Rhabdomyosarcoma of the eye: symptoms and treatment

Rhabdomyosarcoma (RMS) is a malignant tumor of mesenchymal origin with skeletal muscle features. In pediatric ophthalmology, it is the most common primary malignant orbital tumor; it most commonly affects young children. Typical onsets include rapid unilateral exophthalmos, eyelid edema, ptosis, chemosis, and orbital "pseudocellulitis." Timely diagnosis is essential, as early initiation of protocol therapy can save the eye and life. [1]

Over the past decades, the treatment approach has changed dramatically: from mutilating exenteration to organ-preserving multimodal therapy (biopsy, systemic chemotherapy, local control with radiation therapy; surgery is strictly indicated). For orbital RMS, this has resulted in high overall survival rates (90-95% at 10 years in modern series), but has increased the emphasis on late treatment effects and quality of life. [2]

The key to personalization is risk stratification: “favorable location” (orbit), histologic subtype (most often embryonal RMS), size/nodes/metastases, and PAX-FOXO1 fusion status. A positive PAX3/7-FOXO1 is an unfavorable feature requiring a different approach, while most orbital tumors are “fusion-negative” embryonal. [3]

Pathogenetically, orbital RMS is a model of "myogenesis failures": in the embryonic variant, 11p15 imprinting abnormalities with IGF2 overexpression are typical; in the alveolar variant, PAX-FOXO1 driver fusions are present. These molecular factors are increasingly being taken into account in risk-based treatment and clinical trials. [4]

Code according to ICD-10 and ICD-11

For orbital RMS, "soft tissue" codes specifying the head/neck region are routinely used. In ICD-10 (ICD-10-CM), code C49.0 is appropriate—malignant neoplasm of connective and soft tissue of the head, face, and neck; in the case of metastases, appropriate codes for secondary lesions are added. There is no specific "orbital" code for RMS, which is also reflected in epidemiological reviews. [5]

In ICD-11, RMS as a nosology is grouped in block 2B55 “Rhabdomyosarcoma, primary site” with details by localization; for the orbit, 2B55.Y “Other specified primary site” is used in practice (with the possibility of post-coordination of anatomical clarification). [6]

Table 1. RMS orbit coding

System	Block/section	Recommended code	Comment
ICD-10 (ICD-10-CM)	C49.* (soft tissues)	C49.0	"Head, face and neck"; most applicable for orbital RMS. [7]
ICD-10 (others)	C79.*	Additional metastasis code	In case of distant foci. [8]
ICD-11	2B55	2B55.Y	"Other specified primary localization" with postcoordination "orbit". [9]
ICD-11	2B55.0-2B55.2	By organs	For certain areas (oropharynx, respiratory tract, male genitalia). [10]

Epidemiology

RMS is the most common soft tissue sarcoma in children; approximately 250-350 new cases of RMS are reported annually in the United States, of which the orbit is a favorable site and one of the leading locations in the head/neck. Ophthalmology registries estimate that approximately 35 cases of orbital RMS are diagnosed annually in the United States. [11]

Onset is most common between the ages of 4 and 8, with a slight predominance of boys. In adolescents and adults, orbital RMS is less common and has a more aggressive course (more common in unfavorable subtypes), which impacts outcomes. [12]

Survival with modern therapy is high: in the institutional cohort from 1995 to 2016, the 10-year overall survival was 95%, and the preservation of the eyeball was about 77%; in cases of relapse and metastasis, the prognosis is worse. [13]

Remote adverse outcomes (death) are now rare; however, the incidence of late complications (cataracts, dry eye, orbital hypoplasia, etc.) is increasing, which dictates long-term monitoring and prevention of radiation toxicities. [14]

Table 2. Epidemiological characteristics

Indicator	Grade
The proportion of RMS among soft tissue sarcomas in children	The most common (peak up to 7% of all childhood cancers) [15]
Share of orbit among RMS localizations	≈10% of all RMS; “favorable site” [16]
Age of peaks	4-8 years
10-year overall survival (orbit)	~95% (institutional series) [17]

Reasons

There is no single "cause": RMS is a consequence of the accumulation of genetic events that disrupt the differentiation of myogenic precursors. Embryonic RMS (common in the orbit) is characterized by imprinting abnormalities in the 11p15 region (IGF2/H19/CDKN1C), leading to abnormal growth. [18]

For alveolar RMS, PAX3/7-FOXO1 fusions are critical, forming a chromatin “pathfinder” oncoprotein; PAX3-FOXO1 is associated with a worse prognosis. [19]

