscle markers such as desmin and Myf-4 in neoplastic cells. The differential diagnosis includes small round blue cell tumours and pleomorphic sarcomas, among other entities. RMS may also be present as a heterologous component of other tumour types, such as malignant peripheral nerve sheath tumour and dedifferentiated liposarcoma. Because of the scarcity of data in the adult population, staging and treatment of adult RMS is usually based on modified paediatric protocols. However, prognosis is worse in adults when compared to children, with an overall 5-year survival of less than 30%. This review will discuss the clinicopathological characteristics of RMS in adults, the different histological variants, heterologous rhabdomyoblastic differentiation in other tumour types and differential diagnosis.
Paediatric rhabdomyosarcoma In infants and children younger than 14 years of age, embryonal RMS is the most common subtype, affecting 3.0 in a million in this age group, followed by alveolar RMS.2 Embryonal RMS shows a distinct predilection for visceral sites, such as the genitourinary tract, followed by the head and neck, and extremities.1 In contrast, alveolar RMS affects the head and neck, extremities and trunk equally, and is much less frequent in visceral locations.1 Morphologically, embryonal RMS is characterized by a polymorphous proliferation of small spindle cells with rounded to oval or elongated, hyperchromatic nuclei, inconspicuous nucleoli and a small amount of pale indistinct cytoplasm, arranged haphazardly in sheets or in broad fascicles (Figure 1a). Larger cells, also known as ‘strap cells’ or ‘tadpole cells’, with more abundant eosinophilic cytoplasm and occasional cross striations, are usually scattered throughout the lesion in variable amounts (Figure 1b), and represent more differentiated rhabdomyoblasts. These cells are particularly frequent in tumours of patients who have undergone chemotherapy.4,5 The stroma is generally composed of loose fibrous tissue, with focal or extensive myxoid change. Rarely, embryonal RMS may contain large atypical hyperchromatic cells (known as the ‘anaplastic’ variant), which may be focal or diffuse in an otherwise typical embryonal RMS (Figure 2).6 The presence of these anaplastic features may also be noted in alveolar RMS, but is more common in the embryonal variant.6 This finding portends a worse prognosis.6 In the botryoid variant of embryonal RMS, the neoplastic cells form a distinctive condensed, hypercellular area immediately under the epithelial surface, known as the ‘cambium layer’. This subepithelial growth pattern imparts the characteristic macroscopic nodular appearance to this variant of RMS (resembling ‘bunches of grapes’ within visceral lumina). Alveolar RMS is histologically characterized by a nested proliferation of round to epithelioid cells separated by thick fibrous septa, which mimic alveolar structures (Figure 3a). The cells composing this neoplasm are usually large and show a monotonous appearance with round, hyperchromatic nuclei, prominent
Keywords adults; alveolar; embryonal; pleomorphic; rhabdomyosarcoma; spindle cell; sclerosing; sarcoma
Introduction Rhabdomyosarcoma (RMS) is a highly aggressive mesenchymal neoplasm that shows skeletal muscle differentiation. In the current World Health Organization Classification of Soft Tissue and Bone Neoplasms, RMS is divided into three distinct subtypes: embryonal, alveolar and pleomorphic.1 Embryonal and alveolar RMS are the most common soft tissue sarcomas in the paediatric population, affecting approximately 4.6 in a million children under the age of 14,2 whereas pleomorphic RMS generally affect adults. More recently, other variants, such as spindle cell and sclerosing RMS, have been recognized in the adult population. Overall, RMS is a rare disease in adulthood and, therefore, the clinicopathological characteristics, natural history and treatment options are not as well established in this population.
Alessandra F Nascimento MD is at the Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.
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a Alveolar rhabdomyosarcoma is characterized by the presence of nests of malignant cells separated by thick fibrous septa. b The neoplastic cells have round nuclei, prominent nucleoli and small to moderate amounts of cytoplasm, and scattered multinucleated cells may be seen throughout the tumour.
a Embryonal rhabdomyosarcoma showing a fascicular arrangement of small spindled cells with hyperchromatic nuclei and scant cytoplasm. b ‘Strap cells’ are present throughout the lesion. Figure 1
Figure 3
ucleoli and a small to moderate amount of cytoplasm (Figure 3b). n Scattered rhabdomyoblasts containing large amounts of brightly eosinophilic cytoplasm are noted. The cells in the central portion of the nests tend to be discohesive and smaller, while the ones at the periphery of the nests are adherent to the fibrous septa and show larger amounts of cytoplasm. Multinucleated giant cells can be encountered throughout the tumour (Figure 3b). In the solid variant of alveolar RMS, the neoplastic cells form sheets, and there is less prominent fibrous septation (Figure 4). The alveolar growth pattern is not present; however, the cytological features are similar to those of classic alveolar RMS. Rarely, cases showing juxtaposed embryonal and alveolar cytomorphology may be seen.1 Because of their natural history, these cases are best regarded as alveolar RMS.1 Although there are no specific karyotypic abnormalities that characterize embryonal RMS, a subset of cases shows loss of heterozygosity (LOH) at chromosome region 11p15.5, which contains several imprinted genes such as IGF2, H19 and p57.7,8 The hypothesis for the pathogenesis of embryonal RMS is that there is LOH of the active imprinted allele.1
Figure 2 Anaplastic variant of embryonal rhabdomyosarcoma (RMS) is characterized by scattered large atypical cells in a background of otherwise typical embryonal RMS.
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Mini-symposium: soft tissue tumour pathology
in a dense desmoplastic stroma. The cells have hyperchromatic nuclei, indistinct nucleoli and scant cytoplasm. Immunohistochemistry is helpful in establishing the diagnosis of DSRCT. Characteristically, the vast majority of these lesions show expression of cytokeratins, epithelial membrane antigen (EMA), neuron-specific enolase (NSE) and desmin; however, these tumours are negative for fast myosin and myf-4. Cytogenetics is also helpful in the diagnosis of DSRCT. These tumours show a typical t(11;22) (p13;q12) translocation, in which the WT1 gene on chromosome 11 is fused with the EWS gene on chromosome 22. The prognosis of DSRCT is poor even with therapy. ES/PNET characteristically occurs in adolescents and young adults; however, older adults may also be affected. Tumours present in bone or soft tissue, and are characterized by a proliferation of small round monotonous cells with scant cytoplasm. Although CD99 is not a specific marker for ES/PNET, it typically shows a prominent membranous pattern of staining of the vast majority of neoplastic cells. Other markers that may also occasionally be positive in ES/PNET include keratins, S-100 and NSE. Approximately 85% of cases show a reciprocal balanced translocation between chromosomes 11 and 22, namely, t(11;22) (q24;q12), which juxtaposes the EWS gene on chromosome 22 and the FLI1 gene on chromosome 11.1 The remaining 10–15% of cases contain other variant translocations, most involving the EWS gene.1 Similar to RMS, ES/PNET are also treated with specific chemotherapeutic regimens, and therefore, precise diagnosis is very important.
Figure 4 In the solid variant of alveolar rhabdomyosarcoma, fibrous septa are not as prominent and tumour cells are arranged in sheets.
