Comprehensive notes on Soft Tissue Sarcomas (STS) and Feline Injection Site Sarcomas (ISS) - key concepts, data, and clinical implications

Soft Tissue Sarcomas (STS) – General Considerations

• STS are a diverse group of tumors accounting for 15% of cutaneous and subcutaneous (SQ) tumors in dogs and 7% in cats, representing ~1% of all malignancies.

• Over 20 histologic subtypes exist, but STS are treated as a collective group due to similar biologic behavior and histologic features.

• Biologic behavior: local invasiveness with a low-to-moderate risk of metastatic spread (grade dependent).

• Demographics: most STS are solitary lesions occurring in middle-aged to older dogs and cats.

• Breed/sex predilection: no specific predilection, though large-breed dogs may be overrepresented; rhabdomyosarcoma variants tend to occur in younger animals.

• General prognosis is driven more by local control than by distant metastasis.

STS – Presenting Complaint & Signalment

• Classic presentation: a slow-growing, non-painful dermal or hypodermal mass.

• Clinical signs depend on location and tumor invasiveness:- Nerve root or peripheral nerve sheath tumor can cause pain, lameness, muscle atrophy, paralysis.

  • Abdominal sarcomas can cause GI signs, weight loss, vomiting, etc.

STS Variants (Major Origins)

• Tumors of fibrous origin: Fibrosarcoma (FSA)

• Tumors of adipose tissue: Lipoma, intermuscular lipomas, infiltrative lipoma, liposarcoma

• Tumors of skeletal muscle: Rhabdomyosarcoma

• Tumors of vascular/lymphatics: Lymphangiosarcoma, Hemangioma, Hemangiosarcoma (HSA)

• Tumors of peripheral nerves: Hemangiopericytomas, peripheral nerve sheath tumors (PNST)

• Tumors of synovial tissue: Synovial cell sarcoma

• Tumors of smooth muscle: Leiomyoma, Leiomyosarcoma

• Tumors of uncertain origin: Myxosarcoma

Tumors of Fibrous Origin

• Nodular Fasciitis (Fibromatosis, “Desmoid tumor”)- Benign; rare; arises from fascia in dogs

  • Features: nodular, poorly circumscribed, firm, invasive; can be misdiagnosed as FSA; require aggressive resection for cure

• Fibrosarcoma (FSA)- Malignant fibroblasts; common in skin, SQ, and mouth

  • Predilection: older dogs and cats; no strong sex/breed predilection (e.g., Golden Retrievers, Dachshunds mentioned as possible associations)

  • Behavior: infiltrative masses with relatively low metastasis rate (~20%)

  • Important pitfall: high–low variations in oral lesions; treat with careful resection

Tumors of Adipose Tissue

• Lipoma- Benign adipose tumor; very common in older dogs; can occur anywhere

  • Indication for excision: when problematic

• Intermuscular Lipoma- Arises from fat between muscles; common caudal thigh region (between semimembranosus and semitendinosus)

  • May feel infiltrative but is not; avoid overcalling as liposarcoma

• Infiltrative Lipoma- Well-differentiated adipose tissue but locally aggressive by invading muscle, fascia, nerve, and even bone

  • Requires aggressive surgical excision; preop CT recommended

• Liposarcoma- Does not arise from malignant transformation of lipomas

  • Features: firm, poorly circumscribed, locally invasive with usually low metastatic rate

  • Recommended management: wide excision; reported MST (median survival time) ~1188 days

Tumors of Skeletal Muscle – Rhabdomyosarcoma

• Malignant tumors from myoblasts/primitive mesenchymal tissue with potential to differentiate into striated muscle

• Common sites: tongue, larynx, myocardium; Botryoid rhabdomyosarcoma described as grape-like clusters in the bladder of young, large-breed dogs

• Metastasis: low-to-moderate rate; data limited but overall considered rare

Tumors of Vascular & Lymphatic Tissue

• Lymphangiosarcoma- Origin: lymphatic endothelial tissue

  • Presentation: soft, cyst-like, ill-defined SQ masses; often extensive with massive edema; lymph may translocate through skin

  • FNA may yield deceptively normal-looking fluid

  • Behavior: very aggressive; margins difficult to define

  • Treatment: reported success with radiation therapy, doxorubicin, and toceranib

• Hemangioma- Benign vascular endothelial tumor; often solar-induced in short-haired/low-pigmented skin

  • May be a precursor to HSA

  • Treatment: surgical excision can be curative but lesions may be multifocal; cryotherapy effective if caught early

• Cryotherapy for Hemangioma- Best for small/superficial lesions < 1 cm

  • Protocol: apply until tissue blanched white; perform 3 freeze-thaw cycles; treat tumor margins with surrounding normal tissue

