Summary: definition, molecular etiology, and the aggressive subgroup

Adenoid cystic carcinoma (ACC) is a malignancy of secretory glands that arises most often in the major and minor salivary glands of the head and neck, and less often in the tracheobronchial tree, breast, lacrimal glands, and other sites. It accounts for approximately 1% of head and neck malignancies. Tumors are biphasic (ductal and myoepithelial cells) and grow in cribriform, tubular, and solid patterns, often mixed within a single tumor. No lifestyle risk factors such as smoking or alcohol use have been linked to ACC.

The t(6;9) translocation producing the MYB-NFIB fusion is the hallmark genetic event. The reported frequency varies by detection method (28% of primary tumors by RT-PCR in one series of 123 salivary cancers; 40% to 70% by FISH), while MYB RNA expression is detected in 80% to 90% of tumors regardless of fusion status. Activating NOTCH pathway alterations, most often in NOTCH1, occur in a subset of tumors; in a genomic analysis of 1,045 ACCs, NOTCH1 alterations were present in 26.3% of recurrent or metastatic tumors and 8.5% of primary tumors.

Proteogenomic profiling of 54 tumors at MD Anderson Cancer Center defined two molecular subtypes: ACC-I (20 of 54, 37%), with MYC upregulation, enrichment of NOTCH-activating mutations, enrichment for solid histology, and median overall survival of 3.44 years; and ACC-II (34 of 54, 63%), with TP63 upregulation, predominantly cribriform and tubular histology, and median overall survival of 23.2 years. MYC and p63 immunohistochemistry reproduced this classification. Solid histology and high-grade transformation (a rare progression with nuclear enlargement and irregularity, higher mitotic counts, and loss of the biphasic ductal-myoepithelial differentiation) define the aggressive ACC population addressed in this report. Day One Biopharmaceuticals reports that up to 40% of patients have this aggressive form.

Definition: a secretory gland malignancy arising mainly in the salivary glands

“Adenoid cystic carcinoma (ACC) is a rare malignancy arising from the secretory glands, most commonly seen involving the salivary glands. It accounts for approximately 1% of all malignancies of the head and neck region.” (opens the source at this quote in a new tab)
“Unlike other carcinomas of the head and neck region like squamous and basal cell carcinoma, smoking and the use of alcohol have not been linked as potential risk factors for the development of ACC.” (opens the source at this quote in a new tab)
“Three distinct histological patterns are associated with ACC: tubular, cribriform, and solid, which are seen in varying degrees, often mixed, with the cribriform subtype being the most common.” (opens the source at this quote in a new tab)
“In the solid subtype, basaloid cells are arranged solid sheets, often having prominent mitotic activity and central necrosis.” (opens the source at this quote in a new tab)

“Adenoid cystic carcinoma (AdCC) is a rare malignancy originating from secretory glands with yet unknown aetiology and accounts for approximately 1% of malignant head and neck tumours” (opens the source at this quote in a new tab)

“Adenoid cystic carcinoma (ACC) is a rare malignancy arising in salivary glands and other sites, characterized by high rates of relapse and distant spread.” (opens the source at this quote in a new tab)

Etiology: MYB-NFIB fusion from the t(6;9) translocation

“We show that the t(6;9)(q22–23;p23–24) translocation in adenoid cystic carcinomas (ACC) of the breast and head and neck consistently results in fusions encoding chimeric transcripts predominantly consisting of MYB exon 14 linked to the last coding exon(s) of NFIB.” (opens the source at this quote in a new tab)
“Our data indicate that the MYB-NFIB fusion is a hallmark of ACC and that deregulation of the expression of MYB and its target genes is a key oncogenic event in the pathogenesis of ACC.” (opens the source at this quote in a new tab)

“The MYB-NFIB fusion was detected in 28% primary and 35% metastatic ACCs, but not in any of the non-ACC salivary carcinomas analyzed.” (opens the source at this quote in a new tab)
“Notably, MYB was overexpressed in the vast majority of the ACCs, although MYB expression was significantly higher in tumors carrying the MYB-NFIB fusion.” (opens the source at this quote in a new tab)