Alveolar RMS is characterized by two reciprocal translocations, namely t(2;13) (q35;q14) and t(1;13) (p36;q14). The former translocation juxtaposes the PAX3 gene on chromosome 2 with the FKHR (FOX01A) gene on chromosome 13, and the latter juxtaposes the PAX7 gene on chromosome 1 with the FKHR (FOX01A) gene.9–11 The chimeric fusion proteins act as transcription factors.12,13 In the differential diagnosis with embryonal and alveolar RMS, the main tumours to be considered are in the category of the so-called ‘small round blue cell tumours’, which in adults should include small cell carcinoma, Merkel cell carcinoma and small cell malignant melanoma. Less commonly in this population, desmoplastic small round cell tumour (DSRCT) and Ewing sarcoma/peripheral neuroectodermal tumour (ES/PNET) may also be diagnosed. Small cell carcinoma affects mainly adults, arises in virtually any organ system and carries a poor prognosis. It is histologically characterized by small cells with round, hyperchromatic nuclei, finely granular chromatin pattern (‘salt and pepper’ pattern), inconspicuous nucleoli and scant cytoplasm. Necrosis, numerous mitoses and prominent ‘crush’ artefact are frequent features in small cell carcinoma. The neoplastic cells are positive for cytokeratins and neuroendocrine markers, such as chromogranin and synaptophysin. Merkel cell carcinoma shares morphological similarities with small cell carcinoma, and also expresses cytokeratins. Unlike small cell carcinoma, however, Merkel cell carcinoma expresses cytokeratin 20 (CK20) in a characteristic perinuclear dot-like pattern. Small cell malignant melanoma is positive for S-100 protein as well as for other melanocytic markers, such as Melan-A, HMB-45 and MiTF. Importantly, small cell carcinoma, Merkel cell carcinoma and small cell malignant melanoma are negative for the skeletal muscle markers myogenin (myf-4) and fast myosin. DSRCT affects mainly children and young adults but may also rarely be seen in older adults. In the paediatric population it shows a marked male predilection. Patients characteristically present with large intra-abdominal tumour masses, which are commonly multiple. Microscopically, DSRCT is characterized by nests of monotonous, small, round to slightly spindled cells embedded
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Pleomorphic rhabdomyosarcoma Pleomorphic RMS is rare in patients under the age of 40, with only a few cases described in the paediatric population.14 Although embryonal RMS was reported to be the commonest variant in two large series analyzing adults with RMS, comprising approximately 50% of the cases,15,16 while alveolar RMS was the most common variant in another series,17 affecting 56% of the patient, these findings may reflect bias of the referral centres. Pleomorphic RMS was the most common variant in two other large series of adult RMS,18,19 which is more in keeping with this author’s experience. In all studies, males were slightly more affected than females, comprising roughly 60% of the cases.15–19 Caucasians appear to be almost exclusively affected, accounting for over 80% of the cases in adults.15,18 Pleomorphic RMS arises predominantly in the extremities, in particular the lower limbs. Overall, RMS presents as a soft tissue mass which most commonly causes mass effect and/or visceral obstruction depending on its anatomical location. Median tumour size is approximately 6 cm.15–17,19 Tumours located on the extremities and in visceral locations tend to be bigger as compared to those located in the head and neck region.15–17,19 Pleomorphic RMS is a rapidly growing, expansile lesion that is often well delineated, surrounded by a fibrous pseudocapsule. The cut surface is usually tan and fleshy or firm, with variable extent of haemorrhage and necrosis. Pleomorphic RMS is characterized by a proliferation of rounded or spindled pleomorphic cells and a variable mixture of large atypical polygonal, strap-like cells showing abundant brightly eosinophilic cytoplasm (Figure 5). In the largest series of pleomorphic RMS, these tumours were subclassified into 540
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Mini-symposium: soft tissue tumour pathology
among the different subtypes. It is quite extensively expressed by the cells of alveolar RMS as compared to embryonal, pleomorphic and spindle cell/sclerosing variants, in which expression of these markers may be somewhat limited.21,22 More differentiated cells within these lesions may also express fast myosin. In this author’s experience and that of others, although expression of MyoD1, another myogenic transcription factor, is quite sensitive for skeletal muscle differentiation, it lacks specificity, limiting its utility as a diagnostic tool.23 To date, karyotypes of only seven cases of pleomorphic RMS have been reported.24 All cases showed highly complex karyotypes, including several structural and numerical chromosomal abnormalities, none of which appears to be specific for this disease.24 The differential diagnosis of pleomorphic RMS includes other pleomorphic sarcomas such as high-grade myxofibrosarcoma (MFS), pleomorphic leiomyosarcoma (LMS) and pleomorphic liposarcoma (LPS). MFS is among the most common sarcomas in older adults and affects mainly the extremities, in particular the lower limbs. It is characterized by a multinodular growth pattern and alternation between myxoid, hypocellular areas and solid, hypercellular areas. Within the myxoid areas, a typical vascular pattern composed of long thin-walled curvilinear vessels is recognized. Neoplastic cells tend to concentrate around these vessels. Additionally, there are large cells with vacuolated cytoplasm (‘pseudolipoblasts’) scattered throughout this myxoid area. In hypercellular areas, this vascular pattern is usually absent. In high-grade MFS, there is marked nuclear pleomorphism, frequent mitoses and necrosis. MFS shows neither expression of any definite immunostains nor any specific cytogenetic abnormality and, therefore, its diagnosis relies solely on morphological recognition. Pleomorphic LMS is a disease of adults with a male predominance and it most commonly affects extremities.25 It is characterized by a haphazard proliferation of bizarre, atypical and multinucleated cells in a background of spindle cells with blunt-ended nuclei and abundant eosinophils, consistent with conventional leiomyosarcoma. Pleomorphic LMS is positive for α-smooth muscle actin (SMA), desmin and h-caldesmon in many cases; however, myf-4 and fast myosin are consistently negative. Therefore, correct identification of pleomorphic LMS relies on the identification of conventional LMS and confirmatory immunostains. Pleomorphic LPS is a rare sarcoma of older adults, affecting predominantly the lower extremities.26,27 Histologically, it is a pleomorphic neoplasm with spindle cell or epithelioid features with at least focal areas containing large multivacuolated lipoblasts. Additionally, cells may have intracytoplasmic eosinophilic globules.27 These lesions show variable, inconsistent expression of markers such as SMA, S-100, keratins, EMA and desmin in a subset of cases.26,27 They are negative for myf-4 and fast myosin. The diagnosis of pleomorphic LPS is often one of exclusion and requires careful sampling of the lesion.
Pleomorphic rhabdomyosarcoma is characterized by the presence of large polygonal rhabdomyoblasts in a background of small to medium sized rounded a to spindled b cells. Figure 5
three histological variants: classic (type I), round cell (type II) and spindle cell (type III).20 In the first, large atypical rhabdomyoblasts with abundant eosinophilic cytoplasm form sheets.20 In the round cell variant, there are clusters of these large rhabdomyoblasts in a background of rounded medium sized cells.20 Lastly, the spindle cell variant demonstrates a ‘malignant fibrous histiocytomas (MFH)-like’ background with only scattered large rhabdomyoblasts.20 In routine practice, subclassification into types I, II and III is unnecessary, as it does not have implications for therapy or prognosis.20 Immunoperoxidase studies play a critical role in the diagnosis of RMS. These tumours show phenotypic evidence of muscle differentiation, and thus, are positive for markers such as muscle-specific actin (HHF-35) and desmin. However, none of these markers is specific for skeletal muscle differentiation, and are also positive in smooth muscle and myofibroblastic neoplasms, among others. As a sine qua non criterion for the diagnosis of RMS and its variants, expression of skeletal muscle markers such as myf-4, a myogenic transcription factor, and fast myosin are necessary. Nuclear positivity for myf-4 is noted in all cases of rhabdomyosarcoma; however, its expression is quite variable
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Spindle cell/sclerosing rhabdomyosarcoma Spindle cell RMS was initially described in the paediatric population by Cavazzana et al. as a rare variant that occurred mainly in males, arose preferentially in the paratesticular area, and carried 541
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a better prognosis when compared with other RMS variants.28 In 1998, this variant was also described in adults and, subsequently, larger adult series showed it to be a disease predominantly affecting males with a marked predilection for the head and neck area.29–31 Because of this marked difference between the clinical findings in children and adults with spindle cell RMS, it is possible that these two neoplasm in fact represent different disease processes. Although this author believes that the spindle cell variant represents a distinct subtype of RMS, in the current WHO Classification of Soft Tissue and Bone Tumours, it is included as a variant of embryonal RMS.1 Histologically, spindle cell RMS is characterized by a proliferation of spindle cells arranged in a storiform pattern or in long fascicles (Figure 6a). The cells show oval, elongated and tapered nuclei, vesicular chromatin, inconspicuous nucleoli and scant pale cytoplasm. Scattered larger polygonal cells with abundant brightly eosinophilic cytoplasm (rhabdomyoblasts) are usually present in the neoplasm, and vary in number from rare to frequent (Figure 6b). Sclerosing RMS is a more recently described unusual subtype of RMS which appears to affect males and females equally,
and occurs more frequently on the limbs.32–34 It is characterized by dense stromal sclerosis which leads to tumour cells being arranged in nests and cords, often imparting a pseudovascular appearance to the neoplasm (Figure 7). Although some believe sclerosing RMS is a distinct subtype, this phenomenon may be focally or diffusely present in the spindle cell variant of RMS, which argues that sclerosing and spindle cell RMS may instead represent morphological variants of the same disease.30,31 One reported case of sclerosing RMS showed a complex karyotype with abnormalities similar to those seen in embryonal RMS, suggesting that this entity may indeed be in the morphological spectrum of embryonal RMS.35 However, this remains to be validated. The differential diagnosis of spindle cell RMS includes spindle cell carcinoma, desmoplastic or spindle cell malignant melanoma, and conventional LMS. Spindle cell carcinoma and desmoplastic melanoma are relatively common disorders of older adults, and diagnosis of these entities depends on the immunodetection of keratins and melanocytic markers in the neoplastic cells, respectively. Conventional LMS is among the most common sarcomas arising in the retroperitoneum, as well as in association with large calibre veins, where they predominantly affect females.1 When LMS arises in somatic soft tissues of the extremities, males and females are equally affected.1 Morphologically, it is characterized by a fascicular spindle cell proliferation with elongated, bluntended nuclei, vesicular chromatin, variably prominent nucleoli and abundant brightly eosinophilic cytoplasm. It expresses desmin, α-SMA and h-caldesmon in the majority of cases. However, skeletal muscle markers (myf-4 and fast myosin) are negative. Sclerosing RMS should be differentiated from angiosarcoma and osteosarcoma. Angiosarcoma, when morphologically high grade, may be composed of fascicles of spindle cells with only focal poorly-formed vascular structures. Unlike RMS, angiosarcomas are positive for at least one marker of endothelial differentiation, namely CD31, CD34, D2-40, FLI-1 and/or von Willebrand factor (vWF). Keratins may be positive in a subset of cases. In contrast to RMS, fast myosin and myf-4 are negative. There are no characteristic cytogenetic findings in angiosarcoma.
