Rhabdomyosarcoma (RMS)

Definition and Epidemiology

• Peak incidence: before age 20 (embryonal/alveolar subtypes)
• Pleomorphic subtype: occurs in adults
• ~35% of RMS cases present in the head and neck region

Histologic Subtypes

Embryonal RMS - Histology

Alveolar RMS - Histology

Embryonal vs. Alveolar (Robbins Pathology)

Molecular Genetics

• Alveolar RMS carries characteristic chromosomal translocations:
  • t(2;13) → PAX3-FOXO1 fusion (most common, worse prognosis)
  • t(1;13) → PAX7-FOXO1 fusion (less common)
  • PAX3 is a transcription factor that initiates skeletal muscle differentiation. The chimeric fusion protein interferes with normal differentiation (analogous to fusion proteins in acute leukemias) and drives aggressive behavior.
• Embryonal and pleomorphic subtypes are genetically heterogeneous (no defining translocation).

Clinical Presentation

• Nasal obstruction, rhinorrhea, sinusitis, epistaxis
• Otitis media, aural polyps, otorrhea
• Hoarseness, epiphora
• Cranial nerve deficits if skull base erosion occurs

• Orbit (~25% of head/neck RMS) - favorable site
• Parameningeal sites (50% of head/neck RMS): middle ear/mastoid, nasal cavity, parapharyngeal space, paranasal sinuses, pterygopalatine/infratemporal fossa - higher risk of intracranial extension
• Genitourinary tract
• Extremities (pleomorphic type)

• Regional lymph node involvement: ~12%
• Distant metastasis at diagnosis: 5-15% (primarily lungs and bone)
• Bone marrow involvement can occur

Diagnosis and Workup

• Small round blue cell tumor of childhood (differential includes Ewing sarcoma, lymphoma, neuroblastoma)
• IHC staining for muscle-specific proteins (myogenin, MyoD1, desmin) confirms skeletal myogenic lineage
• Rhabdomyoblasts with strap-like cytoplasm and visible cross-striations on light microscopy
• Cytogenetics/FISH for PAX-FOXO1 fusion (alveolar subtype)

• MRI - isointense to skeletal muscle on T1, high signal on T2; best for soft tissue extent and perineural spread
• CT - superior for bony erosion assessment near skull base
• FDG-PET/CT - sensitive/specific for macroscopic metastatic disease
• Technetium-99 bone scan - for osseous metastases

• CBC, electrolytes, renal/liver function, coagulation studies
• Bone marrow aspirate (staging)
• Lumbar puncture for CSF cytology (parameningeal disease)

Staging

Pretreatment TNM Staging (summarized for Head/Neck RMS):

• Surgical/clinical grouping (post-treatment extent of resection)
• Histologic subtype (alveolar = worse prognosis)
• Together these define the patient's prognostic risk stratification (low, intermediate, high risk) which drives treatment intensity.

Treatment

1. Surgery: Wide local excision with clear margins when possible. For head/neck/orbital sites, function-preserving surgery is preferred. Mutilating surgery generally avoided.
2. Radiation: Indicated for most cases. Local control at the primary site, especially when margins are positive or for parameningeal disease.
   • Recent evidence: A 2025 systematic review (PMID 40494941) compared photon radiotherapy vs. proton beam therapy in pediatric RMS - proton therapy may reduce toxicity while maintaining control.
3. Chemotherapy: Backbone regimen is VAC (Vincristine, Actinomycin D, Cyclophosphamide). Treatment stratified by risk group under Children's Oncology Group (COG) protocols.
4. Enrollment in clinical trials is strongly encouraged for all pediatric patients.

Prognosis

• 1960s: 5-year OS ~50%
• By 1990s (with multimodal chemo): ~70%
• Current outcomes highly dependent on risk stratification:
  • Low risk (favorable histology, localized, complete resection): >90% 5-year OS
  • Intermediate risk: ~60-80%
  • High risk (metastatic or alveolar with poor features): <30%
• Alveolar RMS (especially PAX3-FOXO1 fusion) carries a worse prognosis than embryonal RMS

Key Associations

Orbital Rhabdomyosarcoma (RMS)

Overview

• ~90% occur in children under 16 years; average age of onset is 7 years
• The orbit accounts for ~25% of all head/neck RMS cases, and is classified as a favorable site due to its excellent response to treatment
• The tumor arises from undifferentiated mesenchymal cells with the potential to differentiate into striated muscle - NOT from mature extraocular muscles

Histologic Subtypes in the Orbit

Histology - Fig. 4.42A (Kanski's Clinical Ophthalmology)

Clinical Presentation

Symptoms

• Rapidly progressive unilateral proptosis - the hallmark presentation
• Can mimic orbital cellulitis (KEY: RMS can mimic orbital infection in a child)
• Diplopia is frequent; pain is less common
• Swelling and redness of overlying skin, but skin is not warm (helps distinguish from true cellulitis)

