Soft tissue

• Botryoid embryonal rhabdomyosarcoma (sarcoma botryoides) only occurs in certain locations, specifically beneath mucosal epithelial lined viscera, such as the bladder, biliary tract, vagina or upper respiratory tract, extrahepatic bile ducts or near a space; rarely in eyelid or anal region
  • Often has a grape-like (botryoid) growth pattern
  • 25% of rhabdomyosarcomas, 10% of embryonal subtype
  • Considered a subtype of embryonal rhabdomyosarcoma (ERMS) (Am J Surg Pathol 2001;25:856)
• Anaplasia is an important prognostic feature and is defined similar to anaplastic Wilms tumor: significant nuclear variation (cells that are 3x larger than background tumor cells) and the presence of atypical multipolar mitotic figures
• Spindle cell rhabdomyosarcoma:
  • Over the years, tumors with spindled morphology have been regarded as a variant of ERMS
  • 2020 WHO has now included a spindle cell / sclerosing subtype category
  • It is important to remember that ERMS can still display spindled growth; however, there are now several molecularly defined subtypes of spindle cell / sclerosing RMS, which are considered separate
  • For an excellent recent review, see Am J Surg Pathol 2016;40:224
  • These entities will be better defined in future editions of the WHO classification, which will likely undergo additional revision

• Newborn boy with embryonal rhabdomyosarcoma (ERMS) presenting as a mass of the urethra at birth (Urology 2015;86:805)
• Newborn girl with anaplastic rhabdomyosarcoma (Iran J Pathol 2016;11:80)
• 7 year old boy with primary ERMS of the anterior neck and thyroid (Laryngoscope 2013;123:2072)
• 11 year old boy with tonsillar mass (Case #276)
• 16 year old girl with ERMS of the cervix (J Med Case Rep 2014;8:241)
• 46 year old man with ERMS arising from a mediastinal teratoma (J Korean Med Sci 2013;28:476)
• 55 year old postmenopausal woman with ERMS arising from the uterine corpus (Diagn Pathol 2016;11:3)
• 58 year old man with cardiac ERMS (Eur J Cardiothorac Surg 2014;45:e233)

Contributed by Mark R. Wick, M.D. and AFIP


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• Anaplasia specifically requires multipolar mitotic figures
  • Make sure you are not overinterpreting degenerating or apoptotic cells
  • Look for organization of the division and exclude cells that appear to be exploding
  • Also try to avoid interpreting overlapping cells as 1 larger cell
• Absence of a translocation does not result in the default diagnosis of embryonal rhabdomyosarcoma; tumor must adhere to the described histologic features
• Some rhabdomyosarcomas defy classification (rhabdomyosarcoma, not otherwise specified); this designation is preferable to misclassification, especially in small or otherwise limited samples
• Beware nonspecific staining (aberrant positivity for cytokeratin or S100 protein) versus true staining (S100 protein as a component of malignant peripheral nerve sheath tumor)
• Damaged skeletal muscle can express MyoD1 and myogenin; a different sarcoma that otherwise infiltrates skeletal muscle will very much mimic a rhabdomyosarcoma on immunohistochemistry staining
  • Look for the MyoD1 / myogenin to be positive in tumor cells in a linear pattern, which suggests the staining is of background muscle and not the tumor

• Composed of primitive mesenchymal cells that show variable degrees of skeletal muscle differentiation
• They are moderately cellular but in the typical pattern often contain both hypocellularity and hypercellular areas with a loose, myxoid stroma
• Perivascular condensations of tumor cells in the less cellular regions are common
• Sheets of small, stellate, spindled or round cells with scant or deeply eosinophilic cytoplasm and eccentric, small oval nuclei with a light chromatin pattern and inconspicuous nucleoli
• Can occasionally identify tumor cells that contain generous amounts of eosinophilic cytoplasm, a feature of rhabdomyoblastic differentiation (so called strap cells)
  • These may become more prominent with chemotherapy (chemotherapeutic induced cytodifferentiation)
• May have cells with elongated tails of cytoplasm (tadpole cells)
• If densely cellular, may resemble solid alveolar rhabdomyosarcoma (Am J Clin Pathol 2013;140:82)
• Botryoid variant frequently shows a cambium layer: a hypercellular zone immediately beneath the epithelial surface
  • Cells are undifferentiated, round or spindled with minimal cytoplasm, frequent mitotic figures
  • Deeper layers of the tumor are typically less cellular but overall conform to the histology of embryonal rhabdomyosarcoma (ERMS) with variation by region
• Rare morphological patterns:
  • Rhabdomyosarcoma with rhabdoid features (epithelioid or rhabdoid-like RMS) (Am J Surg Pathol 2011;35:1523)
  • Clear cell change (Pediatr Pathol Lab Med 1996;16:951)
  • Cartilaginous metaplasia (Oral Surg Oral Med Oral Pathol Oral Radiol 2017;124:e288)
  • Do not confuse with the following different entities:
    • Ectomesenchymoma: melanocytic, neuroblastic / ganglionic or Schwannian differentiation in the setting of background ERMS
    • Malignant triton tumor: rhabdomyosarcomatous differentiation in a malignant peripheral nerve sheath tumor; very bad prognosis

Contributed by Erdener Özer, M.D., Ph.D. and Mark R. Wick, M.D.


Contributed by Carolina Martinez Ciarpaglini, M.D., Ph.D. (Case #276) - tonsillar mass



AFIP images - anaplastic rhabdomyosarcoma


AFIP images - botryoid variant

Contributed by Erdener Özer, M.D., Ph.D.

