What are the recommended markers for diagnosing Leiomyosarcoma, particularly in an adult patient with a suspected tumor at the gastroesophageal junction?

Leiomyosarcoma Immunohistochemical Markers

For diagnosing leiomyosarcoma, particularly at the gastroesophageal junction, the essential immunohistochemical panel should include smooth muscle actin (most sensitive at 95%), desmin, and caldesmin, with negative staining for CD117 and CD34 to distinguish from GIST. 1

Core Diagnostic Markers for Leiomyosarcoma

Primary Smooth Muscle Markers (in order of sensitivity)

• Smooth muscle actin is the most sensitive marker with 95% positivity in leiomyosarcomas, making it the first-line screening marker 2, 3

• Muscle-specific actin (HHF35) demonstrates 91% sensitivity and consistently stains all leiomyosarcomas regardless of differentiation 2, 3

• Calponin shows 88% sensitivity and is expressed in the majority of leiomyosarcomas, with diffuse cytoplasmic staining throughout tumor cells 2, 3

• Desmin is positive in 73-76% of cases, though less sensitive than actins; it is particularly useful when positive but its absence does not exclude leiomyosarcoma 1, 2, 3

• h-Caldesmon demonstrates only 36-66% sensitivity overall but shows higher expression (94%) in retroperitoneal tumors; it is highly specific for smooth muscle differentiation when present 4, 3

• Smooth muscle myosin is positive in 64% of cases and tends to be coexpressed with caldesmon, particularly in retroperitoneal locations 3

Critical Negative Markers to Distinguish from GIST

• CD117 (c-kit) must be negative to differentiate leiomyosarcoma from GIST, as over 95% of GISTs express CD117 1

• CD34 should be negative in leiomyosarcoma, whereas 70-90% of GISTs express CD34 1

• DOG1 should be negative to exclude GIST, as this marker is highly specific for GIST and expressed even in some CD117-negative GISTs 1

• S-100 protein should be negative to exclude neural origin tumors like schwannoma, which express S-100 in 8-10% of cases 1

Practical Diagnostic Algorithm

Step 1: Initial Screening Panel

• Order smooth muscle actin, desmin, CD117, and CD34 as the initial panel 1
• If smooth muscle actin is positive AND CD117/CD34 are negative, proceed to confirmatory markers 2, 3

Step 2: Confirmatory Panel

• Add calponin, h-caldesmon, and muscle-specific actin to confirm smooth muscle differentiation 2, 4, 3
• A diagnosis of leiomyosarcoma requires positivity for at least 2-3 smooth muscle markers with negative CD117 and CD34 1

Step 3: Additional Markers for Specific Clinical Contexts

• In female patients with retroperitoneal or gastroesophageal junction tumors, consider adding estrogen receptor (ER) and progesterone receptor (PR), as these are positive in 63-86% of uterine and female retroperitoneal leiomyosarcomas 3
• WT1 nuclear staining may be present in 11% of ER-positive uterine and female retroperitoneal tumors 3

Important Caveats and Pitfalls

Variable Expression Based on Differentiation

• Well-differentiated leiomyosarcomas show more consistent expression of h-caldesmon and myosin compared to poorly differentiated tumors 4, 3
• Poorly differentiated leiomyosarcomas, particularly in external soft tissues, may be h-caldesmon negative despite being true leiomyosarcomas 4
• The absence of h-caldesmon does not exclude leiomyosarcoma, especially in poorly differentiated or soft tissue locations 4

Anatomic Location Affects Marker Expression

• Retroperitoneal leiomyosarcomas show the highest expression of caldesmon and myosin (94%) 3
• External soft tissue leiomyosarcomas are frequently h-caldesmon negative and may show less consistent smooth muscle marker expression 4, 3
• Gastroesophageal junction location requires particular attention to exclude GIST, as both can present as hypoechoic fourth-layer masses on endoscopic ultrasound 1

Desmin Expression Variability

• While desmin is traditionally considered a smooth muscle marker, only 2-4% of GISTs express desmin, making its presence helpful but not diagnostic 1
• Approximately 30% of CD117-negative GISTs may express desmin, particularly in gastric locations with epithelioid morphology 1

Morphologic Correlation is Essential

• Leiomyosarcomas show spindle cell morphology similar to GIST, making immunohistochemistry mandatory for definitive diagnosis 1
• The presence of fascicular arrangement of spindle cells supports leiomyosarcoma when combined with appropriate immunoprofile 1

Differential Diagnosis Considerations at the Gastroesophageal Junction

• GIST remains the primary differential diagnosis and is distinguished by CD117 and/or DOG1 positivity with variable CD34 expression 1
• Schwannomas express S-100 protein and are negative for desmin and smooth muscle actin 1
• Inflammatory fibroid polyps are CD34-positive but CD117-negative 1