Immunohistochemical Markers in Spindle Cell Neoplasms
For diagnosing spindle cell neoplasms, use a targeted panel approach: EMA and pan-CK establish epithelial differentiation, S100 identifies melanocytic or neural lesions, CD34 suggests fibroblastic/vascular tumors, and p63 confirms squamous or myoepithelial origin.
Pan-Cytokeratin (Pan-CK) and EMA
Pan-CK is the cornerstone marker for identifying epithelial differentiation in spindle cell lesions. For spindle cell squamous cell carcinoma (SCSCC), high-molecular-weight cytokeratin 34βE12 demonstrates 100% sensitivity, making it the most reliable cytokeratin marker for this diagnosis 1, 2. Standard pan-cytokeratins (AE1/AE3) show lower sensitivity at 67%, while low-molecular-weight keratins perform even worse at 58% 2.
- EMA (Epithelial Membrane Antigen) serves dual purposes: it identifies epithelioid mesothelioma when showing nuclear staining patterns (calretinin and WT-1 positive), and helps distinguish mesothelioma from adenocarcinoma when used in a panel 3.
- In occult primary workup, broad-spectrum cytokeratins should be positive while S100, HMB45, and CD45 remain negative to confirm carcinomatous tumors 3.
p63 Expression
p63 is highly specific for squamous differentiation, with 86% of poorly differentiated squamous cell carcinomas showing immunoreactivity 3. This nuclear transcription factor identifies carcinomas with squamous cell, urothelial, and myoepithelial differentiation 3.
- p63 demonstrates 80-100% sensitivity in spindle cell squamous carcinoma, though slightly lower than 34βE12 1, 2.
- Critical caveat: p63 shows suboptimal specificity as it can overlap with adenocarcinoma; p40 (ΔNp63 isoform) is superior with 100% sensitivity and specificity for squamous differentiation 3.
- In the differential diagnosis, 70-95% of urothelial carcinomas express p63, while mesotheliomas are consistently negative 3.
- Pitfall alert: Malignant phyllodes tumors can express p63 (65% of cases, though typically focal or patchy), which can mimic metaplastic breast carcinoma 4.
S100 Protein
S100 is the primary marker for melanocytic and neural differentiation, showing high sensitivity for melanoma and peripheral nerve sheath tumors 5. S100 positivity strongly indicates melanocytic origin when combined with SOX10 nuclear staining 5.
- In spindle cell differential diagnosis, S100 positivity (with negative cytokeratins, desmin, and CD68) confirms desmoplastic melanoma 2, 6.
- Important exception: Novel S100-positive and CD34-positive spindle cell tumors with EGFR mutations have been identified in the uterine cervix, representing a variant of NTRK-rearranged spindle cell neoplasms 7.
- S100 is typically negative in spindle cell squamous carcinoma (100% of cases), atypical fibroxanthoma, and leiomyosarcoma 2, 6.
- In neurofibromatosis type 1 context, decreased S100 expression suggests higher-grade lesions (MPNST) rather than benign neurofibroma 5.
CD34 Expression
CD34 positivity suggests fibroblastic, vascular, or specific spindle cell tumor origins, but has limited specificity 8, 6. CD34 is included in comprehensive spindle cell panels as a confirmatory marker 8.
- Key diagnostic pattern: The combination of CD34+/S100+/CD30+ with EGFR mutations or kinase gene fusions characterizes NTRK-rearranged spindle cell neoplasms of the uterus 7.
- CD34 is typically positive in dermatofibrosarcoma protuberans and some atypical fibroxanthomas 6.
- Critical for phyllodes tumors: CD34 expression helps distinguish malignant phyllodes tumor from metaplastic carcinoma, though 30% of malignant phyllodes tumors are CD34-negative 4.
- CD34 should be negative when confirming sarcomatoid mesothelioma (use with desmin and S100 as negative markers) 3.
Recommended Diagnostic Algorithm
For undifferentiated spindle cell neoplasms, start with this sequential approach:
First-line screening panel: Broad-spectrum cytokeratin (preferably 34βE12), S100/SOX10, and CD45 to categorize as epithelial, melanocytic/neural, or hematopoietic 5.
If cytokeratin-positive: Add p63 (or preferably p40) to confirm squamous differentiation versus adenocarcinoma; use TTF-1 and napsin A if adenocarcinoma suspected 3.
If S100-positive: Add melanocytic markers (HMB-45, Melan-A) to distinguish melanoma from neural tumors; check CD34 and CD30 if considering NTRK-rearranged neoplasm 5, 7.
If all negative: Add desmin and smooth muscle actin for myogenic tumors, CD34 for fibroblastic lesions, and CD68 for histiocytic processes 8, 6.
Tissue preservation is paramount: Use a minimal, targeted panel rather than extensive immunohistochemistry to preserve tissue for molecular studies, especially in advanced-stage disease 3.