Spindle cell rhabdomyosarcoma is a fascicular spindle cell neoplasm a composed of cells with elongated and hyperchromatic nuclei and scant cytoplasm, with scattered rhabdomyoblasts b. Figure 7 Sclerosing rhabdomyosarcoma shows dense hyalinized stroma which imparts a pseudovascular arrangement to tumour cells.
Figure 6
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DDLPS usually arises as a deep-seated large mass in the retroperitoneum, mediastinum or spermatic cord of middle-aged and older adults. It is only very rarely seen in the extremities. By current definition, it is characterized by abrupt transition from well-differentiated liposarcoma (WDLPS) into a non-lipogenic sarcoma. It may arise in recurrent WDLPS or as the initial presentation of liposarcoma. Interestingly, it maintains similar karyotypic abnormalities that typify WDLPS/atypical lipomatous tumours, i.e. giant markers and ring chromosomes derived from amplified material from chromosome 12. It is important to correctly differentiate between DDLPS with heterologous rhabdomyosarcomatous differentiation and RMS because the former carries a high risk of local recurrence but a relatively low metastatic potential of approximately 15–20%, despite the presence of rhabdomyosarcomatous or any other heterologous elements,37 while RMS is aggressive and often requires systemic therapy. Histologically, up to 10% of DDLPS demonstrate focal heterologous elements, such as rhabdomyosarcoma, leiomyosarcoma and osteosarcoma, among others.1 Heterologous rhabdomyosarcomatous differentiation within DDLPS is characterized by the presence of scattered large polygonal rhabdomyoblasts with eosinophilic cytoplasm. DDLPS will consistently express markers such as MDM2 and CDK4,38 two oncogenes located on the long arm of chromosome 12 (at the q13–q15 region) that are overexpressed in WDLPS and DDLPS. However, these markers have to be interpreted with caution and within the appropriate clinicopathological context because they may also be expressed in a small subset of RMS.38 MPNST may occur sporadically or in association with neurofibromatosis type 1 (NF1; von Recklinghausen disease). It arises de novo or as malignant transformation of a pre-existing neurofibroma. It affects predominantly adults in a wide age range, with no gender predilection. More commonly, it is encountered in the somatic soft tissues of the extremities but may also be seen in the retroperitoneum. Histologically, MPNST is characterized by a proliferation of spindle cells with tapered, elongated and hyperchromatic nuclei, variably prominent nucleoli and scant pale cytoplasm. There is often a characteristic alternation between less cellular areas with variably myxoid stroma and hypercellular fibrous areas. In approximately 15% of cases of MPNST, heterologous elements, such as osteosarcoma, chondrosarcoma, rhabdomyosarcoma and, rarely, angiosarcoma may be identified.39 This phenomenon is particularly common in patients with NF1.39 Heterologous rhabdomyosarcomatous differentiation in MPNST (also known as malignant Triton tumour) is usually multifocal within the neoplasm and is characterized by the presence of clusters of large atypical cells as well as small, primitive-appearing rhabdomyoblasts. Recognition of this phenomenon is of particular importance because patients with malignant Triton tumour show a worse prognosis when compared with those not showing this aberrant differentiation.40,41 Rarely, MPNST may undergo subtotal heterologous rhabdomyosarcomatous differentiation, making histological distinction from RMS virtually impossible. Clinical history is of critical importance in the diagnosis in this circumstance. MPNST is positive for S-100 protein and glial fibrillary antigen protein (GFAP) in a subset of cases (approximately 30%), and expression of these markers may be quite focal, particularly
The diagnosis of osteosarcoma depends on the identification of osteoid formation by neoplastic cells. In osteosarcoma the matrix often undergoes calcification and osteoclasts may be identified. Giant cells and calcification are not features of sclerosing RMS. Additionally, osteosarcoma is negative for specific skeletal muscle markers.
Staging, prognosis and treatment Staging of RMS is based on surgical resectability and pathological extent of disease. According to the Intergroup Rhabdomyosarcoma Study group, patients with RMS should be subclassified into four stages or groups, as follows: stage I includes patients with localized disease, amenable to complete surgical resection; in stage II disease, there is microscopic evidence of disease at resection margins of the specimen or in regional lymph nodes; patients with stage III have macroscopic residual disease after surgery with or without lymph node metastasis; and stage IV includes patients with metastasis to distant sites.36 Most adult patients present with advanced disease stages (stages III or IV).15–17,19 The treatment of adults with RMS is not uniform in the literature because of the rarity of this neoplasm in this population. Most series analyzing adult patients with RMS demonstrate a non-standardized multimodality approach including surgery, chemotherapy (mostly as part of clinical trial protocols) and radiation therapy, similar to what is offered to the paediatric group.15–19 Radiation therapy includes both external beam radiotherapy and brachytherapy.15–17,19 The most commonly used chemotherapeutic agents included vincristine, actinomycin, cyclophosphamide, doxorubicin, isophosphamide and etoposide, among others.15–17,19 Overall, there is a higher mortality rate in this population as compared to children, with 5-year survival averaging 35% in most larger studies.15–19 The most important predictors of poor outcome common to all studies are tumour size, margin status after surgical resection, and presence of metastasis at diagnosis.15–19 Although age and histological subtype appear to be important prognostic indicators in the paediatric population, the influence of these parameters in adults is controversial.15–19
Tumours with heterologous rhabdomyosarcomatous differentiation Heterologous rhabdomyosarcomatous differentiation is a relatively common phenomenon seen in mesenchymal neoplasms, such as dedifferentiated liposarcoma (DDLPS) and malignant peripheral nerve sheath tumour (MPNST). Moreover, it may also be seen, albeit less commonly, in other non-mesenchymal tumours such as malignant mixed Müllerian tumour (MMMT) or carcinosarcoma, poorly differentiated carcinoma and germ cell tumour (GCT). Importantly, because the RMS component is in fact true heterologous differentiation, immunoperoxidase markers such as desmin and myf-4 will be positive in a subset of neoplastic cells. The diagnosis of entities with heterologous rhabdomyosarcomatous differentiation will depend on histological identification of other elements that compose the neoplasm by thorough sampling of the lesion, as well as the clinical context.