Some cases of RMS develop due to hereditary tumor syndromes (primarily Li-Fraumeni with germline TP53 variants), where atypical/anaplastic forms are possible in children. However, the proportion of such patients is small. [20]

Exogenous factors (history of radiation exposure, teratogens) are discussed, but there is little convincing data specifically for orbital RMS; endogenous molecular mechanisms play a leading role. [21]

Risk factors

Clinical factors for an unfavorable course include large tumor size (>5 cm), lymph node involvement and distant metastases, age <1 year or ≥10 years, and alveolar histology/FOXO1-positive status. [22]

Molecular genetics: PAX3-FOXO1 is worse than PAX7-FOXO1 or fusion-negative; anaplasia is often associated with germline TP53 variants and carries a higher risk. [23]

For orbital localization, the prognosis is generally better (site "favorable"), but with relapse or metastasis, outcomes worsen sharply. [24]

Table 3. Risk and prognosis factors

Category	Factor	Influence
Clinical	Size >5 cm; N1/M1	Increased risk of relapse/death [25]
Biology	PAX3-FOXO1	The most unfavorable of the frequent fusions [26]
Heredity	TP53 (Li-Fraumeni)	Association with anaplastic variant, early age [27]
Localization	Orbit	"Favorable" site; better local control [28]

Pathogenesis

The basis is a “disruption” of the myogenesis program: in embryonic RMS, there is a loss of heterozygosity of 11p15 and an imprinting imbalance (IGF2↑, H19/CDKN1C↓), which activates growth and prevents the maturation of myoblasts. [29]

In alveolar RMS, PAX-FOXO1 acts as a transcriptional driver, reprogramming chromatin and maintaining an “embryonic” state of cells with increased invasiveness. This determines a poorer response to therapy. [30]

Immunohistochemically, the tumor is confirmed by nuclear expression of myogenin/MyoD1 and cytoplasmic desmin; this “trio panel” remains the benchmark for confirming myogenic differentiation.[31]

Symptoms

The onset is usually acute: rapid exophthalmos, eyelid edema/erythema, ptosis, pain, and diplopia. The presentation often mimics orbital cellulitis, which may delay oncological alertness. [32]

There may be chemosis, limited eye movements, decreased vision due to compression of the optic nerve or radiation/ischemic neuropathy, and less commonly, hemorrhage/necrosis with heterogeneity on CT/MRI. [33]

Orbital bone lesions (erosions) occur in large lesions; according to modern data, only severe erosion is considered a “paramenigial” risk. [34]

Classification, forms and stages

Histology (WHO 5th ed.): embryonal (including botryoid), alveolar, spindle cell/sclerosing, pleiomorphic (adults). For the orbit, embryonal, fusion-negative, predominates. [35]

Clinical staging systems: TNM (COG/IRS), Clinical Group (I-IV) by extent of resection/residual disease and risk stratum (low/intermediate/high), where the orbit is a favorable site (Stage 1). [36]

Table 4. Brief COG staging map (TNM → Stage)

Stage	What does it mean?	Example for orbit
1	Favorable site (orbit, non-paramenigal head-neck, GU-not B/P), any T/N, no M1	Typical for orbital RMS
2-3	Unfavorable site ± N, without M1	Not applicable for orbit
4	M1 (distant metastases)	Lungs/bone marrow/bones, etc. [37]

Complications and consequences

Without treatment, RMS progresses rapidly with optic nerve compression, muscle infiltration, and extension into the sinuses/cranial cavity.[38]

Against the background of therapy, the main “cost of treatment” is the late effects of radiation therapy: cataracts, dry eye, orbital hypoplasia, retinopathy, neuropathy, stenosis of the lacrimal ducts; proton therapy reduces the dose load on critical structures. [39]

Late systemic risks include second malignancies and cardiotoxicities (depending on regimens), which are taken into account in the COG LTFU surveillance protocols. [40]

When to see a doctor

Any rapid unilateral exophthalmos, “cellulite-like” eyelid swelling without response to antibiotics within 24-48 hours, new diplopia/ptosis, or decreased vision warrant urgent referral to an ophthalmic/pediatric oncologist. [41]

If a tumor is suspected, long-term steroid use prior to imaging/biopsy should not be considered as this may mask the picture and delay diagnosis. [42]

Table 5. Orbital RMS "Red Flags"

