What pathological and immunohistochemical (IHC) tests can help rule out salivary gland squamous cell carcinoma (SG-SCC)?

Pathological and Immunohistochemical Tests for Ruling Out Salivary Gland Squamous Cell Carcinoma (SG-SCC)

A comprehensive panel of histopathological examination and immunohistochemical (IHC) markers is essential to rule out salivary gland squamous cell carcinoma, with androgen receptor (AR), GCDFP-15, and p63 staining being the most critical differentiating tests.

Diagnostic Approach

Initial Histopathological Assessment

• Perform tissue biopsy (either fine needle aspiration biopsy [FNAB] or core needle biopsy [CNB]) to distinguish salivary gland cancers from non-malignant lesions 1
• If FNAB is inadequate, proceed with CNB, especially for deep minor salivary glands 1
• Examine for histologic features characteristic of squamous cell carcinoma:
  • Keratinization
  • Intercellular bridges
  • Extensive desmoplastic reaction
  • Peritumoral inflammation 2

Critical Immunohistochemical Panel

1. Primary IHC Panel (Most Important):

   • Androgen receptor (AR) - typically positive in salivary duct carcinoma (SDC) but negative in true SG-SCC 3, 2
   • Gross cystic disease fluid protein-15 (GCDFP-15) - positive in SDC but negative in SG-SCC 3, 2
   • p63 - negative in SDC but positive in SG-SCC 3

2. Secondary IHC Panel:

   • p40 (ΔNp63) - superior to p63 for squamous differentiation 1
   • CK5/6 - positive in squamous components 4
   • Mammaglobin - often positive in salivary gland carcinomas 3
   • MUC1/MUC2 - helps differentiate salivary gland tumor types 3
   • TTF-1 and napsin A - to rule out metastatic lung adenocarcinoma 1

Special Stains

• Mucicarmine or periodic acid-Schiff (PAS) with and without diastase - to detect mucin production (negative in true SG-SCC) 1, 2
• Elastic tissue histochemical staining (van Gieson) - to assess pleural invasion in metastatic cases 1

Differential Diagnosis Considerations

Rule Out Salivary Duct Carcinoma with Squamous Differentiation

• SDC can show extensive squamous differentiation (up to 95% of tumor) 4
• Key finding: AR expression may be retained in conventional SDC component but lost in squamous areas 4
• Look for conventional SDC component (comedo-type necrosis, cribriform patterns) which may comprise <5% of the tumor 4

Rule Out Metastatic SCC

• Examine for:
  • Central necrosis (more common in metastatic SCC) 2
  • Involvement of salivary gland ducts and transition into ductal epithelium (suggests primary origin) 2
  • Location within salivary gland (central location with extraparenchymal extension is common in both primary and metastatic SCC) 2

Rule Out Other Salivary Malignancies

• Consider HPV testing if oropharyngeal involvement is present 1
• Examine for features of carcinoma ex pleomorphic adenoma (look for benign pleomorphic adenoma component) 5

Clinical Correlation

• Comprehensive review of medical history is essential as true primary SG-SCC is exceptionally rare 2, 6
• Perform imaging (neck ultrasound, CT with contrast, and/or MRI) to evaluate extent of disease and rule out other primary sites 1
• Consider PET/CT for high-grade salivary gland cancers to rule out distant metastases 1

Pitfalls to Avoid

1. Failing to recognize that primary SG-SCC is extremely rare and requires extensive exclusion of other entities
2. Relying solely on morphology without immunohistochemical confirmation
3. Missing small foci of conventional SDC in a predominantly squamous-appearing tumor
4. Overlooking metastatic SCC from other primary sites (especially head and neck, lung)
5. Not examining for ductal involvement, which may indicate primary salivary origin
6. Inadequate sampling of the tumor, as diagnostic components may be focal

True primary squamous cell carcinoma of salivary glands is considered exceptionally rare, and most cases previously diagnosed as such are now recognized as high-grade salivary malignancies with squamous differentiation or metastatic disease 2, 6.