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in high-grade lesions. In these cases, the diagnosis of MPNST requires correlation with clinical history, typical histological features and/or association with a nerve. MMMT or carcinosarcoma is by definition a malignant neoplasm of the gynaecological tract composed of an epithelial as well as a mesenchymal component, which is believed to arise as an aberrant differentiation of the former element. It is characterized by a prominent variation in histological appearances with the recognition of both carcinoma and sarcomatous elements. The outcome of patients diagnosed with MMMT is directly correlated with the presence of high-grade epithelial components, such as papillary serous or clear cell carcinoma, deep myometrial invasion, cervical involvement and lymphovascular invasion.42 The presence and type of heterologous sarcomatous elements play no role in the prognosis.42 Heterologous rhabdomyosarcomatous differentiation may also very rarely be seen in poorly differentiated carcinomas such as those arising in skin, bladder, thyroid and lung, among others.43–46 Usually, the presence of any heterologous sarcomatoid elements within these neoplasms portends a very poor prognosis, as most of these are diagnosed in advanced stage and are less responsive to conventional treatments.43–46 Correct diagnosis depends on identification of an underlying epithelial lesion as well as expression of cytokeratins, such as AE1/AE3, CAM5.2 and MNF-116, which may be rather limited given the poorly differentiated nature of these neoplasms. GCT in either gonadal or extragonadal locations infrequently shows sarcomatous elements, either in the primary tumour or subsequent local recurrences and/or metastases.47,48 In two large series of GCT showing malignant transformation of somatic components (‘ex-teratoma’), sarcoma was the most common somatic malignancy, and RMS was the most common sarcomatous component.47,48 The presence of RMS or any other sarcomatous element in GCT carries a dismal prognosis, because patients tend to present in more advanced disease stages, and these tumours appear to be resistant to cisplatinum-based chemotherapy, which is the mainstay of treatment of patients with GCT.47,48 ◆
7 Koufos A, Hansen MF, Copeland NG, Jenkins NA, Lampkin BC, Cavenne WK. Loss of heterozygosity in three embryonal tumours suggest a common pathogenic mechanism. Nature 1985; 316: 330–334. 8 Anderson J, Gordon A, McManus A, Shipley J, Pritchard-Jones K. Disruption of imprinted genes at chromosome region 11p15.5 in paediatric rhabdomyosarcoma. Neoplasia 1999; 1: 340–348. 9 Barr FG, Galili N, Holick J, Biegel JA, Rovera G, Emanuel BS. Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma. Nat Genet 1993; 3: 113–117. 10 Galili N, Davis RJ, Fredericks WJ, et al. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nature Genet 1993; 5: 230–235. 11 Davis RJ, D’Cruz CM, Lovell MA, Biegel JA, Barr FG. Fusion of PAX7 to FKHR by the variant t(1;13) (p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res 1994; 54: 2869–2872. 12 Bennicelli JL, Edwards RH, Barr FG. Mechanism for transcriptional gain of function resulting from chromosomal translocation in alveolar rhabdomyosarcoma. Proc Natl Acad Sci U S A 1996; 93: 5455–5459. 13 Bennicelli JL, Advani S, Schafer BW, Barr FG. PAX3 and PAX7 exhibit conserved cis-acting transcription repression domains and utilize a common gain of function mechanism in alveolar rhabdomyosarcoma. Oncogene 1999; 18: 4348–4356. 14 Furlong MA, Fanburg-Smith JC. Pleomorphic rhabdomyosarcoma in children: four cases in the pediatric age group. Ann Diagn Pathol 2001; 5: 199–206. 15 La Quaglia MP, Heller G, Ghavimi F, et al. The effect of age at diagnosis on outcome in rhabdomyosarcoma. Cancer 1994; 73: 109–117. 16 Hawkins WG, Hoos A, Antonescu CR, et al. Clinicopathologic analysis of patients with adult rhabdomyosarcoma. Cancer 2001; 91: 794–803. 17 Esnaola NF, Rubin BP, Baldini EH, et al. Response to chemotherapy and predictors of survival in adult rhabdomyosarcoma. Ann Surg 2001; 234: 215–223. 18 Ariel IM, Briceno M. Rhabdomyosarcoma of the extremities and trunk: analysis of 150 patients treated by resection. J Surg Oncol 1975; 7: 269–287. 19 Little DJ, Ballo MT, Zagars GK, et al. Adult rhabdomyosarcoma. Outcome following multimodality treatment. Cancer 2002; 95: 377–388. 20 Furlong MA, Mentzel T, Fanburg-Smith JC. Pleomorphic rhabdomyosarcoma in adults: a clinicopathologic study of 38 cases with emphasis on morphologic variants and recent skeletal musclespecific markers. Mod Pathol 2001; 14: 595–603. 21 Kumar S, Perlman E, Harris CA, Raffeld M, Tsokos M. Myogenin is a specific marker for rhabdomyosarcoma: an immunohistochemical study in paraffin-embedded tissues. Mod Pathol 2000; 13: 988–993. 22 Morotti RA, Nicol KK, Parham DM, et al. An immunohistochemical algorithm to facilitate diagnosis and subtyping of rhabdomyosarcoma: the Children’s Oncology Group experience. Am J Surg Pathol 2006; 30: 962–968. 23 Cessna MH, Zhou H, Perkins SL, et al. Are myogenin and myoD1 expression specific for rhabdomyosarcoma? A study of 150 cases, with emphasis on spindle cell mimics. Am J Surg Pathol 2001; 25: 1150–1157. 24 Mitelman Database of Chromosome Aberrations in Cancer. http://cgap.nci.nih.gov/Chromosomes/Mitelman, 2007.
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39 Ducatman BS, Scheithauer BW. Malignant peripheral nerve sheath tumor with divergent differentiation. Cancer 1984; 54: 1049–1057. 40 Hruban RH, Shiu MH, Senie RT, Woodruff JM. Malignant peripheral nerve sheath tumors of the buttock and lower extremity. A study of 43 cases. Cancer 1990; 66: 1253–1269. 41 Woodruff JM, Perino G. Non-germ cell or teratomatous malignant tumors showing additional rhabdomyoblastic differentiation, with emphasis on the malignant Triton tumor. Semin Diagn Pathol 1994; 11: 69–81. 42 Silverberg SG, Major FJ, Blessing JA, et al. Carcinosarcoma (malignant mixed mesodermal tumor) of the uterus. A Gynecologic Oncology Group pathologic study of 203 cases. Int J Gynecol Pathol 1990; 9: 1–19. 43 Perret L, Chaubert P, Hessler D, Guillou L. Primary heterologous carcinosarcoma (metaplastic carcinoma) of the urinary bladder: a clinicopathologic, immunohistochemical, and ultrastructural analysis of eight cases and a review of the literature. Cancer 1998; 82: 1535–49. 44 Patel NK, McKee PH, Smith NP, Fletcher CD. Primary metaplastic carcinoma (carcinosarcoma) of the skin. A clinicopathologic study of four cases and review of the literature. Am J Dermatopathol 1997; 19: 363–372. 45 Carda C, Ferrer J, Vilanova M, Peydro A, Llombart-Bosch A. Anaplastic carcinoma of the thyroid with rhabdomyosarcomatous differentiation: a report of two cases. Virchows Arch 2005; 446: 46–51. 46 Koss MN, Hochholzer L, Frommelt RA. Carcinosarcomas of the lung: a clinicopathologic study of 66 patients. Am J Surg Pathol 1999; 23: 1514–1526. 47 Motzer RJ, Amsterdam A, Pietro V, et al. Teratoma with malignant transformation: diverse malignant histologies arising in men with germ cell tumors. J Urol 1998; 159: 133–138. 48 Malagón HD, Valdez AMC, Moran CA, Suster S. Germ cell tumors with sarcomatous components. A clinicopathologic and immunohistochemical study of 46 cases. Am J Surg Pathol 2007; 31: 1356–1362.
25 Oda Y, Miyajima K, Kawaguchi K, et al. Pleomorphic leiomyosarcoma: clinicopathologic and immunohistochemical study with special emphasis on its distinction from ordinary leiomyosarcoma and malignant fibrous histiocytoma. Am J Surg Pathol 2001; 25: 1030–1038. 26 Gebhard S, Coindre JM, Michels JJ, et al. Pleomorphic liposarcoma: clinicopathologic, immunohistochemical, and follow-up analysis of 63 cases: a study from the French Federation of Cancer Centers Sarcoma Group. Am J Surg Pathol 2002; 26: 601–616. 27 Hornick JL, Bosenberg MW, Mentzel T, McMenamin ME, Oliveira AM, Fletcher CD. Pleomorphic liposarcoma: clinicopathologic analysis of 57 cases. Am J Surg Pathol 2004; 28: 1257–1267. 28 Cavazzana AO, Schmidt D, Ninfo V, et al. Spindle cell rhabdomyosarcoma. A prognostically favorable variant of rhabdomyosarcoma. Am J Surg Pathol 1992; 16: 229–235. 29 Rubin BP, Hasserjian RP, Singer S, Janecka I, Fletcher JA, Fletcher CD. Spindle cell rhabdomyosarcoma (so-called) in adults: report of two cases with emphasis on differential diagnosis. Am J Surg Pathol 1998; 22: 459–464. 30 Nascimento AF, Fletcher CD. Spindle cell rhabdomyosarcoma in adults. Am J Surg Pathol 2005; 29: 1106–1113. 31 Mentzel T, Kuhnen C. Spindle cell rhabdomyosarcoma in adults: clinicopathological and immunohistochemical analysis of seven new cases. Virchows Arch 2006; 449: 554–560. 32 Mentzel T, Katenkamp D. Sclerosing, pseudovascular rhabdomyosarcoma in adults. Clinicopathological and immunohistochemical analysis of three cases. Virchows Arch 2000; 436: 305–311. 33 Folpe AL, McKenney JK, Bridge JA, Weiss SW. Sclerosing rhabdomyosarcoma in adults: report of four cases of a hyalinizing, matrix-rich variant of rhabdomyosarcoma that may be confused with osteosarcoma, chondrosarcoma, or angiosarcoma. Am J Surg Pathol 2002; 26: 1175–1183. 34 Chiles MC, Parham DQ, Qualman SJ, et al. Sclerosing rhabdomyosarcomas in children and adolescents: a clinicopathologic review of 13 cases from the Intergroup Rhabdomyosarcoma Study Group and Children’s Oncology Group. Pediatr Dev Pathol 2004; 7: 583–594. 35 Croes R, Debiec-Rychter M, Cokelaere K, De Vos R, Hagemeijer A, Sciot R. Adult sclerosing rhabdomyosarcoma: cytogenetic link with embryonal rhabdomyosarcoma. Virchows Arch 2005; 446: 64–7. 36 Maurer HM, Beltangady M, Gehan EA, et al. The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer 1988; 61: 209–220. 37 Binh MD, Guillou L, Hostein L, et al. Dedifferentiated liposarcomas with divergent myosarcomatous differentiation developed in the internal trunk: a study of 27 cases and comparison to conventional dedifferentiated liposarcomas and leiomyosarcomas. Am J Surg Pathol 2007; 31: 1557–1566. 38 Binh MD, Sastre-Garau X, Guillou L, et al. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing welldifferentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol 2005; 29: 1340–1347.
