Summary: survival in aggressive ACC compared with cribriform and tubular ACC

ACC overall has an indolent early course with continued late recurrence and mortality. In SEER (3,026 head and neck cases), 5-, 10-, and 15-year survival was 90.3%, 79.9%, and 69.2%. In institutional series, 5-year survival of 74% to 85% declines to 50% to 64% at 10 years and 20% at 25 years, and more than 50% of tumors recur or metastasize. Mortality continues beyond 20 years: a review of long-followed series reports 5-, 10-, and 20-year survival of 68%, 52%, and 28% in one cohort of 105 participants, 40% of participants alive at 20 years in a United Kingdom series in which the actuarial primary site recurrence rate at 30 years was 100%, and attributes the low long-term survival to failure to control distant disease. In a contemporary cohort of 161 participants at one center, 86% of whom had recurrent disease, median overall survival from diagnosis was 13.9 years (95% CI 9.39 to 17.8), and NOTCH1 status was associated with survival from diagnosis (P = 0.040) and from recurrence (P = 0.007).

Solid histology and ACC-I status are associated with shorter survival. In the original Szanto grading series (79 participants), 15-year survival was 39%, 26%, and 5% for grades I, II, and III (predominantly solid), and grade III tumors caused death within 4 years. In a proteogenomic cohort of 54 participants, median overall survival was 3.44 years for ACC-I and 23.2 years for ACC-II; a 2026 meta-analysis of 247 participants from 5 cohorts found a pooled hazard ratio for death of 3.88 (95% CI 2.55 to 5.90) for ACC-I versus ACC-II. NOTCH1-mutant tumors had median overall survival of 30 months versus 122 months for wild-type tumors. High-grade transformation carries the poorest reported outcomes. In a 9-participant series, 5 died within 5 years and median overall survival was 12 months. In a 1:1 matched series of 23 transformed and 23 non-transformed cases drawn from 412 ACCs, mortality was 47.8% (11 of 23) versus 8.7% (2 of 23), 3-year mortality was 34.8% (8 of 23) versus 4.3% (1 of 23), average survival was 35.9 versus 55.9 months, and median progression-free survival was 18.0 versus 37.0 months, although median follow-up was shorter in the transformed group (29.0 versus 39.0 months); distant metastasis occurred in 78.3% (18 of 23), the lung was the first site in 83.3% (15 of 18), and median survival after metastasis was 8.0 versus 16.5 months. A pathology review describes salivary gland carcinomas with high-grade transformation as more aggressive than conventional carcinomas, with higher local recurrence, a high propensity for cervical lymph node metastasis, and poorer prognosis. After distant metastasis, solid-type ACC had shorter survival and more frequent multiorgan metastases (17 of 28, 61%) than non-solid ACC, and metastases outside the lung were associated with shorter survival (median 11.04 versus 44.52 months in one series of 51 participants).

ACC overall: long-term survival in SEER and institutional cohorts

“The overall 5-year, 10-year, and 15-year survival outcomes for ACCHN patients were 90.3%, 79.9%, and 69.2%, respectively.” (opens the source at this quote in a new tab)

“Median overall survival was 11.0 (95% CI: 9.2-NR years), 14.3 (95% CI: 12.4–16.4 years), 11.3 (95% CI: 9.7–14.8 years), and 12.0 (95% CI: 11.3–13.0 years) for Midwest, Northeast, South, and West regions, respectively.” (opens the source at this quote in a new tab)

“Due to its slow growth, the disease often runs an indolent course, with 5-year survival rates of 80–85%, but contrary to other head and neck cancers, these promising numbers decline when following 10- and 15-year survival rates, which are 50–60% and 30–35%, respectively” (opens the source at this quote in a new tab)

“Five-year, 10-year, 15-year, 20-year, and 25-year OS rates were 74.0, 63.7, 41.0, 27.3, and 20.0%, respectively.” (opens the source at this quote in a new tab)

ACC overall: recurrence and distant metastasis over time

“More than 50% of ACCs recur or develop distant metastases over time. Relapsed tumors are generally incurable because no systemic agents to date have been found to be effective. Therefore, overall prognosis has remained poor, with long-term overall survival (OS) rates of 23%–40%” (opens the source at this quote in a new tab)

“AdCC is usually treated with surgery upfront, often followed by postoperative radiotherapy, but despite an aggressive therapy regimen late (>5 years after primary treatment), local relapse (15–85%) and distant metastases (25–55%) are common” (opens the source at this quote in a new tab)

