What tumor markers and stains are used to diagnose and manage adenoid cystic carcinoma (ACC)?

Tumor Markers and Stains for Adenoid Cystic Carcinoma

The diagnosis and management of adenoid cystic carcinoma (ACC) relies primarily on immunohistochemical staining panels that include CD117 (c-KIT), TTF-1, cytokeratins, and myoepithelial markers such as S-100 protein and actin. These markers help distinguish ACC from other malignancies and guide treatment decisions that impact patient survival.

Key Diagnostic Markers for ACC

Essential Immunohistochemical Markers

• CD117 (c-KIT): Overexpressed in glandular epithelia of ACC in approximately 75% of cases 1
• S-100 protein: Positive in myoepithelial component of ACC 2
• Actin: Positive in myoepithelial cells of ACC 2
• Cytokeratins: Positive in tumor cells, particularly in glandular structures 2

Differential Diagnosis Markers

• TTF-1 (Thyroid Transcription Factor-1):

  • Can be positive in some ACC cases (approximately 33%) 1
  • Important for distinguishing primary pulmonary ACC from metastatic disease
  • Generally negative in salivary gland origin ACC

• Estrogen/Progesterone Receptors (ER/PR):

  • Typically negative in ACC 3
  • Useful for distinguishing ACC from invasive cribriform carcinoma of the breast which is usually ER/PR positive

Diagnostic Algorithm for ACC

1. Initial Panel:

   • CD117 (c-KIT)
   • S-100 protein
   • Actin
   • Cytokeratin panel (CK7, CK20)
   • TTF-1

2. Extended Panel (for difficult cases):

   • Calretinin
   • p63/p40
   • CEA (Carcinoembryonic Antigen)
   • ER/PR (especially for breast lesions)

Histopathological Patterns

ACC demonstrates three main growth patterns that should be identified and reported:

• Cribriform (cylindromatous)
• Tubular
• Solid

The solid pattern is associated with more aggressive behavior and poorer prognosis 2, 4.

Clinical Significance of Markers

1. Prognostic Value:

   • Histological pattern is more prognostically significant than marker expression
   • Cribriform/tubular types have better prognosis than solid type (HR: 0.32,95% CI: 0.11-0.93) 4
   • CD117 expression alone has not shown significant correlation with prognosis 1

2. Treatment Implications:

   • Complete surgical resection with negative margins is the most important prognostic factor (HR: 0.19,95% CI: 0.06-0.61) 4
   • Adjuvant radiotherapy improves overall survival in skull base ACC (16.2 vs 5.5 years, p=0.03) 5
   • No significant benefit has been demonstrated for chemotherapy 5

Common Pitfalls in ACC Diagnosis

1. Misdiagnosis as adenocarcinoma: ACC can be mistaken for adenocarcinoma, particularly in lung specimens. The dual cell population (epithelial and myoepithelial) in ACC is key to differentiation.

2. Overreliance on single markers: No single marker is pathognomonic for ACC. Always use a panel approach.

3. Failure to distinguish primary vs. metastatic ACC: TTF-1 expression can help determine if lung ACC is primary or metastatic.

4. Inadequate sampling: ACC has heterogeneous patterns; limited sampling may miss the characteristic architecture.

Molecular Testing

While not yet standard in all clinical settings, emerging molecular markers for ACC include:

• EML4-ALK gene rearrangements (rare but reported) 1
• MYB-NFIB fusion (common in ACC but not routinely tested)

By using these markers and stains appropriately, clinicians can accurately diagnose ACC, distinguish it from mimics, and guide appropriate treatment decisions to improve patient outcomes.