Adenoid Cystic carcinoma of minor salivary glands (AdCCmSG): a multidisciplinary update.

INTRODUCTION: Adenoid cystic carcinoma of minor salivary glands (AdCCmSG) represents a 'rarity in the rarity,' posing a clinical challenge in lack of standardized, evidence-based recommendations. At present, AdCCmSG management is mostly translated from major salivary gland cancers (MSGCs). Ideally, AdCCmSG diagnostic-therapeutic workup should be discussed and carried out within a multidisciplinary, high-expertise setting, including pathologists, surgeons, radiation oncologists and medical oncologists. AREAS COVERED: The present review provides an overview of epidemiology and pathologic classification. Moreover, the most recent, clinically relevant updates in the treatment of AdCCmSG (Pubmed searches, specific guidelines) are critically discussed, aiming to a better understanding of this rare pathologic entity, potentially optimizing the care process, and offering a starting point for reflection on future therapeutic developments. EXPERT OPINION: The management of rare cancers is often hindered by limited data and clinical trials, lack of evidence-based guidelines, and hardly represented disease heterogeneity, which cannot be successfully tackled with a 'one-size-fits-all' approach. Our goal is to address these potential pitfalls, providing an easy-to-use, updated, multidisciplinary collection of expert opinions concerning AdCCmSG management as of today's clinical practice. We will also cover the most promising future perspectives, based on the potential therapeutic targets highlighted within AdCCmSG's molecular background.

Secretory carcinoma of minor salivary glands.

Secretory carcinoma is a malignant salivary gland tumor, which typically presents as an indolent painless mass within the parotid gland. Involvement of the minor gland is reported but less common. Secretory carcinoma was often misclassified as other salivary gland mimics, particularly acinic cell carcinoma, prior to 2010. It was first recognized as a molecularly distinct salivary gland tumor harboring the same fusion gene as well as histologic and cytogenetic features seen in juvenile breast cancer. Secretory carcinoma is generally managed in the same way as other low-grade salivary gland neoplasms and has a favorable prognosis; however, high-grade transformation requiring aggressive therapeutic interventions have been documented. Recent studies of biologic agents targeting products of this fusion gene offer the promise of a novel therapeutic option for treatment of this malignancy. Due to the limited number of reported cases, the spectrum of clinical behavior, best practices for management, and long-term treatment outcomes for secretory carcinoma remain unclear. A long-standing secretory carcinoma involving minor salivary glands of the mucobuccal fold, which was detected years after it was first noted by the patient, is reported. This case brings to light the importance of a thorough clinical exam during dental visits and reviews diagnostic differentiation of this malignancy from other mimics and discusses decision making for its management.

The extent of androgen receptor and HER2 expression allows for targeted therapy in most cases of salivary duct carcinoma: analysis of clinical and histopathological data in a tertiary care center.

PURPOSE: The incidence of salivary duct carcinoma (SDC) seems to be underestimated due to inaccurate classification. Further, the frequency of SDC patients with targeted therapy options according to current guidelines is unclear. Therefore, this study aimed at (a) describing the proportion of SDC among salivary gland carcinoma (SGC) before and after reclassification of cases initially classified as adenocarcinoma, not otherwise specified (ANOS); and (b) quantifying the frequency of SDC patients with targeted therapy options. METHODS: All patients with SDC or ANOS treated in a tertiary care center between 1996 and 2023 were identified. Histopathological diagnosis was verified for patients primarily diagnosed with SDC and reviewed for patients initially diagnosed with ANOS. Clinical data for SDC patients were retrieved from clinical charts. Immunohistochemical (IHC) androgen receptor (AR) and HER2 staining was performed. RESULTS: Among 46 SDC, 34 were primarily diagnosed as SDC and 12 had initially been classified as ANOS. The proportion of SDC among SGC was 12.1% and was rising when comparing the time periods 2000-2015 (7.1-11.5%) versus 2016-2023 (15.4-18.1%). Nuclear AR staining in > 70% of tumor cells was found in 56.8% and HER2 positivity (IHC 3 +) in 36.4% of cases. 70.5% of patients showed AR staining in > 70% of tumor cells and/or HER2 positivity and therefore at least one molecular target. 5-year overall and disease-free survival (DFS) were 62.8% and 41.0%. Multivariate Cox regression revealed positive resection margins (HR = 4.0, p = 0.03) as independent negative predictor for DFS. CONCLUSIONS: The results suggest a rising SDC incidence and show that the extent of the AR and HER2 expression allows for targeted therapy in most SDC cases.

Non-squamous Cancers of the Larynx.