“ACC usually is an aggressive, although slowly growing, cancer with a long-term poor prognosis. Most patients (80–90%) with ACC of the head and neck die within 10–15 years after diagnosis.” (opens the source at this quote in a new tab)

Solid histology versus cribriform and tubular histology: histologic grade and survival

“Three histologic grades were established: Grade I, tumors with tubular and cribriform areas but without solid components; Grade II, cribriform tumors that were either pure or mixed with less than 30% of solid areas; and Grade III, tumors with a predominantly solid pattern. Cumulative survival rates at 15 years were 39%, 26%, and 5%, for Grades I, II, and III, respectively. Grade III tumors were larger, recurred frequently, and killed the patients within 4 years.” (opens the source at this quote in a new tab)

“The presence of any solid component in ACC is a negative prognosticator, and can histopathologically be diagnosed with a high reliability.” (opens the source at this quote in a new tab)

“Conducting surgery (HR: 0.19, 95% CI: 0.06–0.61, p = 0.005) and C-T type (HR: 0.32, 95% CI: 0.11–0.93, p = 0.036) were independent prognostic predictors of DSS.” (opens the source at this quote in a new tab)

Molecular subtype: ACC-I versus ACC-II survival

“Notably, the expression groups were highly prognostic, with ACC-I subjects exhibiting markedly worse OS than ACC-II; specifically, median OS was 3.44 years (95% CI=2.31–6.00) for ACC-I, and 23.2 years (95% CI= 14.0-inf.) for ACC-II (p<0.001)” (opens the source at this quote in a new tab)

“ACC I was associated with significantly worse overall survival compared with ACC II, with a pooled HR of 3.88 (95% CI: 2.55–5.90; p < 0.001).” (opens the source at this quote in a new tab)
“ACC I tumors confer an approximately four-fold higher mortality risk compared with ACC II tumors.” (opens the source at this quote in a new tab)

“When pooling systemic treatment categories, ACC-I patients had worse outcomes with available therapies (HR, 3.06; 95% confidence interval, 1.65-5.68; P < 0.01), with no significant difference in overall survival between ACC-I/II based on chemotherapy or VEGFR tyrosine kinase inhibitor exposure in smaller subsets.” (opens the source at this quote in a new tab)

NOTCH1-mutant ACC: relapse-free and overall survival

“NOTCH1 mutations define a distinct aggressive ACC subgroup with a significantly higher likelihood of solid subtype (P < .001), advanced-stage disease at diagnosis (P = .02), higher rate of liver and bone metastasis (P ≤ .02), shorter relapse-free survival (median, 13 v 34 months; P = .01), and shorter overall survival (median 30 v 122 months; P = .001) when compared with NOTCH1 wild-type tumors.” (opens the source at this quote in a new tab)

“Molecular findings predicted outcomes: 10-y OS: 100% MYB, 53.3% PI3K, 32.1% NOTCH1 and others, p = 0.03.” (opens the source at this quote in a new tab)

High-grade transformation: survival and mortality

“Five of 9 patients (55.6%) died, all within 5 years with a median overall survival of 12 months.” (opens the source at this quote in a new tab)
“ACC-high-grade transformation is a highly aggressive salivary gland tumor with a variety of histologic patterns.” (opens the source at this quote in a new tab)

“HGT was associated with increased recurrence (55.0%) and distant metastasis (78.3%), leading to an average survival of 35.9 months and a 3-years mortality rate of 35.0%. Overall and progression-free survival rates were significantly decreased in the HGT group.” (opens the source at this quote in a new tab)

Metastatic disease: survival by histology and metastatic site

“Forty-two percent of the patients were diagnosed with distant metastases.” (opens the source at this quote in a new tab)
“Median distant metastatic survival was 13.8 months. The most frequent organ sited was the lung. Solid type ACC showed a preponderance for multiorgan metastases (17/28; 61%).” (opens the source at this quote in a new tab)
“Solid type ACC had a significant poorer survival after development of distant metastases.” (opens the source at this quote in a new tab)

“The median overall survival (OS) for the entire cohort was 29.21 months. Patients with lung metastases had significantly longer OS compared to those without (44.52 vs. 11.04 months, p = 0.008).” (opens the source at this quote in a new tab)

“One hundred seventy-four patients with metastatic HNACC were enrolled and median overall survival (OS) was 45.6 months.” (opens the source at this quote in a new tab)

Aggressive ACC: progression-free and overall survival as reported by the manufacturer

“ACC-1 is a rare and aggressive cancer that most frequently originates in the salivary glands. With no approved therapies, median PFS and median overall survival for patients with ACC-1 are reported to be 2-3 months and 2-3 years, respectively.” (opens the source at this quote in a new tab)