Tumors of Hemangiosarcoma (HSA)

• Staging by depth of involvement:- I: skin

  • II: subcutaneous (SQ)

  • III: muscle (acts like splenic HSA)

• Treatment: wide surgical excision with adjunctive doxorubicin for stage II/III

• Feline notes: usually solitary in the dermis; aggressive surgical treatment can yield MST ~1460 days vs ~60 days with no treatment

Tumors of Peripheral Nerves (PNSTs)

• Malignant tumors of nerve sheath: include hemangiopericytoma, neurofibrosarcoma, malignant schwannoma

• Location: occur in small peripheral nerves or in large nerves near the spinal cord (plexus or nerve roots)

• Behavior: slow-growing but infiltrative; can become large; often mistaken for lipomas

• Treatment and prognosis: aggressive resection; prognosis generally good unless origin is plexus/nerve root

Tumors of Synovial Tissue – Synovial Cell Sarcoma

• Origin: malignant tumors from synoviocytes of the joint capsule and tendon sheath

• Metastasis: higher metastatic rate compared with other sarcomas; ~32% at diagnosis and ~54% by euthanasia, with lungs and regional lymph nodes as common sites

• Breed and joint preference: larger breeds (Flat-Coated Retriever, Golden Retriever); tends to involve larger joints (stifle, elbow, shoulder)

• Distinction from osteosarcoma (OSA): can cross joints; bone involvement is rare in cats

• Treatment: limb amputation considered the best option; MST ~850 days vs ~455 days with marginal excision

Tumors of Smooth Muscle

• Origin: smooth muscle; common sites include GI tract, spleen, genitourinary tract (vagina), liver, and vessel walls

• Paraneoplastic syndrome: hypoglycemia (more common with GI variants)

• Leiomyoma- Benign, small, well-encapsulated; hormone-dependent (often in vagina); treatment: marginal excision with concurrent ovariohysterectomy (OHE)

• Leiomyosarcoma- Malignant; moderate metastatic potential; second most common GI tumor; may involve the liver with very high metastasis rate (approaching 100% when liver is involved)

Tumors of Uncertain Origin – Myxosarcoma

• Derived from fibroblasts; characterized by an abundant myxoid matrix rich in mucopolysaccharides

• Clinically resembles a salivary mucocoele

• Demographics: rare in middle-aged to older dogs

• Location: most commonly subcutaneous on trunk or limbs

• Behavior: tends to be infiltrative with ill-defined margins

STS – Important Common Features

• Pseudo-encapsulated soft-to-firm masses with poorly defined margins; highly infiltrative into surrounding tissues

• Local recurrence after conservative excision is common; exceptions possible

• Metastasis: hematogenous spread generally < 20%; regional LN metastasis uncommon

• Synovial cell sarcoma has a higher metastasis rate than other sarcomas

• Grade predicts metastasis; resection margins predict local recurrence

• The "1, 2, 3 → 10, 20, 30" rule links tumor size/grade to outcomes: larger/poorly marginated tumors have worse prognosis

• Measurable/bulky tumors (> 5 cm) tend to be less responsive to chemotherapy or radiotherapy

STS – Work-up & Staging

• Local tumor assessment:- Fine-needle aspiration (FNA) to rule out lipoma, seroma, inflammation, or abscess

  • If sarcoma is confirmed, consider tumor grade for therapeutic strategy (location, size, invasiveness, owner goals, and patient comorbidities)

• Incisional biopsy: Tru-cut or wedge preferred; punch biopsy not typically used if grade information is needed or FNA is equivocal

• Thoracic radiographs for pulmonary metastasis in ALL cases; ideally for all

• Regional imaging (radiographs, ultrasound, CT, MRI) if the mass is fixed to underlying structures

• Abdominal ultrasound for presurgical staging is generally not indicated for most STS

• CT may be used for surgical margin planning and thorough staging

STS – Surgical Considerations

• Wide excision: at least 3 cm radial margin and at least 1 fascial plane, or 2 muscle planes deep; remove biopsy tracts and areas of fixation en bloc

• Radical surgery (amputation or pelvic exenteration) may be required in some cases

• The first surgery offers the best opportunity for local control and potential cure; incomplete resection increases morbidity, costs, recurrence risk, and reduces survival

• Thorough planning and execution are essential; anticipate need for adjunctive therapies in some cases

STS – Exceptions to the “Rules”

• In cases where wide excision cannot be guaranteed, management requires case-by-case decision-making that weighs patient function, owner wishes, and realistic outcomes

STS – Difficult Locations and Historical Data on Marginal Excision

• Historically, marginal excisions have high recurrence rates (range: 26% - 60%)

