Soft Tissue

Cas 0808984

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Masse paratesticulaire. M 14 ans. Marqueurs sérologiques négatifs


Paratesticular mass, M 14 yo. Blood serum markers negative.








Macroscopie: Section à l'état frais


Gross: Fixed tissue section
























Coloration des fibres de Réticuline


Reticulin stain






Myogenin (MYF 4)









Diagnostic proposé:









Rhabdomyosarcome embryonnaire avec composante anaplasique.


Proposed diagnosis:









Embryonal rhabdomyosarcoma with anaplastic features.






Dans le texte en gras de la référence ci-dessous

In the highlighted text of the reference below


Embryonal rhabdomyosarcoma (Soft tissue and Bone tumours, WHO)

A primitive, malignant soft tissue sarcoma that recapitulates the phenotypic and biological features of embryonic skeletal muscle. The term embryonal rhabdomyosarcoma encompasses the spindle cell, botryoid, and anaplastic variants.
Myosarcoma, malignant rhabdomyoma, rhabdomyosarcoma, rhabdopoietic sarcoma, rhabdosarcoma, embryonal Sarcoma
Rhabdomyosarcomas comprise the single largest category of soft tissue sarcomas in children and adolescents, occurring in 4.6/million U.S. children <15 years of age. Embryonal rhabdomyosarcomas constitute the most common subtype of rhabdomyosarcoma, occurring in 3.0/million U.S. children <15 years of age. Children less than ten years of ages are typically affected; among patients <15 years of age, only 17% of embryonal rhabdomyosarcome arise in adolescents. The greatest proportion (46%) of embryonal rhabdomyosarcomas occur in children less than 5 years of age. Five per cent of rhabdomyosarcomas affect infants, and a few are congenital. Embryonal rhabdomyosarcome also constitutes important histological variant in adults, albeit such cases are rare. In the U.S., embryonal rhabdomyosarcomas show a slight male:female predominance (1.2:1) . Seventy per cent of U.S. rhabdomyosarcomas occur in non-Hispanic whites, compared to 14% in African-Americans, 10% in Hispanics, and 4.5% in Asians, and incidence rates are higher in whites. Incidence figures in Europe resemble those in the U.S., with a similar male excess, whereas incidence rates appear somewhat lower in eastern and southern Asia.
  Sites of involvement
Although embryonal rhabdomyosarcomas contain cells that are histologically identical to developing striated muscle, less than 9% arise within the skeletal musculature of the extremities. The greatest proportion occur within head and neck (about 47%), followed by the genitourinary system (about 28%). Common locations in the genitourinary tract include the urinary bladder, prostate, and paratesticular soft tissues. Typical sites of origin in the head and neck include the soft tissues intrinsic to or surrounding the orbit and eyelid, oropharynx, parotid, auditory canal and middle ear, pterygoid fossa, nasopharynx, nasal passages and paranasal sinuses, tongue, and cheek. Besides these two general regions, embryonal rhabdomyosarcomas occur in the biliary tract, retroperitoneum, pelvis, perineum, and abdomen and have been reported in various visceral organs, such as the liver, kidney, heart, and lungs. Embryonal rhabdomyosarcomas may involve the soft tissues of the trunk and appendicular skeleton but much less frequently than alveolar rhabdomyosarcomas (see below). Primary origin in the skin also rarely occurs.
Spindle cell and botryoid variants of rhabdomyosarcoma involve a relatively limited repertoire of organs. Spindle cell rhabdomyosarcomas most commonly arise in the scrotal soft tissues, with the remainder mostly involving head and neck regions. Spindle cell rhabdomyosarcoma also occurs in adults, usually in non-paratesticular locations. By definition, botryoid rhabdomyosarcomas must arise beneath a mucosal epithelial surface, limiting it to organs such as the urinary bladder, biliary tract, pharynx, conjunctiva, or auditory canal.
  Clinical features
Coincident with the diversity of their anatomic origins, embryonal rhabdomyosarcomas produce a variety of clinical symptoms, generally related to mass effects and obstruction. Hence, head and neck lesions can cause proptosis, diplopia, sinusitis, or unilateral deafness, depending on their location. Similarly, genitourinary lesions may produce a scrotal mass or urinary retention, and biliary tumours may cause jaundice. Otherwise, the symptoms are generally those of a rapidly growing soft tissue mass.