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Practice points • Rhabdomyosarcoma is a rare sarcoma in adults • Pleomorphic rhabdomyosarcoma is the most common subtype to occur in adults. Other subtypes also diagnosed in adulthood include spindle cell and sclerosing rhabdomyosarcoma • The diagnosis of rhabdomyosarcoma depends on the demonstration of skeletal muscle differentiation in neoplastic cells, by immunohistochemical expression of markers such as myf-4 • Rhabdomyosarcoma may also be present as heterologous elements in other tumours, such as dedifferentiated liposarcoma, malignant peripheral nerve sheath tumour, malignant mixed Müllerian tumour, poorly differentiated carcinomas and germ cell tumours
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Rhabdomyosarcomas in adults: classification and differential diagnosis
Recognition of the correct diagnosis and histological subtype of RMS is of critical importance in the therapy of this disease. Treatment of RMS in adults is largely based on the North American and European Cooperative Groups for the treatment of children with RMS, and requires a multimodality approach that includes surgery, radiotherapy and chemotherapeutic regimens, often comprising a combination of drugs such as vincristine and dactinomycin with either cyclophosphamide or isophosphamide.3 Additionally, RMS may be present as a component of heterologous differentiation in other soft tissue sarcomas, such as dedifferentiated liposarcoma and malignant peripheral nerve sheath tumour (also known as malignant Triton tumour). Much less commonly, this form of heterologous differentiation is also present in other non-mesenchymal neoplasms, such as poorly differentiated carcinomas and germ cell tumours. This article will briefly review paediatric RMS, as context to discuss the clinicopathological characteristics of RMS in adults, the different histological variants, heterologous rhabdomyoblastic differentiation in other tumours and the approach to differential diagnosis.
Alessandra F Nascimento
Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. In contrast, RMS is rare in adults, accounting for <1% of all malignancies. It is subdivided into three main subtypes, namely embryonal, alveolar and pleomorphic RMS. Embryonal and alveolar RMS are nearly exclusive to the paediatric population, whereas pleomorphic RMS generally affects older adults. In recent years, spindle cell and sclerosing variants of RMS have also been recognized in adults. The diagnosis of RMS depends on the confirmatory detection of skeletal muscle markers such as desmin and Myf-4 in neoplastic cells. The differential diagnosis includes small round blue cell tumours and pleomorphic sarcomas, among other entities. RMS may also be present as a heterologous component of other tumour types, such as malignant peripheral nerve sheath tumour and dedifferentiated liposarcoma. Because of the scarcity of data in the adult population, staging and treatment of adult RMS is usually based on modified paediatric protocols. However, prognosis is worse in adults when compared to children, with an overall 5-year survival of less than 30%. This review will discuss the clinicopathological characteristics of RMS in adults, the different histological variants, heterologous rhabdomyoblastic differentiation in other tumour types and differential diagnosis.
Paediatric rhabdomyosarcoma In infants and children younger than 14 years of age, embryonal RMS is the most common subtype, affecting 3.0 in a million in this age group, followed by alveolar RMS.2 Embryonal RMS shows a distinct predilection for visceral sites, such as the genitourinary tract, followed by the head and neck, and extremities.1 In contrast, alveolar RMS affects the head and neck, extremities and trunk equally, and is much less frequent in visceral locations.1 Morphologically, embryonal RMS is characterized by a polymorphous proliferation of small spindle cells with rounded to oval or elongated, hyperchromatic nuclei, inconspicuous nucleoli and a small amount of pale indistinct cytoplasm, arranged haphazardly in sheets or in broad fascicles (Figure 1a). Larger cells, also known as ‘strap cells’ or ‘tadpole cells’, with more abundant eosinophilic cytoplasm and occasional cross striations, are usually scattered throughout the lesion in variable amounts (Figure 1b), and represent more differentiated rhabdomyoblasts. These cells are particularly frequent in tumours of patients who have undergone chemotherapy.4,5 The stroma is generally composed of loose fibrous tissue, with focal or extensive myxoid change. Rarely, embryonal RMS may contain large atypical hyperchromatic cells (known as the ‘anaplastic’ variant), which may be focal or diffuse in an otherwise typical embryonal RMS (Figure 2).6 The presence of these anaplastic features may also be noted in alveolar RMS, but is more common in the embryonal variant.6 This finding portends a worse prognosis.6 In the botryoid variant of embryonal RMS, the neoplastic cells form a distinctive condensed, hypercellular area immediately under the epithelial surface, known as the ‘cambium layer’. This subepithelial growth pattern imparts the characteristic macroscopic nodular appearance to this variant of RMS (resembling ‘bunches of grapes’ within visceral lumina). Alveolar RMS is histologically characterized by a nested proliferation of round to epithelioid cells separated by thick fibrous septa, which mimic alveolar structures (Figure 3a). The cells composing this neoplasm are usually large and show a monotonous appearance with round, hyperchromatic nuclei, prominent
Keywords adults; alveolar; embryonal; pleomorphic; rhabdomyosarcoma; spindle cell; sclerosing; sarcoma
Introduction Rhabdomyosarcoma (RMS) is a highly aggressive mesenchymal neoplasm that shows skeletal muscle differentiation. In the current World Health Organization Classification of Soft Tissue and Bone Neoplasms, RMS is divided into three distinct subtypes: embryonal, alveolar and pleomorphic.1 Embryonal and alveolar RMS are the most common soft tissue sarcomas in the paediatric population, affecting approximately 4.6 in a million children under the age of 14,2 whereas pleomorphic RMS generally affect adults. More recently, other variants, such as spindle cell and sclerosing RMS, have been recognized in the adult population. Overall, RMS is a rare disease in adulthood and, therefore, the clinicopathological characteristics, natural history and treatment options are not as well established in this population.
Alessandra F Nascimento MD is at the Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.
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a Alveolar rhabdomyosarcoma is characterized by the presence of nests of malignant cells separated by thick fibrous septa. b The neoplastic cells have round nuclei, prominent nucleoli and small to moderate amounts of cytoplasm, and scattered multinucleated cells may be seen throughout the tumour.
a Embryonal rhabdomyosarcoma showing a fascicular arrangement of small spindled cells with hyperchromatic nuclei and scant cytoplasm. b ‘Strap cells’ are present throughout the lesion. Figure 1
Figure 3
ucleoli and a small to moderate amount of cytoplasm (Figure 3b). n Scattered rhabdomyoblasts containing large amounts of brightly eosinophilic cytoplasm are noted. The cells in the central portion of the nests tend to be discohesive and smaller, while the ones at the periphery of the nests are adherent to the fibrous septa and show larger amounts of cytoplasm. Multinucleated giant cells can be encountered throughout the tumour (Figure 3b). In the solid variant of alveolar RMS, the neoplastic cells form sheets, and there is less prominent fibrous septation (Figure 4). The alveolar growth pattern is not present; however, the cytological features are similar to those of classic alveolar RMS. Rarely, cases showing juxtaposed embryonal and alveolar cytomorphology may be seen.1 Because of their natural history, these cases are best regarded as alveolar RMS.1 Although there are no specific karyotypic abnormalities that characterize embryonal RMS, a subset of cases shows loss of heterozygosity (LOH) at chromosome region 11p15.5, which contains several imprinted genes such as IGF2, H19 and p57.7,8 The hypothesis for the pathogenesis of embryonal RMS is that there is LOH of the active imprinted allele.1
Figure 2 Anaplastic variant of embryonal rhabdomyosarcoma (RMS) is characterized by scattered large atypical cells in a background of otherwise typical embryonal RMS.
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in a dense desmoplastic stroma. The cells have hyperchromatic nuclei, indistinct nucleoli and scant cytoplasm. Immunohistochemistry is helpful in establishing the diagnosis of DSRCT. Characteristically, the vast majority of these lesions show expression of cytokeratins, epithelial membrane antigen (EMA), neuron-specific enolase (NSE) and desmin; however, these tumours are negative for fast myosin and myf-4. Cytogenetics is also helpful in the diagnosis of DSRCT. These tumours show a typical t(11;22) (p13;q12) translocation, in which the WT1 gene on chromosome 11 is fused with the EWS gene on chromosome 22. The prognosis of DSRCT is poor even with therapy. ES/PNET characteristically occurs in adolescents and young adults; however, older adults may also be affected. Tumours present in bone or soft tissue, and are characterized by a proliferation of small round monotonous cells with scant cytoplasm. Although CD99 is not a specific marker for ES/PNET, it typically shows a prominent membranous pattern of staining of the vast majority of neoplastic cells. Other markers that may also occasionally be positive in ES/PNET include keratins, S-100 and NSE. Approximately 85% of cases show a reciprocal balanced translocation between chromosomes 11 and 22, namely, t(11;22) (q24;q12), which juxtaposes the EWS gene on chromosome 22 and the FLI1 gene on chromosome 11.1 The remaining 10–15% of cases contain other variant translocations, most involving the EWS gene.1 Similar to RMS, ES/PNET are also treated with specific chemotherapeutic regimens, and therefore, precise diagnosis is very important.