PURPOSE OF REVIEW: Although non-squamous tumors of the larynx are really rare, they may not always be viewed from the same perspective in the multidisciplinary treatment approach once the diagnosis is made. In this review, non-squamous tumors of the larynx and current approaches in treatment will be discussed. RECENT FINDINGS: When the studies and meta-analyses presented in the last 5 years are evaluated, it is seen that these tumors usually show non-specific symptoms. Due to their submucosal location, the stage of the disease at the time of diagnosis is often advanced. In the literature, treatment may vary in these particular cases. The majority of non-squamous tumors of the larynx includes minor salivary gland tumors, neuroendocrine carcinomas, sarcomas, cartilage tumors, and malignant melanomas. Once treating a patient with these diagnoses, it should be kept in mind that the histopathological subtype is almost as important as the stage of the tumor.

High-grade salivary carcinomas: A current insight on diagnostic pathology and the key to clinical decision making.

High-grade carcinomas of the salivary glands are a group of several tumor entities with highly malignant histologic appearances, and have an aggressive biological behavior accompanied by poor a prognosis. In general, they require more intensive treatment than low- or intermediate-grade carcinomas. High-grade salivary carcinomas are rare and the microscopic features often overlap between different tumor types, making an appropriate diagnosis challenging in daily practice settings. However, with recent rapid advances in molecular pathology and molecular-targeted therapy in this field, there is a growing need to properly classify tumors, rather than just diagnosing the cases as "high-grade carcinomas". This leads to specific treatment strategies. In this article, we review representative high-grade salivary gland carcinomas, including salivary duct carcinoma and its histologic subtypes, high-grade mucoepidermoid carcinoma, solid-type adenoid cystic carcinoma, and high-grade transformation of low- or intermediate-grade carcinomas, and discuss their differential diagnoses and clinical implications. Other rare entities, such as neuroendocrine carcinoma, NUT carcinoma, and metastatic carcinoma, should also be considered before diagnosing high-grade carcinoma, NOS. Of these tumors, salivary duct carcinoma has received the most attention because of its strong association with androgen deprivation and anti-HER2 therapies. Other tumor-type-specific treatments include anti-TRK therapy for high-grade transformation of secretory carcinoma, but further therapeutic options are expected to be developed in the future. It should be emphasized that detailed histological evaluation with adequate sampling, in addition to the effective use of molecular ancillary tests, is of the utmost importance for a suitable diagnosis.

Appraisal of clinical practice guidelines for salivary gland cancer management utilizing AGREE II instrument.

OBJECTIVE: Salivary gland cancers (SGC) are rare neoplasms which comprise 1-5 % of all head and neck cancers. SGCs can be managed by resection, radiosurgery, chemotherapy, or a combination of these. Our team appraised the quality of clinical practice guidelines (CPGs) for SGC treatment and management using the Appraisal of Guidelines for Research and Evaluation (AGREE-II) instrument. DATA SOURCES: PubMed, Scopus, & EMBASE were reviewed for CPGs regarding SGC management from database inception to January 1st, 2023. REVIEW METHODS: The AGREE-II instrument was used by 4 reviewers to independently evaluate guidelines. Domain scores were generated with a satisfactory threshold being >60 % - a "high" quality CPG required >4 satisfactory domains. Intraclass correlation coefficients (ICCs) were used, via R 4.2.1., to determine inter-reviewer variability. RESULTS: Literature review identified 645 articles, with six being included after applying inclusion and exclusion criteria. Of the six included articles, one CPG was "high" quality and 5 were "low" quality. The domains with the highest scores were "Editorial Independence" (72.57 ± 36.60) and "Clarity and Presentation" (63.19 ± 26.08), while the lowest were "Rigor of Development" (34.03 ± 30.63) and "Applicability" (30.21 ± 30.46). ICC scores for each domain ranged from 0.937 to 0.983, indicating a high level of inter-rater agreement. CONCLUSION: This study found that most CPGs for the treatment and management of SGC were of "low" quality, with only one guideline being considered "high" quality based on the standard set by the AGREE-II instrument. These findings indicate that there is a high level of variability and little standardization when it comes to the quality of CPGs.

Patterns and Trends in Adjuvant Therapy for Major Salivary Gland Cancer.