“Evidence for this fusion transcript is considered diagnostic of ACC. However, by fluorescence in situ hybridization (FISH), a commonly employed technique in clinical practice, this fusion is present in only 40 to 70% of cases” (opens the source at this quote in a new tab)
“On the other hand, persistent MYB RNA expression has been noted in 80 to 90% of ACC regardless of translocation status” (opens the source at this quote in a new tab)

Etiology: low mutational burden with chromatin regulator and NOTCH pathway alterations

“These analyses revealed a low exonic somatic mutation rate (0.31 non-silent events/megabase) and wide mutational diversity.” (opens the source at this quote in a new tab)
“Interestingly, mutations selectively involved chromatin state regulators, such as SMARCA2, CREBBP, and KDM6A, suggesting aberrant epigenetic regulation in ACC oncogenesis.” (opens the source at this quote in a new tab)

“An integrated genomic analysis of 1,045 ACCs (177 primary, 868 R/M) was performed to identify alterations associated with advanced and metastatic tumors.” (opens the source at this quote in a new tab)

“NOTCH1 mutations define a distinct disease phenotype characterized by solid histology, liver and bone metastasis, poor prognosis, and potential responsiveness to Notch1 inhibitors.” (opens the source at this quote in a new tab)

“Genotypically, the aggressive form of ACC is enriched for NOTCH‐activating mutations, particularly in NOTCH1 which are present in approximately 25% of cases and are significantly associated with shorter OS, higher likelihood of solid histology, higher rate of bone and liver metastases, and shorter relapse‐free survival” (opens the source at this quote in a new tab)

Molecular subtypes: ACC-I and ACC-II from proteogenomic profiling

“Both unbiased RNA-seq and RPPA analysis revealed two molecular subtypes; ACC-I (37%) and ACC-II (63%).” (opens the source at this quote in a new tab)
“ACC-I had strong upregulation of MYC, MYC target genes, and mRNA splicing, enrichment of NOTCH activating mutations and dramatically worse prognosis.” (opens the source at this quote in a new tab)
“ACC-II exhibited upregulation of TP63 and receptor tyrosine kinases (AXL, MET, EGFR), and less aggressive clinical course.” (opens the source at this quote in a new tab)
“Our data suggests a model in which ACC-I is driven by MYC signaling through either NOTCH mutations or direct amplification, which in turn suppress P63 signaling observed in ACC-II producing unique therapeutic vulnerabilities for each subtype.” (opens the source at this quote in a new tab)
“As MYB/MYBL1-NFIB fusion are hallmark genetic events of ACC, we assessed if these fusions correlated to clustering.” (opens the source at this quote in a new tab)
“there was no difference in MYB/MYBL1-NFIB fusion events between ACC-I (65%, 13/20) and ACC-II (64%, 22/34)” (opens the source at this quote in a new tab)

“Recent studies have identified two molecular subtypes based on transcriptomic profiling and MYC/TP63 expression (ACC I: MYC-high/TP63-low; ACC II: MYC-low/TP63-high) with potential prognostic significance.” (opens the source at this quote in a new tab)
“ACC I tumors are characterized by enhanced proliferative signaling, loss of myoepithelial differentiation, and aggressive clinical behavior, whereas ACC II tumors retain features of myoepithelial lineage differentiation and demonstrate more favorable outcomes.” (opens the source at this quote in a new tab)

“Recent molecular profiling efforts have identified two important subtypes: the more aggressive ACC-I is characterized by Notch pathway alterations and MYC amplification whereas ACC-II demonstrates a more indolent phenotype and TP63 overexpression.” (opens the source at this quote in a new tab)

Solid histology: loss of myoepithelial cells and association with ACC-I

“Usually, loss of myoepithelial cells within a tumor is associated with emergence of a solid epithelial form and aggressive behavior, although solid subtype may be composed of myoepithelial cells” (opens the source at this quote in a new tab)
“Cluster I (ACC-I) (20 of 54; [37%]) was enriched for tumors with any solid component” (opens the source at this quote in a new tab)
“In contrast, samples in cluster II (ACC-II, 34 of 54; [63%]) contained more tumors with cribriform and tubular histology” (opens the source at this quote in a new tab)