• 11p15.5 loss of heterozygosity or loss of imprinting is a frequent finding
• Chromosomal aneuploidies are very common, especially with gains of chromosome 8 (seen in 90% of patients)
  • Additional gains frequently seen include chromosomes 2, 11, 12, 13 and 20
• No diagnostic translocation found to date (see Terminology regarding spindled rhabdomyosarcoma)
• Inactivating mutations of TP53 and CDKN2A and activating mutations of RAS family genes (Genes Chromosomes Cancer 2011;50:397)
• Frequency of ALK dysregulation is debatable, as are any significant associated clinical features (Mod Pathol 2013;26:772)

• Alveolar rhabdomyosarcoma (ARMS):
  • Diffuse and strong nuclear staining for myogenin and MyoD1; molecular studies (including FISH) show PAX-FOXO1 fusion gene product in approximately 85% of cases (Am J Clin Pathol 2013;140:82)
  • Histologically, ARMS is more uniform and shows more predictable patterns of growth (a finding which correlates with its consistent driver fusion event; it looks like a translocation sarcoma)
• Desmoplastic small round cell tumor:
  • Tumor nodules on serosal surfaces, strongly keratin+ and EMA+, may be desmin+ but muscle specific actin-
  • Associated with desmoplasia and histologically more closely mimic alveolar rather than embryonal rhabdomyosarcoma (ERMS)
  • Will not display myogenin or MyoD1 positivity; beware false positivity if they infiltrate background skeletal muscle
  • See Pitfalls and tips above
• Ewing / PNET:
  • Another round cell tumor, often displays Homer Wright rosettes
  • Nuclei are far more uniform and pale, not dense and hyperchromatic; CD99+, desmin-, MyoD1-, myogenin-
  • Look for characteristic rearrangements including t(11;22) or t(12;22)
  • Although there can be histologic overlap, if you sample the tumor enough you will find more atypia and cell to cell variability in rhabdomyosarcoma
• Large cell lymphoma:
  • CD45+, B / T cell markers present, desmin-, myogenin-, MyoD1-, muscle specific actin-
  • Histologically, can be very difficult to distinguish but lack of myogenic antibodies can be very helpful
• Monophasic synovial sarcoma:
  • Negative for muscle markers, usually far more spindled and organized (long fascicles) when compared to ERMS
  • Cytokeratin and EMA expression will show scattered and focal positivity in the spindled cells, the characteristic pattern seen in nearly all of these lesions
  • Molecular or FISH testing for the t(X;18) fusion, if needed
• Myxoid liposarcoma (MLS):
  • Although MLS typically is very easy to distinguish from ERMS, it can have a very similar background matrix that is loose and lightly basophilic
  • Cells can focally resemble one another as well
  • Look for signet ring lipoblasts in MLS, more bland histology and more uniformity when compared to ERMS
  • Immunostaining and molecular features are also easily utilized to differentiate the 2 entities
• Neuroblastoma:
  • Undifferentiated neuroblastoma can be very difficult to distinguish histologically; you may need to rely on the clinical presentation and the immunoprofile
  • Elevated urinary catecholamines, rosettes, granular chromatin, neuropil
  • S100+ (often), chromogranin+, synaptophysin+, GFAP+
  • Absence of myogenic markers
• Pleomorphic rhabdomyosarcoma:
  • Exclusively adults, usually in their 60s - 70s
  • Usually deep soft tissue of the extremity and remarkable for its universal diffuse cytologic atypia
  • Uniformly pleomorphic and does not contain elements of embryonal rhabdomyosarcoma
  • Anaplastic, as opposed to ERMS, which occasionally displays anaplasia in a background of classic EMRS
• Wilms tumor:
  • Can have rhabdomyoblastic differentiation, especially in the setting of chemotherapy
  • Beware any tumor in the kidney or any metastatic site in a patient with a previous Wilms tumor
  • Epithelial and blastemal components can be very focal following chemotherapy
  • If a Wilms tumor displays this pattern, it usually shows abundant cytodifferentiation, as opposed to classic rhabdomyosarcoma, which is usually focal

Which FISH testing may assist in making distinction between the dense pattern of embryonal rhabdomyosarcoma and the alveolar subtype of rhabdomyosarcoma?

1. ETV6::NTRK3
2. EWS::FLI1
3. PAX3::FOXO1
4. SYT::SSX1
5. TPM3::ALK

C. PAX3::FOXO1. This fusion gene product occurs in approximately 80% of alveolar rhabdomyosarcoma cases. Additionally, PAX7::FOXO1 rearrangements are present in a minority of cases.

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Reference: Embryonal rhabdomyosarcoma

Which histologic features in embryonal rhabdomyosarcoma are needed to diagnose anaplasia?

1. 3x nuclear size variability and tripolar mitotic figures
2. Alternating hypercellular and hypocellular areas
3. Coagulative necrosis
4. More than 20 mitoses per 10 high power fields
5. Solid growth pattern

A. 3x nuclear size variability and tripolar mitotic figures. Multipolar mitotic figures (including tripolar mitoses) and nuclear anaplasia (3x variation in nuclear size) are required to diagnose anaplastic embryonal rhabdomyosarcoma (ERMS). Solid growth pattern is irrelevant and necrosis can be seen in any subtype of rhabdomyosarcoma. ERMS typically displays the alternating pattern of hypocellularity and hypercellularity (also a buzzword for high grade malignant peripheral nerve sheath tumors). There is no requirement for a specific mitotic rate.

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Reference: Embryonal rhabdomyosarcoma