Time to locoregional recurrence or metastasis after diagnosis

“Approximately 50% to 70% of patients develop locally recurrent or metastatic disease within 5 years of diagnosis, although late recurrences more than a decade after treatment are not uncommon (1, 9–12).” (opens the source at this quote in a new tab)

Survival and recurrence in ACC series followed beyond 20 years

“In a large European study on AdCC of the head and neck, the 10-year survival rate was 65%” (opens the source at this quote in a new tab)
“reported 5-, 10- and 20-year survival rates of 68%, 52% and 28%, respectively, on a series of 105 patients.” (opens the source at this quote in a new tab)
“reported that overall and recurrence-free survival rates at three years were 84.6% and 58.2%, respectively, while the rate of survival with recurrence was 26.4%. After 15 years, the overall survival rate was 24.5%, and the recurrence-free survival rate was 22.6%.” (opens the source at this quote in a new tab)
“In a UK series, 40% of AdCC patients were alive at 20 years and survival continued to drop until 30 years; the actuarial primary site recurrence rate at 30 years in that study was 100%” (opens the source at this quote in a new tab)
“and it was 54% in the Australian series.” (opens the source at this quote in a new tab)
“The low long-term survival rate of AdCC patients is uniformly linked to the failure to control distant disease. These distant metastases occur most frequently in the lung.” (opens the source at this quote in a new tab)

High-grade transformation versus matched conventional ACC: mortality with follow-up duration

“After a median follow-up of 29.0 months (range 6–108 months), the mortality rate was 47.8% (11/23), with an average survival of 35.9 months. The 3-year mortality rate was 34.8% (8/23), and the median PFS was 18.0 months (mean 25.1 months).” (opens the source at this quote in a new tab)
“Their median follow-up was 39.0 months (range 13–152 months), with a mortality rate of 8.7% (2/23) and an average survival time of 55.9 months. The 3-year mortality rate was 4.3% (1/23), and the median PFS was 37.0 months (mean 36.1 months).” (opens the source at this quote in a new tab)
“The HGT group had a median survival time of 29.0 months, a 5-year mortality rate of 34.8% (8/23), and a mean survival time of 35.8 months, consistent with the poor prognosis reported in the literature.” (opens the source at this quote in a new tab)

High-grade transformation: survival after distant metastasis

“In the HGT group, distant metastasis was 78.3% (18/23), with the lungs being the primary site in 83.3% (15/18). Post-metastasis survival averaged 9.0 months (median 8.0 months).” (opens the source at this quote in a new tab)
“Post-metastasis survival averaged 25.8 months (median 16.5 months), and 8.7% (2/23) had cervical lymph node metastasis at initial diagnosis.” (opens the source at this quote in a new tab)

High-grade transformation across salivary gland carcinomas: recurrence and prognosis

“Salivary gland carcinomas with HGT are more aggressive than conventional carcinomas, with a higher local recurrence rate and a poorer prognosis. They have a high propensity for cervical lymph node metastasis suggesting a need for a wider resection and neck dissection.” (opens the source at this quote in a new tab)
“AdCC-HGT is a biologically aggressive tumor, and hence it displays a high frequency of locoregional recurrence and metastasis to lymph nodes and distant sites.” (opens the source at this quote in a new tab)

EQ-5D value score and risk of death: time-dependent Cox proportional hazards model

Model parameter	Value
Hazard ratio (95% confidence intervals), time-dependent linear Cox model	“0.118 (0.057–0.244)”
Standard error	“0.371”
P value, chi-squared comparison with a non-linear model built using penalised splines	“0.011”

Non-linear relationship between EQ-5D value score and survival

“However, there was a significant non-linear relationship between EQV and survival over time (p = 0.011; Table 3). Fig. 3 shows the modelled non-linear survival probability over time per EQV decile. A greater marginal effect on survival was seen for the difference in EQV above the median value of 0.81.” (opens the source at this quote in a new tab)

Overall survival and prognostic factors in the 161-participant EQ-5D-5L cohort

“As expected, median overall survival from diagnosis was 13.9 years (95 % confidence interval: 9.39 – 17.8)” (opens the source at this quote in a new tab)
“we found NOTCH1 status to be significantly associated with both survival from diagnosis (p = 0.040) and survival from recurrence (p = 0.007) in our cohort.” (opens the source at this quote in a new tab)
“The other parameters evaluated were location of primary site, sex, and recurrence status, with no significant associations found.” (opens the source at this quote in a new tab)

Emiltatug ledadotin (Emi-Le)

Natural history, survival, and mortality