Figure 4 In the solid variant of alveolar rhabdomyosarcoma, fibrous septa are not as prominent and tumour cells are arranged in sheets.
Alveolar RMS is characterized by two reciprocal translocations, namely t(2;13) (q35;q14) and t(1;13) (p36;q14). The former translocation juxtaposes the PAX3 gene on chromosome 2 with the FKHR (FOX01A) gene on chromosome 13, and the latter juxtaposes the PAX7 gene on chromosome 1 with the FKHR (FOX01A) gene.9–11 The chimeric fusion proteins act as transcription factors.12,13 In the differential diagnosis with embryonal and alveolar RMS, the main tumours to be considered are in the category of the so-called ‘small round blue cell tumours’, which in adults should include small cell carcinoma, Merkel cell carcinoma and small cell malignant melanoma. Less commonly in this population, desmoplastic small round cell tumour (DSRCT) and Ewing sarcoma/peripheral neuroectodermal tumour (ES/PNET) may also be diagnosed. Small cell carcinoma affects mainly adults, arises in virtually any organ system and carries a poor prognosis. It is histologically characterized by small cells with round, hyperchromatic nuclei, finely granular chromatin pattern (‘salt and pepper’ pattern), inconspicuous nucleoli and scant cytoplasm. Necrosis, numerous mitoses and prominent ‘crush’ artefact are frequent features in small cell carcinoma. The neoplastic cells are positive for cytokeratins and neuroendocrine markers, such as chromogranin and synaptophysin. Merkel cell carcinoma shares morphological similarities with small cell carcinoma, and also expresses cytokeratins. Unlike small cell carcinoma, however, Merkel cell carcinoma expresses cytokeratin 20 (CK20) in a characteristic perinuclear dot-like pattern. Small cell malignant melanoma is positive for S-100 protein as well as for other melanocytic markers, such as Melan-A, HMB-45 and MiTF. Importantly, small cell carcinoma, Merkel cell carcinoma and small cell malignant melanoma are negative for the skeletal muscle markers myogenin (myf-4) and fast myosin. DSRCT affects mainly children and young adults but may also rarely be seen in older adults. In the paediatric population it shows a marked male predilection. Patients characteristically present with large intra-abdominal tumour masses, which are commonly multiple. Microscopically, DSRCT is characterized by nests of monotonous, small, round to slightly spindled cells embedded
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Pleomorphic rhabdomyosarcoma Pleomorphic RMS is rare in patients under the age of 40, with only a few cases described in the paediatric population.14 Although embryonal RMS was reported to be the commonest variant in two large series analyzing adults with RMS, comprising approximately 50% of the cases,15,16 while alveolar RMS was the most common variant in another series,17 affecting 56% of the patient, these findings may reflect bias of the referral centres. Pleomorphic RMS was the most common variant in two other large series of adult RMS,18,19 which is more in keeping with this author’s experience. In all studies, males were slightly more affected than females, comprising roughly 60% of the cases.15–19 Caucasians appear to be almost exclusively affected, accounting for over 80% of the cases in adults.15,18 Pleomorphic RMS arises predominantly in the extremities, in particular the lower limbs. Overall, RMS presents as a soft tissue mass which most commonly causes mass effect and/or visceral obstruction depending on its anatomical location. Median tumour size is approximately 6 cm.15–17,19 Tumours located on the extremities and in visceral locations tend to be bigger as compared to those located in the head and neck region.15–17,19 Pleomorphic RMS is a rapidly growing, expansile lesion that is often well delineated, surrounded by a fibrous pseudocapsule. The cut surface is usually tan and fleshy or firm, with variable extent of haemorrhage and necrosis. Pleomorphic RMS is characterized by a proliferation of rounded or spindled pleomorphic cells and a variable mixture of large atypical polygonal, strap-like cells showing abundant brightly eosinophilic cytoplasm (Figure 5). In the largest series of pleomorphic RMS, these tumours were subclassified into 540
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among the different subtypes. It is quite extensively expressed by the cells of alveolar RMS as compared to embryonal, pleomorphic and spindle cell/sclerosing variants, in which expression of these markers may be somewhat limited.21,22 More differentiated cells within these lesions may also express fast myosin. In this author’s experience and that of others, although expression of MyoD1, another myogenic transcription factor, is quite sensitive for skeletal muscle differentiation, it lacks specificity, limiting its utility as a diagnostic tool.23 To date, karyotypes of only seven cases of pleomorphic RMS have been reported.24 All cases showed highly complex karyotypes, including several structural and numerical chromosomal abnormalities, none of which appears to be specific for this disease.24 The differential diagnosis of pleomorphic RMS includes other pleomorphic sarcomas such as high-grade myxofibrosarcoma (MFS), pleomorphic leiomyosarcoma (LMS) and pleomorphic liposarcoma (LPS). MFS is among the most common sarcomas in older adults and affects mainly the extremities, in particular the lower limbs. It is characterized by a multinodular growth pattern and alternation between myxoid, hypocellular areas and solid, hypercellular areas. Within the myxoid areas, a typical vascular pattern composed of long thin-walled curvilinear vessels is recognized. Neoplastic cells tend to concentrate around these vessels. Additionally, there are large cells with vacuolated cytoplasm (‘pseudolipoblasts’) scattered throughout this myxoid area. In hypercellular areas, this vascular pattern is usually absent. In high-grade MFS, there is marked nuclear pleomorphism, frequent mitoses and necrosis. MFS shows neither expression of any definite immunostains nor any specific cytogenetic abnormality and, therefore, its diagnosis relies solely on morphological recognition. Pleomorphic LMS is a disease of adults with a male predominance and it most commonly affects extremities.25 It is characterized by a haphazard proliferation of bizarre, atypical and multinucleated cells in a background of spindle cells with blunt-ended nuclei and abundant eosinophils, consistent with conventional leiomyosarcoma. Pleomorphic LMS is positive for α-smooth muscle actin (SMA), desmin and h-caldesmon in many cases; however, myf-4 and fast myosin are consistently negative. Therefore, correct identification of pleomorphic LMS relies on the identification of conventional LMS and confirmatory immunostains. Pleomorphic LPS is a rare sarcoma of older adults, affecting predominantly the lower extremities.26,27 Histologically, it is a pleomorphic neoplasm with spindle cell or epithelioid features with at least focal areas containing large multivacuolated lipoblasts. Additionally, cells may have intracytoplasmic eosinophilic globules.27 These lesions show variable, inconsistent expression of markers such as SMA, S-100, keratins, EMA and desmin in a subset of cases.26,27 They are negative for myf-4 and fast myosin. The diagnosis of pleomorphic LPS is often one of exclusion and requires careful sampling of the lesion.
