Soft tissue tumors - Alveolar rhabdomyosarcoma

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Soft tissue tumors

Skeletal muscle

Alveolar rhabdomyosarcoma

Reviewer: Vijay Shankar, M.D. (see Reviewers page)
Revised: 21 February 2013, last major update November 2012
Copyright: (c) 2003-2013, PathologyOutlines.com, Inc.

Subtypes discussed below: anaplastic variant, solid variant

Definition
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● High grade round cell malignancy with solid and alveolar growth and partial skeletal muscle differentiation
● Resembles lymphoma

Sites
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● Deep muscles of extremities, axial muscles or perineum

Clinical features
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● 20% of all rhabdomyosarcomas
● More common in early to mid-teens but all ages affected
● Neonatal cases have poor prognosis, are associated with skin and brain metastases (Cancer 2001;92:1613)
● Rapid growing, often high stage at presentation

Case reports
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● Infant with perineal tumor (Arch Pathol Lab Med 2002;126:982)
● 2 year old girl with pleural effusion and ovarian mass (Arch Pathol Lab Med 2003;127:e56)
● 2 year old girl with tumor of face (An Bras Dermatol 2011;86:363)
● 51 year old woman with cerebral tumor (Rare Tumors 2011;3:e26)
● 60 year old woman with primary cutaneous tumor of leg (Am J Surg Pathol 2002;26:938)
● 72 year old woman with tumor of uterine corpus (Pathol Int 2011;61:377)

Treatment and prognosis
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● Overall poorer prognosis than embryonal subtype
● Intergroup Rhabdomyosarcoma Study grouping (staging) is predictive of outcome
● Poor prognostic factors: N-myc amplification, PAX3 fusion transcripts (J Clin Oncol 2002;20:2672)
● Mixed forms with alveolar component are classified as alveolar for staging and diagnosis

Clinical images
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Multiple nodules on foot

Progressive enlargement of skin lesions

Paranasal lesion

Gross description
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● Fleshy, tan-gray, mean 5 cm

Gross images
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Congenital post-auricular tumor

Micro description
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● Thin fibrous septae lined by small round blue cells (resembling lymphoma) in an alveolar growth pattern (resembles pulmonary alveoli)
● Loss of cellular cohesion so cells appear to float in alveolar spaces
● Also peripheral cracking artifact at borders of cell clusters
● Amount of alveolar tissue present is NOT significant (i.e. diagnose as alveolar even if only focal alveolar pattern)
● Deep eosinophilic cytoplasm and presence of occasional multinucleated giant cells are important diagnostic features
● 1/3 have rhabdomyoblasts with cytoplasmic cross striations
● Often foci of coagulative tumor cell necrosis
● May have neuroendocrine differentiation (Int J Surg Pathol 2009;17:135)
● Mixed embryonal / alveolar: have foci with embryonal histology (spindle cell myoblasts, myxoid stroma)
● Rarely has rhabdoid features (pink, ground-glass or fibrillar round to oval cytoplasmic bodies, large eosinophilic nucleoli)

Micro images
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Tumor cells grow in nests or clusters separated by fibrous septa (AFIP)

Solid growth (AFIP)

Alveolar type spaces contain desquamated small, round and poorly differentiated skeletal muscle cells. Fibrovascular stroma is lined by undifferentiated round cells and differentiating cells with abundant eosinophilic cytoplasm, but only rare cross striations (AFIP)

Various images

Solid growth with giant cells	Desquamated multinuclear giant cells (AFIP)	Predominantly solid areas with only focal alveolar pattern resembles embryonal rhabdomyosarcoma (AFIP)
May resemble lipoblasts	Focal rhabdoid cells	May resemble embryonal RMS due to small round spindled cells with hyperchromatic nuclei and vacuolated spider cells
Perineal skin of infant	Various images	Various images
Desmin	Myogenin	Myogenin

Cytology images
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Cellular exudate with reactive mesothelial cells (double arrow), lymphocytes (arrowhead), bizarre giant cells (single arrow) and mitotic figures (double arrowhead), cells have vacuolated cytoplasm (inset), tumor cells are desmin+ (3A), myogenin+ (3B), karyotype shows t(2;13) (fig 4)

Various images

Positive stains
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● Muscle specific actin, desmin, myogenin (strong nuclear staining, Am J Surg Pathol 2001;25:1150)
● Myo-D1 (Am J Surg Pathol 2006;30:962), ALK1
● Also CAM 5.2 and broad spectrum cytokeratin (50%), neuroendocrine markers (43% express at least one, Mod Pathol 2008;21:795), p80 (25%, cytoplasmic dot-like pattern, Mod Pathol 2002;15:931), PAX5 (67%, Am J Surg Pathol 2009;33:775)

Electron microscopy description
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● Skeletal muscle differentiation

Molecular / cytogenetics description
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● t(2;13)(q35;q14): PAX3-FKHR in 60-85% (note: FKHR is now known as FOXO1)
● t(1;13)(p36;q14): PAX7-FKHR in 15-20%
● PAX/FKHR fusion negativity in 20% (associated with totally solid alveolar architecture, Am J Surg Pathol 2007;31:895)
● N-myc amplification in 50%
● P-cadherin is a direct PAX3-FOXO1A transcriptional target involved in alveolar RMS aggressiveness (Oncogene 2012 Jun 18 [Epub ahead of print])

Molecular images
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2;13 translocation; G-banding (above); R- banding (below)

t(2;13)(q35;q14) and t(1;13)(p36;q14)

Comparison of wild-type and fusion products associated with t(2;13) and t(1;13)

FISH

Videos
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Dr. Minarcik reviews skeletal muscle of face and alveolar rhabdomyosarcoma

Differential diagnosis
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● Alveolar soft parts sarcoma: PAS+ intracytoplasmic crystalline rods and granules; no pleomorphism, no giant cells, no fibrous septa, negative for muscle specific actin and myoglobin
● Merkel cell carcinoma: negative for muscle specific actin, desmin, myogenin and Myo-D1, lacks fusion gene
● Metastatic neuroendocrine carcinoma: keratin+, EMA+, desmin-, muscle specific actin-, lacks fusion gene

Anaplastic variant

Definition
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● Alveolar rhabdomyosarcoma with anaplastic nuclei
● Not a well characterized entity

Treatment and prognosis
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● Prognosis may be worse than typical alveolar rhabdomyosarcoma

Micro description
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● Anaplastic nuclei are 3x larger than surrounding nuclei

Micro images
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Foci of anaplastic cells (nuclei are hyperchromatic and 3x larger than surrounding cells)

Solid variant

Clinical features
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● Rarely occurs in adults in head and neck (Hum Pathol 2009;40:341)

Case reports
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● 16 year old girl with chest and foot masses (Univ Pittsburgh Case #256)
● 68 year old man with mediastinal tumor (J Cancer Res Ther 2011;7:353)

Micro description
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● Poorly developed alveolar pattern, lacks fibrovascular septa
● Alveolar pattern may be missed on small biopsies
● May resemble lymphoma (J Pediatr Hematol Oncol 2008;30:772)
● Solid component may be spindled sarcomatous to epitheloid cells (J Cancer Res Ther 2011;7:353)

Micro images
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Various images

Positive stains
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● Desmin and muscle specific actin
● May be CD56+ (J Clin Exp Hematop 2008;48:61)
● MyoD1 and myogenin may be positive

Molecular description
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● Associated with lack of fusion gene (Am J Surg Pathol 2007;31:895)

Molecular images
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FISH and karyotype show t(2;13)

End of Soft tissue tumors > Skeletal muscle > Alveolar rhabdomyosarcoma

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