• Contemporary data (Vet Surg, 2008): Extremity STS treated via marginal excision show about a 10% recurrence rate (all Grade I tumors included)

• Case selection is critical; about 43-51% of cases present on the extremity

STS Marginal Excision – Case Example (Summary)

• Example: 13-year-old Shepherd mix with a year-long left antebrachial mass, 4 x 4 cm, movable

• Co-morbidities: severe OA/DJD, hypothyroidism, renal insufficiency

• Therapeutic options discussed: wide vs. radical excision (amputation) or en bloc excision with staged reconstruction; marginal excision with primary closure

• Owner decisions vary based on functional impact and quality of life

STS Marginal Excision – Data Summary

• Margins achieved by marginal excision:- Dirty margins: ≈ 34%

  • Clean but close (1–3 mm): ≈ 34%

  • Clean margins (>3 mm): ≈ 31%

• Local recurrence rate after marginal excision: ≈ 10.5%; time to recurrence observed at multiple intervals (≈ 210, 450, 595, 700 days)

• Practical takeaway: distal extremity, low-grade STS may be reasonable to excise marginally

Difficult Location – Difficult Decisions (Practical & Ethical Considerations)

• Local tumor control must balance patient function and owner expectations

• Preserving anatomic function often takes precedence over aggressive local control when margins are uncertain

Adjunctive Radiation Therapy (RT) – Role and Evidence

• RT is an effective modality with consistently long overall survival in many cases: reported MST > 1,851 days

• Effect on local tumor control has been variable; local recurrence rates after RT range from 17% - 31%

• Given margins, it is not always reasonable to prescribe RT for all incompletely excised STS; outcomes may be improved with alternative strategies

• Aggressive scar revision or re-excision to achieve clean margins can yield favorable results:- After re-excision, clean margins achieved in ≈ 90% (37/41)

  • Local recurrence ~15% (6/39) at median ≈ 142 days, often better than RT without excision

Metronomic Chemotherapy for STS

• Study: 85 dogs with incompletely excised STS; 30 treated with metronomic cyclophosphamide + piroxicam vs 55 not treated

• Outcome: disease-free interval (DFI) significantly longer for dogs receiving surgery plus metronomic chemotherapy than historical controls treated with surgery plus RT

• Regimen: cyclophosphamide 10 mg/m^2 every 24–48 hours and piroxicam 0.3 mg/kg daily

• Conclusion: metronomic therapy can effectively delay recurrence in select incompletely resected STS cases

Chemotherapy for STS

• Study: 39 dogs with high-grade STS; 21 received surgery + doxorubicin; the rest had surgery alone

• Outcome: MST ≈ 856 days; no overall chemotherapy benefit in this study

• Interpretation: chemotherapy rarely provides clear benefit for STS overall; may be considered for aggressive (Grade III) variants, with realistic expectations

STS – Prognosis

• Local disease control drives prognosis; distant metastasis plays a lesser role unless high-grade or aggressive

• Negative prognostic indicators for local control:- Large tumor size;

  • Incomplete surgical margins;

  • High histologic tumor grade

• Global recurrence after incomplete resection: ≈ 28% (range 7-32%)

• Metastasis rate by grade: 10% (Grade I), 20% (Grade II), 30-50% (Grade III)

• MST with surgery alone: ≈ 1,416 days (~4 years); worse with aggressive histotypes

Future Directions (STS)

• Investigate reasons for local recurrence after apparently negative margins

• Explore the relationship between local recurrence and systemic metastasis

• Assess proliferation indices to improve prediction of local STS recurrence

• Aim to improve biologic predictability of individual sarcomas

Feline Injection Site Sarcomas (ISS) – General Considerations

• Emergence timeline: late 1980s; rabies vaccination laws led to heightened vaccine administration

• Change in vaccines: killed rabies vaccine and FeLV vaccine administered SQ; aluminum adjuvant suspected to drive massive inflammatory responses and fibroblastic/myofibroblastic proliferation, potentially leading to tumor formation

• ISS terminology: historically vaccine-associated sarcoma; now ISS acknowledges potential multifactorial etiologies (including interferon injections and microchips)

• Incidence: ~1/1000-1/10000

• Latency: time to tumor development ranges from ~4 weeks - 10 years post-vaccination

• ISS are histologically and biologically more aggressive than conventional STS

Feline ISS – Pathophysiology and Lesion Characteristics

• Perivascular macrophages may contain vaccine components in the lesion

• Vaccine-associated link remains controversial; multiple etiologies implicated

• ISS tumors can be infiltrative and challenging to resect with wide margins

Feline ISS – Presentation, Work-Up, and Diagnostics

• Presentation: similar to conventional STS; mass at vaccination site, often with infiltrative growth