Pleomorphic rhabdomyosarcoma is characterized by the presence of large polygonal rhabdomyoblasts in a background of small to medium sized rounded a to spindled b cells. Figure 5
three histological variants: classic (type I), round cell (type II) and spindle cell (type III).20 In the first, large atypical rhabdomyoblasts with abundant eosinophilic cytoplasm form sheets.20 In the round cell variant, there are clusters of these large rhabdomyoblasts in a background of rounded medium sized cells.20 Lastly, the spindle cell variant demonstrates a ‘malignant fibrous histiocytomas (MFH)-like’ background with only scattered large rhabdomyoblasts.20 In routine practice, subclassification into types I, II and III is unnecessary, as it does not have implications for therapy or prognosis.20 Immunoperoxidase studies play a critical role in the diagnosis of RMS. These tumours show phenotypic evidence of muscle differentiation, and thus, are positive for markers such as muscle-specific actin (HHF-35) and desmin. However, none of these markers is specific for skeletal muscle differentiation, and are also positive in smooth muscle and myofibroblastic neoplasms, among others. As a sine qua non criterion for the diagnosis of RMS and its variants, expression of skeletal muscle markers such as myf-4, a myogenic transcription factor, and fast myosin are necessary. Nuclear positivity for myf-4 is noted in all cases of rhabdomyosarcoma; however, its expression is quite variable
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Spindle cell/sclerosing rhabdomyosarcoma Spindle cell RMS was initially described in the paediatric population by Cavazzana et al. as a rare variant that occurred mainly in males, arose preferentially in the paratesticular area, and carried 541
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a better prognosis when compared with other RMS variants.28 In 1998, this variant was also described in adults and, subsequently, larger adult series showed it to be a disease predominantly affecting males with a marked predilection for the head and neck area.29–31 Because of this marked difference between the clinical findings in children and adults with spindle cell RMS, it is possible that these two neoplasm in fact represent different disease processes. Although this author believes that the spindle cell variant represents a distinct subtype of RMS, in the current WHO Classification of Soft Tissue and Bone Tumours, it is included as a variant of embryonal RMS.1 Histologically, spindle cell RMS is characterized by a proliferation of spindle cells arranged in a storiform pattern or in long fascicles (Figure 6a). The cells show oval, elongated and tapered nuclei, vesicular chromatin, inconspicuous nucleoli and scant pale cytoplasm. Scattered larger polygonal cells with abundant brightly eosinophilic cytoplasm (rhabdomyoblasts) are usually present in the neoplasm, and vary in number from rare to frequent (Figure 6b). Sclerosing RMS is a more recently described unusual subtype of RMS which appears to affect males and females equally,
and occurs more frequently on the limbs.32–34 It is characterized by dense stromal sclerosis which leads to tumour cells being arranged in nests and cords, often imparting a pseudovascular appearance to the neoplasm (Figure 7). Although some believe sclerosing RMS is a distinct subtype, this phenomenon may be focally or diffusely present in the spindle cell variant of RMS, which argues that sclerosing and spindle cell RMS may instead represent morphological variants of the same disease.30,31 One reported case of sclerosing RMS showed a complex karyotype with abnormalities similar to those seen in embryonal RMS, suggesting that this entity may indeed be in the morphological spectrum of embryonal RMS.35 However, this remains to be validated. The differential diagnosis of spindle cell RMS includes spindle cell carcinoma, desmoplastic or spindle cell malignant melanoma, and conventional LMS. Spindle cell carcinoma and desmoplastic melanoma are relatively common disorders of older adults, and diagnosis of these entities depends on the immunodetection of keratins and melanocytic markers in the neoplastic cells, respectively. Conventional LMS is among the most common sarcomas arising in the retroperitoneum, as well as in association with large calibre veins, where they predominantly affect females.1 When LMS arises in somatic soft tissues of the extremities, males and females are equally affected.1 Morphologically, it is characterized by a fascicular spindle cell proliferation with elongated, bluntended nuclei, vesicular chromatin, variably prominent nucleoli and abundant brightly eosinophilic cytoplasm. It expresses desmin, α-SMA and h-caldesmon in the majority of cases. However, skeletal muscle markers (myf-4 and fast myosin) are negative. Sclerosing RMS should be differentiated from angiosarcoma and osteosarcoma. Angiosarcoma, when morphologically high grade, may be composed of fascicles of spindle cells with only focal poorly-formed vascular structures. Unlike RMS, angiosarcomas are positive for at least one marker of endothelial differentiation, namely CD31, CD34, D2-40, FLI-1 and/or von Willebrand factor (vWF). Keratins may be positive in a subset of cases. In contrast to RMS, fast myosin and myf-4 are negative. There are no characteristic cytogenetic findings in angiosarcoma.
Spindle cell rhabdomyosarcoma is a fascicular spindle cell neoplasm a composed of cells with elongated and hyperchromatic nuclei and scant cytoplasm, with scattered rhabdomyoblasts b. Figure 7 Sclerosing rhabdomyosarcoma shows dense hyalinized stroma which imparts a pseudovascular arrangement to tumour cells.
Figure 6
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DDLPS usually arises as a deep-seated large mass in the retroperitoneum, mediastinum or spermatic cord of middle-aged and older adults. It is only very rarely seen in the extremities. By current definition, it is characterized by abrupt transition from well-differentiated liposarcoma (WDLPS) into a non-lipogenic sarcoma. It may arise in recurrent WDLPS or as the initial presentation of liposarcoma. Interestingly, it maintains similar karyotypic abnormalities that typify WDLPS/atypical lipomatous tumours, i.e. giant markers and ring chromosomes derived from amplified material from chromosome 12. It is important to correctly differentiate between DDLPS with heterologous rhabdomyosarcomatous differentiation and RMS because the former carries a high risk of local recurrence but a relatively low metastatic potential of approximately 15–20%, despite the presence of rhabdomyosarcomatous or any other heterologous elements,37 while RMS is aggressive and often requires systemic therapy. Histologically, up to 10% of DDLPS demonstrate focal heterologous elements, such as rhabdomyosarcoma, leiomyosarcoma and osteosarcoma, among others.1 Heterologous rhabdomyosarcomatous differentiation within DDLPS is characterized by the presence of scattered large polygonal rhabdomyoblasts with eosinophilic cytoplasm. DDLPS will consistently express markers such as MDM2 and CDK4,38 two oncogenes located on the long arm of chromosome 12 (at the q13–q15 region) that are overexpressed in WDLPS and DDLPS. However, these markers have to be interpreted with caution and within the appropriate clinicopathological context because they may also be expressed in a small subset of RMS.38 MPNST may occur sporadically or in association with neurofibromatosis type 1 (NF1; von Recklinghausen disease). It arises de novo or as malignant transformation of a pre-existing neurofibroma. It affects predominantly adults in a wide age range, with no gender predilection. More commonly, it is encountered in the somatic soft tissues of the extremities but may also be seen in the retroperitoneum. Histologically, MPNST is characterized by a proliferation of spindle cells with tapered, elongated and hyperchromatic nuclei, variably prominent nucleoli and scant pale cytoplasm. There is often a characteristic alternation between less cellular areas with variably myxoid stroma and hypercellular fibrous areas. In approximately 15% of cases of MPNST, heterologous elements, such as osteosarcoma, chondrosarcoma, rhabdomyosarcoma and, rarely, angiosarcoma may be identified.39 This phenomenon is particularly common in patients with NF1.39 Heterologous rhabdomyosarcomatous differentiation in MPNST (also known as malignant Triton tumour) is usually multifocal within the neoplasm and is characterized by the presence of clusters of large atypical cells as well as small, primitive-appearing rhabdomyoblasts. Recognition of this phenomenon is of particular importance because patients with malignant Triton tumour show a worse prognosis when compared with those not showing this aberrant differentiation.40,41 Rarely, MPNST may undergo subtotal heterologous rhabdomyosarcomatous differentiation, making histological distinction from RMS virtually impossible. Clinical history is of critical importance in the diagnosis in this circumstance. MPNST is positive for S-100 protein and glial fibrillary antigen protein (GFAP) in a subset of cases (approximately 30%), and expression of these markers may be quite focal, particularly
The diagnosis of osteosarcoma depends on the identification of osteoid formation by neoplastic cells. In osteosarcoma the matrix often undergoes calcification and osteoclasts may be identified. Giant cells and calcification are not features of sclerosing RMS. Additionally, osteosarcoma is negative for specific skeletal muscle markers.
Staging, prognosis and treatment Staging of RMS is based on surgical resectability and pathological extent of disease. According to the Intergroup Rhabdomyosarcoma Study group, patients with RMS should be subclassified into four stages or groups, as follows: stage I includes patients with localized disease, amenable to complete surgical resection; in stage II disease, there is microscopic evidence of disease at resection margins of the specimen or in regional lymph nodes; patients with stage III have macroscopic residual disease after surgery with or without lymph node metastasis; and stage IV includes patients with metastasis to distant sites.36 Most adult patients present with advanced disease stages (stages III or IV).15–17,19 The treatment of adults with RMS is not uniform in the literature because of the rarity of this neoplasm in this population. Most series analyzing adult patients with RMS demonstrate a non-standardized multimodality approach including surgery, chemotherapy (mostly as part of clinical trial protocols) and radiation therapy, similar to what is offered to the paediatric group.15–19 Radiation therapy includes both external beam radiotherapy and brachytherapy.15–17,19 The most commonly used chemotherapeutic agents included vincristine, actinomycin, cyclophosphamide, doxorubicin, isophosphamide and etoposide, among others.15–17,19 Overall, there is a higher mortality rate in this population as compared to children, with 5-year survival averaging 35% in most larger studies.15–19 The most important predictors of poor outcome common to all studies are tumour size, margin status after surgical resection, and presence of metastasis at diagnosis.15–19 Although age and histological subtype appear to be important prognostic indicators in the paediatric population, the influence of these parameters in adults is controversial.15–19
Tumours with heterologous rhabdomyosarcomatous differentiation Heterologous rhabdomyosarcomatous differentiation is a relatively common phenomenon seen in mesenchymal neoplasms, such as dedifferentiated liposarcoma (DDLPS) and malignant peripheral nerve sheath tumour (MPNST). Moreover, it may also be seen, albeit less commonly, in other non-mesenchymal tumours such as malignant mixed Müllerian tumour (MMMT) or carcinosarcoma, poorly differentiated carcinoma and germ cell tumour (GCT). Importantly, because the RMS component is in fact true heterologous differentiation, immunoperoxidase markers such as desmin and myf-4 will be positive in a subset of neoplastic cells. The diagnosis of entities with heterologous rhabdomyosarcomatous differentiation will depend on histological identification of other elements that compose the neoplasm by thorough sampling of the lesion, as well as the clinical context.