Signs - Location

• Most commonly superonasal or superior in position (Fig. B below)
• Can arise anywhere in the orbit, including inferiorly (Fig. C)
• Rarely arises in conjunctiva or uvea

Clinical Photos - Fig. 4.42B (Kanski's)

Differential Diagnosis of Acute Proptosis in a Child

• Orbital cellulitis / abscess (most important mimic)
• Lymphangioma with acute hemorrhage
• Leukemia / granulocytic sarcoma
• Metastatic neuroblastoma
• Langerhans cell histiocytosis
• Lymphoproliferative disease
• Dermoid cyst (leaking)

Clinical pearl (Wills Eye Manual): In cases of acute onset + rapid progression + mass on imaging in a child, emergency incisional biopsy is indicated to rule out aggressive malignancy such as RMS.

Imaging

CT Scan

Workup and Staging

• Histopathological subtype confirmation
• Cytogenetic characteristics (PAX-FOXO1 fusion status)
• Frozen section for urgent cases

• Physical exam (lymph node palpation)
• Chest and bone radiographs
• Bone marrow aspiration
• Lumbar puncture
• Liver function studies
• FDG-PET/CT (sensitive for macroscopic metastases)
• Technetium-99 bone scan (osseous metastases)

Treatment

Key evolution: Orbital exenteration (removal of the eye and orbit contents) was once the standard of care - it is no longer indicated. Multimodal chemo + radiation has replaced it with equivalent or superior outcomes while preserving vision and the globe.

• Entinostat (HDAC inhibitor) with chemotherapy may improve prognosis in selected cases, but is not yet approved
• The oncogenic PAX3-FOXO1 fusion gene is associated with treatment resistance and a 40-45% decrease in overall survival - its presence must be identified at diagnosis
• Immunotherapy (e.g., rituximab) is under investigation

Prognosis

• Orbital lesions have the BEST prognosis among all RMS sites
• Localized orbital disease: ~90% long-term survival
• Prognosis decreases substantially with spread to adjacent anatomy:
  • Paranasal sinus extension - worse
  • Intracranial extension - significantly worse
• Embryonal subtype: better prognosis than alveolar
• Overall long-term prognosis has greatly improved over the past 50 years due to advances in chemo and radiotherapy

• Dental and bone alterations after orbital RMS treatment (radiation-related)
• Orbital growth abnormalities (radiation-induced)
• Cataract, radiation retinopathy

Comparison: Adult vs. Pediatric Orbital RMS

Schirmer Test

What It Is

Equipment

• No. 41 Whatman filter paper strip - 5 mm wide × 35 mm long
• Folded 5 mm from one end to create a hook that hangs over the lid margin

Clinical Photo

Two Variants

Note from Cummings Otolaryngology: In the pre-surgical ptosis setting (assessing dry eye before ptosis correction), < 5 mm wetting with topical anesthetic raises concern for significant dry eye and potential post-operative complications.

Technique (Step by Step)

1. Dry the conjunctival sac - delicately blot excess tears from the inferior fornix
2. If using topical anesthesia (Schirmer 2), also remove excess anesthetic with filter paper
3. Fold the strip 5 mm from one end
4. Insert the folded end at the junction of the middle and outer third of the lower lid - take care not to touch the cornea or lashes
5. Ask the patient to keep eyes gently closed
6. Remove after 5 minutes and measure the length of wetting from the fold

Interpretation

• Results are variable - a single Schirmer test should NOT be the sole criterion for diagnosing dry eye
• Repeatedly abnormal results are highly supportive of the diagnosis
• Cannot perfectly separate basic from reflex secretion even with anesthesia

Clinical Indications

• Diagnosis of dry eye disease (keratoconjunctivitis sicca, KCS)
• Sjögren syndrome workup - Schirmer test combined with Rose Bengal staining; the Rose Bengal stain is reported to be more specific for KCS in this context
• Pre-operative assessment before ptosis surgery, blepharoplasty, or other periocular procedures
• Monitoring response to dry eye treatment

Dry Eye Diagnostic Battery (Schirmer in Context)

• Interpalpebral staining pattern on Rose Bengal/Lissamine green suggests aqueous tear deficiency
• Fluorescein stains areas where damage has allowed dye entry into tissues

Associated Conditions

• Sjögren syndrome (primary and secondary)
• Age-related lacrimal gland atrophy
• Lacrimal gland destruction (sarcoidosis, lymphoma, prior radiation)
• Cicatricial conjunctivitis (trachoma, pemphigoid, Stevens-Johnson)
• Riley-Day syndrome (familial dysautonomia)
• Post-ptosis surgery / blepharoplasty complications
• Contact lens wear