• Diagnostic approach:- Cytology can suggest sarcoma but incisional biopsy is preferred to confirm ISS vs conventional STS and to justify aggressive surgical margins

  • Do not perform excisional biopsy; plan for extensive resection if ISS is confirmed

• Imaging: CT recommended for surgical margin planning due to infiltrative margins

Feline ISS – 3-2-1 Rule for Suspected ISS

• 3: Mass persists x 3 months or longer post injection

• 2: Mass > 2 cm in diameter

• 1: Mass continues to increase in size > 1 month after injection

Proactive Planning for ISS – Tail Vaccine Considerations

• Tail vaccine demonstrations and planning emphasize vaccination strategies to minimize ISS risk

• Educational resources (e.g., Maddie’s Fund) promote best practice for vaccine administration in cats

Feline ISS – Injection Location Considerations

• Injections should be given below the stifle (preferred) or below the elbow if given on an extremity

• Accurate documentation and site selection are critical to facilitating future diagnosis and treatment planning

National Guidance and Industry Involvement

• National Feline Vaccine-Associated Sarcoma Task Force endorses collaboration with pharmaceutical companies, which may assist with treatment costs if a vaccine-related ISS is diagnosed at the site of tumor formation

Feline ISS – Treatment and Surgical Margins

• Current standard: surgical excision with 5 cm radial margins and 2 muscle planes deep, including involvement of body wall, soft tissue, or bone (e.g., dorsal scapula/spinous processes or limb)

• Recurrence rate after this aggressive approach: ≈ 14%

• Complication rate: ≈ 11%, with ~8% experiencing dehiscence

• Historically reported local recurrence rates after ISS treatment: as high as 26-59%

• The aggressive surgical approach remains the preferred strategy for local disease control

Feline ISS – Wide Excision (5 cm Margins)

• Demonstrates robust local control with relatively manageable complication rates compared to historical data

• Visuals and case studies emphasize the practical feasibility of wide margins in feline tumors

Feline ISS – Prognosis

• Overall median survival time (MST) ≈ 901 days

• MST for cats with recurrence ≈ 499 days; MST for cats without recurrence ≈ 1,461 days

• Postoperative metastatic rate ≈ 20% (range up to 20% in some reports)

• Cats with metastasis have poorer prognosis (MST ≈ 388 days) vs those without metastasis (MST ≈ 1,528 days)

• Tumor recurrence and metastasis are significantly associated with poorer survival

Practical Connections and Real-World Relevance

• STS management emphasizes complete initial surgical excision with adequate margins to maximize disease control and minimize the need for adjuvant therapies

• When complete margins are not achievable, decision-making must weigh functional outcome, owner preferences, and realistic expectations for recurrence and metastasis

• RT can improve local control in some cases but is not universally superior to thorough re-excision; case-by-case judgment is essential

• Metronomic chemotherapy and targeted agents (e.g., doxorubicin, toceranib) may have selective roles, especially in incompletely resected tumors or challenging locations

• ISS in cats requires early incisional biopsy, careful planning of injection sites to minimize risk, and consideration of aggressive surgical margins to optimize outcomes

Formulas and Quantitative References (LaTeX)

• Prevalence and percentages:- 15% of canine cutaneous/SQ tumors; 7% in cats; ~1% of all malignancies

• Margin and surgical planning:- Wide excision margins: 3 cm radial margin and 1 fascial plane or 2 muscle planes deep

• Recurrence and metastasis statistics:- Local recurrence after incomplete resection: 28% (7-32%)

  • Metastasis by grade: Gr I: 10%, Gr II: 20%, Gr III: 30-50%

• STS prognosis timeframes:- MST with surgery alone: MST = 1416 days

  • RT-associated MST: > 1851 days

• STS marginal excision outcomes:- Margins: dirty 34%, close 34%, clean 31%

  • Local recurrence after marginal excision: 10.5%

  • Time to recurrence: approx 210, 450, 595, 700 days

• Feline ISS: latency and incidence:- Incidence: 1/1000-1/10000

  • Time to development: 4 weeks - 10 years

  • ISS MST: 901 days (overall)

  • Postoperative mets: 20%

Important References to Remember for Exam Preparation

• General STS: local aggressiveness with relatively low distant spread; focus on margins and grading

• Surgical planning: prioritize first surgery; margins and fixation status are critical for outcomes

• Adjunctive therapies: RT and chemotherapy have selective roles; metronomic chemotherapy can delay recurrence in incompletely resected STS

• Feline ISS: strict surgical margins (5 cm) and deep planes; tail/injection-site planning to minimize risk; 3-2-1 Rule for ISS suspicion

• Owner communication: discuss realistic outcomes, function preservation, and costs; ethical considerations in difficult locations