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in high-grade lesions. In these cases, the diagnosis of MPNST requires correlation with clinical history, typical histological features and/or association with a nerve. MMMT or carcinosarcoma is by definition a malignant neoplasm of the gynaecological tract composed of an epithelial as well as a mesenchymal component, which is believed to arise as an aberrant differentiation of the former element. It is characterized by a prominent variation in histological appearances with the recognition of both carcinoma and sarcomatous elements. The outcome of patients diagnosed with MMMT is directly correlated with the presence of high-grade epithelial components, such as papillary serous or clear cell carcinoma, deep myometrial invasion, cervical involvement and lymphovascular invasion.42 The presence and type of heterologous sarcomatous elements play no role in the prognosis.42 Heterologous rhabdomyosarcomatous differentiation may also very rarely be seen in poorly differentiated carcinomas such as those arising in skin, bladder, thyroid and lung, among others.43–46 Usually, the presence of any heterologous sarcomatoid elements within these neoplasms portends a very poor prognosis, as most of these are diagnosed in advanced stage and are less responsive to conventional treatments.43–46 Correct diagnosis depends on identification of an underlying epithelial lesion as well as expression of cytokeratins, such as AE1/AE3, CAM5.2 and MNF-116, which may be rather limited given the poorly differentiated nature of these neoplasms. GCT in either gonadal or extragonadal locations infrequently shows sarcomatous elements, either in the primary tumour or subsequent local recurrences and/or metastases.47,48 In two large series of GCT showing malignant transformation of somatic components (‘ex-teratoma’), sarcoma was the most common somatic malignancy, and RMS was the most common sarcomatous component.47,48 The presence of RMS or any other sarcomatous element in GCT carries a dismal prognosis, because patients tend to present in more advanced disease stages, and these tumours appear to be resistant to cisplatinum-based chemotherapy, which is the mainstay of treatment of patients with GCT.47,48 ◆
7 Koufos A, Hansen MF, Copeland NG, Jenkins NA, Lampkin BC, Cavenne WK. Loss of heterozygosity in three embryonal tumours suggest a common pathogenic mechanism. Nature 1985; 316: 330–334. 8 Anderson J, Gordon A, McManus A, Shipley J, Pritchard-Jones K. Disruption of imprinted genes at chromosome region 11p15.5 in paediatric rhabdomyosarcoma. Neoplasia 1999; 1: 340–348. 9 Barr FG, Galili N, Holick J, Biegel JA, Rovera G, Emanuel BS. Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma. Nat Genet 1993; 3: 113–117. 10 Galili N, Davis RJ, Fredericks WJ, et al. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nature Genet 1993; 5: 230–235. 11 Davis RJ, D’Cruz CM, Lovell MA, Biegel JA, Barr FG. Fusion of PAX7 to FKHR by the variant t(1;13) (p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res 1994; 54: 2869–2872. 12 Bennicelli JL, Edwards RH, Barr FG. Mechanism for transcriptional gain of function resulting from chromosomal translocation in alveolar rhabdomyosarcoma. Proc Natl Acad Sci U S A 1996; 93: 5455–5459. 13 Bennicelli JL, Advani S, Schafer BW, Barr FG. PAX3 and PAX7 exhibit conserved cis-acting transcription repression domains and utilize a common gain of function mechanism in alveolar rhabdomyosarcoma. Oncogene 1999; 18: 4348–4356. 14 Furlong MA, Fanburg-Smith JC. Pleomorphic rhabdomyosarcoma in children: four cases in the pediatric age group. Ann Diagn Pathol 2001; 5: 199–206. 15 La Quaglia MP, Heller G, Ghavimi F, et al. The effect of age at diagnosis on outcome in rhabdomyosarcoma. Cancer 1994; 73: 109–117. 16 Hawkins WG, Hoos A, Antonescu CR, et al. Clinicopathologic analysis of patients with adult rhabdomyosarcoma. Cancer 2001; 91: 794–803. 17 Esnaola NF, Rubin BP, Baldini EH, et al. Response to chemotherapy and predictors of survival in adult rhabdomyosarcoma. Ann Surg 2001; 234: 215–223. 18 Ariel IM, Briceno M. Rhabdomyosarcoma of the extremities and trunk: analysis of 150 patients treated by resection. J Surg Oncol 1975; 7: 269–287. 19 Little DJ, Ballo MT, Zagars GK, et al. Adult rhabdomyosarcoma. Outcome following multimodality treatment. Cancer 2002; 95: 377–388. 20 Furlong MA, Mentzel T, Fanburg-Smith JC. Pleomorphic rhabdomyosarcoma in adults: a clinicopathologic study of 38 cases with emphasis on morphologic variants and recent skeletal musclespecific markers. Mod Pathol 2001; 14: 595–603. 21 Kumar S, Perlman E, Harris CA, Raffeld M, Tsokos M. Myogenin is a specific marker for rhabdomyosarcoma: an immunohistochemical study in paraffin-embedded tissues. Mod Pathol 2000; 13: 988–993. 22 Morotti RA, Nicol KK, Parham DM, et al. An immunohistochemical algorithm to facilitate diagnosis and subtyping of rhabdomyosarcoma: the Children’s Oncology Group experience. Am J Surg Pathol 2006; 30: 962–968. 23 Cessna MH, Zhou H, Perkins SL, et al. Are myogenin and myoD1 expression specific for rhabdomyosarcoma? A study of 150 cases, with emphasis on spindle cell mimics. Am J Surg Pathol 2001; 25: 1150–1157. 24 Mitelman Database of Chromosome Aberrations in Cancer. http://cgap.nci.nih.gov/Chromosomes/Mitelman, 2007.
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39 Ducatman BS, Scheithauer BW. Malignant peripheral nerve sheath tumor with divergent differentiation. Cancer 1984; 54: 1049–1057. 40 Hruban RH, Shiu MH, Senie RT, Woodruff JM. Malignant peripheral nerve sheath tumors of the buttock and lower extremity. A study of 43 cases. Cancer 1990; 66: 1253–1269. 41 Woodruff JM, Perino G. Non-germ cell or teratomatous malignant tumors showing additional rhabdomyoblastic differentiation, with emphasis on the malignant Triton tumor. Semin Diagn Pathol 1994; 11: 69–81. 42 Silverberg SG, Major FJ, Blessing JA, et al. Carcinosarcoma (malignant mixed mesodermal tumor) of the uterus. A Gynecologic Oncology Group pathologic study of 203 cases. Int J Gynecol Pathol 1990; 9: 1–19. 43 Perret L, Chaubert P, Hessler D, Guillou L. Primary heterologous carcinosarcoma (metaplastic carcinoma) of the urinary bladder: a clinicopathologic, immunohistochemical, and ultrastructural analysis of eight cases and a review of the literature. Cancer 1998; 82: 1535–49. 44 Patel NK, McKee PH, Smith NP, Fletcher CD. Primary metaplastic carcinoma (carcinosarcoma) of the skin. A clinicopathologic study of four cases and review of the literature. Am J Dermatopathol 1997; 19: 363–372. 45 Carda C, Ferrer J, Vilanova M, Peydro A, Llombart-Bosch A. Anaplastic carcinoma of the thyroid with rhabdomyosarcomatous differentiation: a report of two cases. Virchows Arch 2005; 446: 46–51. 46 Koss MN, Hochholzer L, Frommelt RA. Carcinosarcomas of the lung: a clinicopathologic study of 66 patients. Am J Surg Pathol 1999; 23: 1514–1526. 47 Motzer RJ, Amsterdam A, Pietro V, et al. Teratoma with malignant transformation: diverse malignant histologies arising in men with germ cell tumors. J Urol 1998; 159: 133–138. 48 Malagón HD, Valdez AMC, Moran CA, Suster S. Germ cell tumors with sarcomatous components. A clinicopathologic and immunohistochemical study of 46 cases. Am J Surg Pathol 2007; 31: 1356–1362.
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Practice points • Rhabdomyosarcoma is a rare sarcoma in adults • Pleomorphic rhabdomyosarcoma is the most common subtype to occur in adults. Other subtypes also diagnosed in adulthood include spindle cell and sclerosing rhabdomyosarcoma • The diagnosis of rhabdomyosarcoma depends on the demonstration of skeletal muscle differentiation in neoplastic cells, by immunohistochemical expression of markers such as myf-4 • Rhabdomyosarcoma may also be present as heterologous elements in other tumours, such as dedifferentiated liposarcoma, malignant peripheral nerve sheath tumour, malignant mixed Müllerian tumour, poorly differentiated carcinomas and germ cell tumours
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