Adenoid Cystic Carcinoma - ACC
Adenoid cystic carcinoma (ACC), particularly the primary cutaneous form (PCACC) or tumors arising from skin adnexal glands and the minor salivary glands of the head and neck, is a rare malignancy with a very distinctive biology: slow growth, highly aggressive local invasion, a very high rate of perineural invasion (PNI) and a tendency toward late distant spread, especially to the lungs.
MYB-NFIB / MYBL1-NFIB Gene Rearrangements
- Chromosomal translocation t(6;9)(q22–23;p23–24): this specific driver alteration is found in more than 80–90% of ACC cases. It fuses the coding region of the MYB gene (chromosome 6) with the NFIB gene (chromosome 9).
- Loss of control over the MYB transcription factor: the fusion gene loses the 3'-UTR region that carries the microRNA binding sites normally responsible for breaking down MYB, so MYB protein builds up and is overexpressed. MYB drives the cell cycle, blocks programmed cell death (apoptosis) and triggers epithelial-mesenchymal transition (EMT).
How Perineural Invasion (PNI) Spreads
- Neurotropism: ACC cells release large amounts of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). These molecules bind TrkA/TrkB receptors on peripheral nerve fibers and sheaths, setting up a concentration gradient that draws cancer cells to creep along the nerve sheath.
- Skip lesions: cancer cells can travel along the nerve sheath, leave a gap, and then resume growing farther along. This means conventional surgical margins can be falsely negative unless they are checked with continuous microscopic margin control.
Two Coexisting Cell Lineages (Dual-Cell Lineage)
ACC is made up of two differentiated cell populations living side by side:
- Luminal ductal cells: strongly express CD117 (c-Kit), CK7 and EMA.
- Myoepithelial / basaloid cells: express p63, p40, SMA, calponin and S100.
Histopathology and Immunohistochemistry (IHC) Criteria
Three Histologic Growth Patterns
Under the microscope, ACC falls into three main patterns, each with direct prognostic significance:
- Cribriform pattern: the most typical form. Basaloid tumor cells form large nests riddled with small spaces containing basophilic mucin or reduplicated basement membrane material (pseudocysts), giving a Swiss-cheese appearance.
- Tubular pattern: tumor cells form small ducts with a clear two-layer structure (inner luminal layer and outer myoepithelial layer). This pattern is the least aggressive and carries a better prognosis.
- Solid pattern: basaloid cells grow in solid sheets without cribriform or tubular structures, with a high mitotic rate and often central necrosis. The solid pattern is the most aggressive, with recurrence and distant metastasis rates >50%.
Immunohistochemistry (IHC) Panel for Differential Diagnosis
| IHC Marker | Where It Is Expressed in the Tumor | Diagnostic Significance |
|---|---|---|
| CD117 (c-Kit) | Cytoplasm/membrane of luminal epithelial cells | Strongly positive (+++): the gold standard for distinguishing ACC from adenoid basal cell carcinoma (BCC) |
| MYB | Tumor cell nuclei | Strongly positive (+++): reflects the presence of the MYB-NFIB fusion gene |
| p63 / p40 | Myoepithelial cell nuclei | Positive (++) in the outer cell layer surrounding cribriform/tubular structures |
| SMA / Calponin | Myoepithelial cell cytoplasm | Positive (++): confirms myoepithelial differentiation |
| S100 | Nucleus and cytoplasm | Diffusely positive (++) in myoepithelial cells and in invaded nerves |
| CK7 / EMA | Luminal cell cytoplasm | Strongly positive (+++): confirms ductal gland origin |
| Ki-67 index | Nuclei of dividing cells | Cribriform/tubular: 5–15%; solid pattern: >30–50% |
Imaging: 50 MHz High-Frequency Ultrasound and Dermoscopy
- High-frequency skin ultrasound (20–50 MHz):
- A heterogeneous hypoechoic mass with ragged, infiltrative borders that blend into the surrounding stroma.
- Abnormal nerve sheath thickening running through the lesion, an ultrasound sign suggestive of PNI.
- Dermoscopy:
- A pinkish-red or gray-brown area with a smooth, shiny surface or interrupted chrysalis structures (shiny white fibrous lines under polarized light).
- Polymorphous vessels: arborizing vessels combined with dotted vessels and surrounding reticular telangiectasia.
Clinical Presentation
- Location: for primary cutaneous ACC (PCACC), the most common site is the scalp, followed by the face, neck and trunk.
- Appearance: a papule or superficial indurated plaque, or a red-purple or skin-colored nodule, that grows slowly over many years.
- Characteristic nerve symptoms: because of PNI, patients often notice stabbing pain, paresthesia, numbness or neuropathic pain in the affected skin before the tumor becomes obviously enlarged.
Multimodal Treatment at Haute-Derma
Because ACC spreads silently along nerves and has a very high local recurrence rate (>30–50% after conventional excision alone), Haute-Derma uses a multimodal approach that closely coordinates microsurgery, adjuvant radiotherapy and systematic follow-up:
Biopsy and Molecular Identification
- Deep biopsy (deep incisional / core biopsy): the sample must extend through the dermis into the subcutaneous fat to assess the cribriform architecture and look for tumor cells along superficial nerve branches.
- IHC diagnosis: a CD117 / MYB / p63 / CK7 / Ki-67 panel is required to confirm the diagnosis and classify the growth pattern (cribriform vs. solid).
Microsurgical Excision With 100% Microscopic Margin Control
Mohs Micrographic Surgery (MMS):
- Indication: the gold standard for ACC of the head, neck and scalp, as it deals with the skip lesions of PNI.
- Technique: tissue is removed layer by layer and 100% of the lateral and deep margins are mapped under the microscope during surgery. If tumor cells are found around a nerve at any point, the surgeon continues to dissect along that nerve branch until the margins are completely clear.
Wide Local Excision (WLE):
- Used when Mohs surgery is not available.
- Clinical surgical margin: excision 1.5–2.0 cm beyond the tumor edge, including the underlying deep fascia. Margin inking and thorough serial sectioning are mandatory.
Adjuvant Radiotherapy and Management of Metastases
- Intensity-modulated radiotherapy (IMRT) or proton beam therapy:
- Required for: perineural invasion (PNI+), the solid pattern, close or positive margins, or recurrent tumors.
- Goal: to destroy hidden microscopic tumor deposits tracking along the nerve toward the central nervous system. Recommended dose: 60–66 Gy.
- Systemic targeted therapy (for distant metastasis or progression):
- ACC metastasizes slowly, mainly to the lungs. For patients with advanced disease, options in use include clinical trials targeting the NOTCH pathway (for tumors with NOTCH1 mutations), tyrosine kinase inhibitors targeting c-Kit (imatinib, which has limited efficacy but may be considered) and MYB-targeted therapies.
- Long-term surveillance:
- Clinical review and skin/regional ultrasound every 3 months for the first 2 years, then every 6 months in the following years.
- Annual chest CT: because lung metastases from ACC can appear very late, 5–10 years after treatment.