Sign	Why is it dangerous?
Rapid exophthalmos (days-weeks)	Typical debut
Cellulitis that does not respond to antibiotics	Often a mimic tumor
New diplopia/ptosis	Muscle/nerve damage
Decreased visual acuity	Nerve compression/ischemia

Diagnostics

Step 1: Imaging. The "gold standard" for local evaluation is MRI of the orbits and brain with contrast; CT is needed for fine bone anatomy/planning and in cases of ambiguity. Chest CT is always performed to search for pulmonary metastases. [43]

Step 2 - Verification. An incisional biopsy is performed through a skin fold/conjunctiva under navigation. The pathologist confirms RMS based on morphology and an IHC panel (myogenin, MyoD1, desmin). Molecular testing (FOXO1 fusions) is also performed. [44]

Step 3 – Staging. Regional nodes are assessed clinically/by MRI; if indicated, PET-CT. The role of bone marrow aspiration/biopsy in favorable sites is reduced and is decided on an individual basis. The result is assignment of a TNM, Clinical Group, and risk stratum. [45]

Step 4: Consultation. The plan is developed jointly by an ophthalmologist, pediatric oncologist, radiation therapist, pathologist, and geneticist/radiologist. This increases the chances of organ preservation and minimizes late toxicities. [46]

Table 6. Minimum diagnostic set

Stage	What are we doing?	For what
MRI of the orbits/head with contrast	Local prevalence	Biopsy/RT planning [47]
CT scan of the chest	Metastases in the lungs	Staging M
Biopsy + IHC (myogenin/MyoD1/desmin)	Confirmation of myogenic nature	Diagnosis of RMS [48]
FISH/RT-PCR/NGS for FOXO1	Risk and tactics	Forecast and strategy [49]

Differential diagnosis

Most often, orbital RMS is disguised as inflammation: bacterial orbital cellulitis/phlegmon. Unlike infection, RMS is characterized by very rapid but "dry" exophthalmos, minimal fever/leukocytosis, and lack of response to antibiotics. [50]

Other mimics: idiopathic orbital inflammation, lymphangioma, hemangioma, dermoid/epidermoid, neuroblastoma/leukemia metastases, lymphoma, histiocytosis. Radiographic criteria (MRI/CT) and biopsy quickly dot the i's. [51]

Table 7. How RMS differs from “pseudocellulite”

Sign	RMS	Cellulite
Pace	Fast, but without significant intoxication	Acute with fever
Antibiotic	There is no quick effect	Improvement in 24-48 hours
MRI	A solid mass, often homogeneous; without an abscess	Diffuse infiltrate/abscess
A biopsy is needed	Yes	No

Treatment

General principles. The orbit is a "favorable" location, so the primary goal is organ preservation with complete oncologic control. Treatment is necessarily multimodal: systemic chemotherapy + local control (primarily radiation therapy; surgery to a limited extent). Dose/regime selection is determined by the risk strategy and response. Early involvement of a radiotherapist and MRI-guided RT planning are standard. [52]

Chemotherapy: North America. In COG protocols for low-/intermediate-risk patients, the basis is VAC (vincristine + dactinomycin + cyclophosphamide) with variations in density/duration. For some subgroups, reduced regimens (VA/VAC) are used in cases of excellent response and "clear" margins. For FOXO1-positive/nodal forms, intensification and prolongation of therapy are used. The goal is sterilization of micrometastases before RT and reduction of the target volume. [53]

Chemotherapy: Europe. In the EpSSG/SIOP networks, IVA (ifosfamide + vincristine + dactinomycin) is widely used with risk-based modifications and options for maintenance/additional local control. For a number of "favorable" sites, radiation dose reduction is being discussed in the setting of complete/near complete response, with the exception of the orbit, where RT remains the cornerstone. Harmonization of approaches is underway within the framework of the FaR-RMS initiative. [54]

Radiation therapy: doses and timing. Historically, a 45 Gy equivalent dose was used for Group III orbital cancer, but a COG analysis showed that 45 Gy is insufficient for incomplete early response, requiring dose escalation and/or adaptation of strategy. For microscopic remnants (Group II), 36 Gy to the bed + 41.4 Gy to involved nodes are acceptable; specific fields and fractionation are individualized. Early planning based on MRI/CT, taking into account the response, is standard. [55]

RT and proton therapy techniques. Modern centers use IMRT/VMAT or proton RT. The latter reduces the integrated dose and stress on the lens, retina, optic nerve, pituitary gland, and brain, which is critical in children. Clinical series demonstrate comparable disease control and a lower risk of severe late toxicities (cataracts, decreased visual acuity). The choice of technique depends on availability, anatomy, age, and target volume. [56]