“Although tubular and cribriform patterns predominate myoepithelial cells, S histology is typically characterized by epithelial cell predominance” (opens the source at this quote in a new tab)
“ACC‐I is characterized by NOTCH pathway activation and MYC overexpression, predominantly represented by S tumors, and usually have an aggressive behavior with a median OS of 3.44 years.” (opens the source at this quote in a new tab)

High-grade transformation: definition

“High-grade transformation of adenoid cystic carcinoma (ACC) (previously referred to as dedifferentiation) is a rare phenomenon that does not fit into the traditional ACC grading schemes.” (opens the source at this quote in a new tab)
“Histologically, ACC with high-grade transformation was distinguished from conventional ACC by nuclear enlargement and irregularity, higher mitotic counts, and the loss of the biphasic ductal-myoepithelial differentiation.” (opens the source at this quote in a new tab)
“The most common morphologies for the high-grade component were poorly differentiated cribriform adenocarcinoma and solid undifferentiated carcinoma.” (opens the source at this quote in a new tab)

“Chromosomal gains were mostly confined to the areas of high-grade transformation while losses were seen only in the conventional areas.” (opens the source at this quote in a new tab)
“Our findings implicate C-MYC amplification in this progression, although the role of HER2/neu is still unclear.” (opens the source at this quote in a new tab)

“Notably, the solid subtype was the most prevalent pattern within HGT, accounting for 69.6% of cases.” (opens the source at this quote in a new tab)
“The findings support classifying HGT in ACC as Grade 4, reflecting its severity.” (opens the source at this quote in a new tab)

Aggressive ACC: share of patients as described by the manufacturer

“Up to 40% of patients have an aggressive form of ACC characterized by solid/basaloid or high-grade transformation histology and poor prognosis with median progression-free survival (PFS) of 2–3 months and median overall survival of approximately 3 years.” (opens the source at this quote in a new tab)

Definition of ACC-I: MYC upregulation, NOTCH1 mutations, and 37% of cases

“However, prior studies have demonstrated that NOTCH1 alterations are associated with worse outcomes, associated with more aggressive and widespread ACC (19, 20). Further, NOTCH1 mutations frequently characterize ACC-I, a subgroup of ACC tumors harboring upregulation of MYC, along with MYC target genes and mRNA splicing pathways comprising 37% of all cases linked with poor outcomes. ACC-II is characterized by increased expression of receptor kinases and TP63, often aligned with a more indolent pattern of disease growth.” (opens the source at this quote in a new tab)
“Adenoid cystic carcinoma (ACC) is a rare malignancy of the salivary glands and other glandular tissue accounting for 10% to 20% of all salivary gland neoplasms (1–3).” (opens the source at this quote in a new tab)

Etiology: absence of established risk factors and age at presentation

“The tumor occurs in all age groups with a high frequency in middle-aged and older patients” (opens the source at this quote in a new tab)
“the 5th and 6th decades being most commonly affected” (opens the source at this quote in a new tab)
“There are no distinct risk factors, and smoking is not known to affect the incidence” (opens the source at this quote in a new tab)
“AdCC is a relentlessly growing tumor characterized by perineural invasion and multiple local recurrences.” (opens the source at this quote in a new tab)

High-grade transformation: definition as an abrupt change in morphology

“The conventional LG and HG areas are usually clearly demarcated, although a transitional zone may be present in some cases.” (opens the source at this quote in a new tab)
“The HG component is composed of solid nests of anaplastic cells with large vesicular pleomorphic nuclei, prominent nucleoli, and abundant cytoplasm. Frequent mitoses and extensive necrosis may be present. The Ki-67 labeling index is consistently higher in the HG component.” (opens the source at this quote in a new tab)
“The histologic hallmarks of HGT in AdCC include necrosis, high mitotic rate, and loss of the biphasic ductal-myoepithelial differentiation.” (opens the source at this quote in a new tab)
“AdCCs with both tubular and cribriform patterns generally have a better prognosis than those with solid pattern. The presence and extent of the solid pattern (currently with a cutoff of 30%) portend an accelerated and worse clinical course.” (opens the source at this quote in a new tab)

Emiltatug ledadotin (Emi-Le)

Definition and etiology