Imaging studies are primarily used in delineating the extent of lesions for staging and prior to definitive surgery. Computed tomography and magnetic resonance imaging are most useful for these purposes, although ultrasonography can be used as a screening modality. Images generally recapitulate those of an expansile soft tissue mass in various organs, with heterogenous signals reflecting the variable vascularity, myxoïde stroma, and necrosis. Of particular note is the striking appearance of botryoid lesions, which create a cluster of tumour nodules of variable size, typically within hollow viscera such as the urinary bladder or gall bladder.
Embryonal rhabdomyosarcomas may result from sporadic or inherited mutations, as discussed below. Generally this occurs as a variation of the Knudson-Strong two-hit hypothesis, which theoretically may involve loss of heterozygosity or aberrant gene methylation as well as DNA mutations.
Malignant transformation of rhabdomyomas very rarely causes rhabdomyosarcoma.Carcinogens causing rhabdomyosarcomas in humans have not been identified but have been found in studies of mice and zebrafish.
Like most primitive pediatric neoplasms, embryonal rhabdomyosarcomas form poorly circumscribed, fleshy, pale tan masses that directly impinge upon neighbouring structures. Spindle cell and botryoid variants display additional distinctive features. Spindle cell rhabdomyosarcomas, like other spindle cell lesions, form firm, fibrous tumours with tan-yellow, whorled cut surfaces. Botryoid tumours, as the name implies, have a characteristic polypoid appearance with clusters of small, sessile or pendunculated nodules that abut an epithelial surface.
Analogous to embryonic skeletal muscle, embryonal rhabdomyosarcomas are composed of primitive mesenchymal cells in various stages of myogenesis, i.e. rhabdomyoblasts. Stellate cells with lightly amphophilic cytoplasm and central, oval nuclei represent the most primitive end of this spectrum. As these cells differentiate, they progressively acquire more cytoplasmic eosinophilia and elongate shapes, manifested in descriptive terms such as "tadpole", "strap", and "spider" cell. Bright eosinophilia, cytoplasmic cross striations, and multinucleation indicate terminal differentiation, and myotube forms may be evident. Differentiation tends to be more evident following chemotherapy, as differentiated elements become the predominant cell population, separated by therapyinduced necrosis and fibrosis.
The histological architecture of embryonal rhabdomyosarcoma also resembles embryonic muscle, which forms aggregates of myoblasts amid loose, myxoid mesodermal tissues. Similarly, alternating areas of dense, compact cellularity and loose, myxoïde tissues constitute embryonal rhabdomyosarcomas. The amount of loose and dense cellularity varies from case to case: an abundant, mucoid stroma containing scattered rhabdomyoblasts and resembling myxomas predominates in some examples, and compact aggregates of densely arrayed spindle cells form other tumours.
The botryoid variant of embryonal rhabdomyosarcoma contains linear aggregates of tumour cells that tightly abut an epithelial surface. This feature, known as a "cambium layer", typifies these tumours. Botryoid rhabdomyosarcomas also contain variable numbers of polypoïde nodules, often with an abundant, loose, myxoid stroma that can appear deceptively benign. Densely arrayed whorls or fascicles of spindle cells constitute the spindle cell variant of embryonal rhabdomyosarcoma. These spindle cells often resemble smooth muscle cells, with blunted central nuclei and tapered ends, but cytoplasmic cross striations, if present, and/or bright eosinophilia indicate striated muscle differentiation, which should be confirmed by immunohistochemistry.
Spindle cell rhabdomyosarcomas may have a storiform architecture similar to fibrous histiocytoma or a wavy character like neurofibroma. The presence of enlarged, atypical cells with hyperchromatic nuclei defines the anaplastic variant of rhabdomyosarcoma. This feature may be seen in both embryonal and alveolar tumours but is more prevalent in the former. Bizarre, multipolar mitoses are also often present. Anaplastic features can be focal or diffuse. Focal anaplasia indicates the presence of only single, dispersed anaplastic cells, whereas diffuse anaplasia indicates the presence of clone-like clusters of anaplastic cells.