Surgery. Initially, incisional biopsy is performed; radical resection within the orbit is extremely limited due to the risk of functional loss. Exenteration is currently a salvage method for refractory local disease/intratherapeutic progression and for some relapses. In response to a good systemic response, delayed limited resection of the residual node is possible (in select cases). [57]

Treatment of relapse/progression. There are no second-line standards; vincristine + irinotecan (VI) or VIT (vincristine-irinotecan-temozolomide) are often used; in a number of European studies, VIT has shown an improved response rate compared with VI. Local methods (repeat RT/stereotaxy, surgery) are considered according to indications. Inclusion in clinical trials is desirable. [58]

Targeted/new therapy. IGF-1R and mTOR inhibitors (cizutumumab, temsirolimus) have shown limited activity individually; combination regimens are being studied but are not yet standard. For selected patients, "personalized" protocol options are possible (angiogenesis inhibitors, metronidazole regimens, etc.). The real role of these approaches is in clinical trials. [59]

Toxicology prophylaxis and support. Prevention of mucositis/nausea, proper management of vincristine-induced neuropathy, protection of fertility (in adolescents), and dental and ophthalmologic support are essential. During/after RT, monitoring for dry eye, cataracts, and orbital hypoplasia is essential; early ophthalmic consultation with a surgeon regarding cataracts and lacrimal drainage improves quality of life. COG LTFU protocols outline the long-term follow-up plan. [60]

Prevention

There is no primary prevention for orbital RMS. Parental and physician awareness of rapid unilateral exophthalmos is key to early detection. [61]

Children from families with hereditary syndromes (Li-Fraumeni, NF1, DICER1, etc.) are recommended genetic counseling and screening according to the syndrome profile. [62]

Reducing radiation exposure (e.g., proton beam RT, sparing fields/doses) is about preventing future toxicities in those already affected, not “MS prevention.” [63]

Table 8. What is really preventative?

Measure	To whom	For what
Oncovigilance in "rapid exophthalmos"	To all children	Early diagnosis
Genetic counseling	Families with TP53/NF1/DICER1	Personal screening [64]
Gentle RT techniques	Already undergoing treatment	Fewer late effects [65]

Forecast

Most children with orbital RMS have a favorable prognosis: low/intermediate stratum, high chance of saving the eye and life. The 10-year overall survival rate in modern series reaches ≈95%, but without routine monitoring, late complications are possible. [66]

Unfavorable factors include PAX3-FOXO1, large size, N1/M1, and age-related margins. In relapse, 10-year survival is reduced, highlighting the value of primary radical control. [67]

Table 9. What determines the outcome?

Parameter	Impact on outcome
Website - Orbit	Plus to the forecast (Stage 1) [68]
PAX3-FOXO1	Strong minus [69]
Relapse	Reduces 10-year OS to ~70% and below (depending on stratum) [70]

FAQ

Is this eye cancer?
It's more often a cancer of the soft tissues of the orbit, not intraocular. The extremely rare intraocular variants are treated using different principles. [71]

Is it possible to treat without radiation?
For the orbit, radiation is almost always needed for local control; rare exceptions are discussed at a consultation after an ideal response to chemotherapy. [72]

Why is proton therapy offered?
In children, it better spares the lens, retina, optic nerve, and brain while providing comparable tumor control. This reduces the risk of cataracts/vision loss in the future. [73]

What is PAX-FOXO1 and should it be tested for?
This "gene fusion" is a marker for a more aggressive course of the disease. It is essential to look for it during verification because it influences risk stratification and treatment. [74]

How long should follow-up be performed after treatment?
Years: frequently at first (every 3-4 months), then less frequently; local recurrence, vision, and late effects (cataracts, dry eye, etc.) are monitored according to COG LTFU protocols. [75]

Additional useful tables

Table 10. Immunohistochemical profile of RMS

Marker	Expected reaction
Myogenin (nuclear)	Positive
MyoD1 (nuclear)	Positive
Desmin (cytoplasmic)	Positive
Ki-67	High proliferation index [76]

Table 11. Most frequently mentioned chemotherapy regimens

Net	Low/intermediate risk (examples)
COG (NA)	VAC/VA (duration/dose options) [77]
EpSSG (EU)	IVA±local modifications (FaR-RMS) [78]
Relapse	VI or VIT (improved responses vs VI in some studies) [79]