Markers of skeletal muscle differentiation typify embryonal rhabdomyosarcomas. The presence of these markers correlates with the degree of tumour cell differentiation, as it does in embryogenesis. Thus, only vimentin is present in the cytoplasm of the most primitive cells, and desmin and actin are acquired by developing rhabdomyoblasts.
Differentiated cells exhibit myoglobin, myosin, and creatine kinase M, markers that correspond to terminal differentiation. A variety of less commonly used muscle markers, such as titin, dystrophin, and acetylcholine receptor antigens alsocharacterize rhabdomyosarcomas. Muscle markers such as desmin and muscle-specific actin (HHF-35) are shared by cells with a myogenic phenotype, including smooth muscle, cardiac muscle, myofibroblasts, myoepithelial cells, pericytes, and some mesothelial cells. Antibodies against MyoD1 and myogenin are highly specific and sensitive for rhabdomyosarcoma and are currently used as standard antibodies for diagnosis. However, one must note that only nuclear staining is specific and that non-specific cytoplasmic MyoD positivity is common in heatretrieved, paraffin-embedded tissues.
Occasional aberrant staining with a variety of immunohistochemical markers has been noted. Aberrantly expressed markers include cytokeratin, S100 protein, neurofilaments, and B cell proteins such as CD20 and immunoglobulins.
Smooth muscle actin and neuron-specific enolase staining occurs more frequently (in 10% and 30% of rhabdomyosarcomas,respectively) .

Rhabdomyosarcomas exhibit a range of ultrastructural characteristics corresponding to those of developing striated muscle, primarily bundles of 5 and 15 nm thick and thin filaments punctuated by abortive Z-bands. Parallel arrays of 15 nm filaments and ribosomes (myosin-ribosome complexes) comprise the earliest diagnostic stage. Earlier cells show non-specific features of primitive mesenchyme, such as discontinuous basal lamina, phagocytosed collagen, and ergastoplasm. These uncommitted cells may contain lipid or subplasmalemmal microfilaments. Leptomeric fibrils may be seen on occasion.

Molecular analyses of polymorphic loci revealed allelic loss in chromosomal region 11p15 in most embryonal rhabdomyosarcomas. The finding of growth suppression when chromosomal fragments containing the 11p15 region were introduced into embryonal rhabdomyosarcoma cells further supports the premise that there is a tumour  suppressor gene within this region. Furthermore, inherited alterations of the 11p15 region occur in Beckwith-Wiedemann syndrome, a heterogeneous overgrowth syndrome with an increased risk for development of several cancers, including embryonal rhabdomyosarcoma.
Expression studies have indicated that several 11p15 genes, such as IGF2, H19, and CDKN1C, are expressed from one of the two alleles in a parent-of-origin specific process termed imprinting. These combined findings suggest a model in which an imprinted tumour suppressor gene is inactivated during embryonal rhabdomyosarcoma tumourigenesis by allelic loss of the active allele and retention of the inactive allele.
Cytogenetic studies of embryonal rhabdomyosarcoma have found complex structural and numerical chromosomal changes, often including extra copies of chromosomes 2, 8, and 13. Rearrangements of the 1p11-q11 and 12q13 regions have also been noted in a fraction of cases. Subsequent comparative genomic hybridization analyses of genomewide copy number changes confirmed chromosomal gains and identified several regions of loss, such as chromosome 16, in embryonal rhabdomyosarcoma subsets. These analyses also indicated that genomic amplification was generally rare in embryonal rhabdomyosarcoma, except for its subset with anaplastic features. Finally, directed analyses of known oncogenes and suppressor genes identified inactivating mutations of TP53  and CDKN2A  and activating mutations of RAS family genes in subsets of embryonal rhabdomyosarcoma. These various
genetic alterations may indicate variable collaborating events that occur during embryonal rhabdomyosarcoma tumourigenesis.

Prognostic factors
Prognosis can be determined by stage, histological classification, age, and site of origin. Staging is accomplished by clinical evaluation (IRSG Stage) or surgicopathological evaluation (IRSG Group). Younger patients tend to have a more favourable prognosis. Histological classification in paediatric patients predicts outcome independent of age, stage, and location, with embryonal tumours having a better prognosis than alveolar tumours. Spindle cell and botryoid variants have a superior outcome as a group. However, the rare spindle cell lesions in adults are more aggressive and, in fact, histological subtype in adults with rhabdomyosarcoma appears to have no prognostic relevance.
Embryonal rhabdomyosarcomas with diffuse anaplasia may have a worse outcome than the other subsets of embryonal rhabdomyosarcoma. Parameningeal and extremity tumours tend to have a bad outcome compared to other locations, whereas orbital and paratesticular tumours tend to have a better one. Tumour cell ploidy predicts outcome in some reports, with hyperdiploid embryonal rhabdomyosarcomas having a better outcome. However, this phenomenon has not been universally confirmed and does not appear to be an independent variable.