OBJECTIVE: To investigate adjuvant therapy indications, utilization, and associated survival disparities in major salivary gland cancer (MSGC). STUDY DESIGN: Retrospective cohort study. SETTING: The 2006 to 2017 National Cancer Database. METHODS: Patients with surgically resected MSGC were included (N = 11,398). pT3-4 classification, pN2-3 classification, lymphovascular invasion, pathologic extranodal extension (pENE), and positive surgical margin (PSM) were considered indications for adjuvant radiotherapy (aRT). pENE and PSM were considered possible indications for adjuvant chemotherapy. Multivariable logistic and Cox regression models were implemented. RESULTS: Among 6694 patients with ≥ $\ge $ 1 indication for aRT, 1906 (28.5%) received no further treatment and missed aRT. Age, race, comorbidity status, facility type, and distance to reporting facility were associated with missed aRT (P < .025). Among 4003 patients with ≥1 possible indication for adjuvant chemoradiotherapy (aCRT), 914 (22.8%) received aCRT. Patients with pENE only (38.5%) and both pENE and PSM (44.0%) received aCRT more frequently than those with PSM only (17.0%) (P < .001). Academic facility was associated with aCRT utilization (P < .05). aCRT utilization increased between 2006 and 2017 in both academic (14.8% vs 23.9%) and nonacademic (8.8% vs 13.5%) facilities (P < .05). Among 2691 patients with ≥1 indication for aRT alone, missed aRT portended poorer OS (hazard ratio [HR]: 1.61, 95% confidence interval [CI]: 1.28-2.03, P < .001). Among 4003 patients with ≥1 possible indication for aCRT, aRT alone (HR: 1.02, 95% CI: 0.89-1.18, P = .780) and aCRT were associated with similar OS. CONCLUSION: Missed aRT in MSGC occurs frequently and portends poorer OS. Further studies clarifying indications for aCRT are required.

Prognosis of primary breast salivary gland-type carcinoma: a propensity score-matching analysis with invasive carcinoma of no special type based on the SEER database for years 2010-2020.

BACKGROUND: Primary breast salivary gland-type carcinoma has weak evidence to support its management due to its rare occurrence and limited data regarding its clinicopathological features and prognosis. Therefore, this study aimed to assess clinicopathological features and prognosis for this type of carcinoma diagnosed over the past decade and compared those to the common breast invasive carcinoma of no special type (NST). METHODS: This study used the Surveillance, Epidemiology, and End Results (SEER) database to extract data regarding primary breast salivary gland-type carcinoma. Using a propensity score-matching approach, the prognosis was compared with invasive carcinoma, NST. RESULTS: This study included 488 cases of salivary gland-type carcinoma and 375,660 cases of invasive carcinoma, NST, giving an occurrence ratio of 1 to 770. Adenoid cystic carcinoma (81%) formed the majority of salivary gland-type carcinoma, followed by secretory carcinoma (13%). For salivary gland-type carcinoma, acinic cell carcinoma histological type, tumor grade 3, HER2-overexpressed status, and higher AJCC stage groups were significant worse prognostic factors for breast cancer-specific survival in univariate analyses (p < 0.05). Nonetheless, tumor grade 3 and higher AJCC stage groups remained as significant independent prognostic factors in multivariate analysis (p < 0.05). The apparent better breast cancer-specific survival of salivary gland-type carcinoma as compared to that of invasive carcinoma, NST, was diminished following adjustment for differences in baseline clinicopathological features and treatment-related variables. CONCLUSIONS: This study suggests that when managing primary breast salivary gland-type carcinoma, greater emphasis should be given to the tumor grade and AJCC stage group in addition to acinic cell carcinoma histological type and HER2 overexpression. Conventional prognostic factors are important as salivary gland-type carcinoma had similar prognosis as invasive carcinoma, NST, following adjustment for confounding variables.

Salivary gland-type cancers: cross-organ demographics of a rare cancer.

BACKGROUND: Salivary gland-type cancers (SGTCs) are histologically heterogeneous and can affect organs other than the salivary glands. Some tumors outside the salivary glands are diagnosed on their unique histological characteristics. Comprehensive cross-organ studies on SGTCs are limited. METHODS: We retrospectively analyzed the data of patients with salivary duct carcinoma (SDC), adenoid cystic carcinoma (AdCC), mucoepidermoid carcinoma (MEC), epithelial-myoepithelial carcinoma (EMC), acinic cell carcinoma (AcCC), and polymorphous adenocarcinoma (PAC) who visited our institution between 2009 and 2019. The primary tumor sites were classified into four categories; major salivary glands, head/neck (H/N) excluding (exc) major salivary glands (MSG) regions, broncho-pulmonary regions, and "others". H/N exc MSG was further divided into three subcategories, nasal/paranasal sinus, oral and pharynx/larynx. RESULTS: We identified 173 patients with SGTCs, with SDC, AdCC, MEC, EMC, AcCC, and PAC accounting for 20%, 42%, 27%, 3%, 8%, and 1% of the cases, respectively. The most frequent primary site was the major salivary glands (64%), followed by H/N exc MSG regions (27%), broncho-pulmonary regions, and "others", thus non-salivary gland origins accounted for 9% of all cases. Patients with SDC, MEC, AcCC, or SGTC of the major salivary glands and broncho-pulmonary regions were more frequently treated by surgery. The overall survival time of the patients with MEC was significantly better than that of patients with SDC or EMC. CONCLUSIONS: This cross-organ study highlights the clinical significance of SGTCs, underscoring the need for developing novel therapies for this rare disease entity.

Salivary gland adenoid cystic carcinoma in the U.S population: Importance of grade, site of metastases, and adjuvant radiation for survival.

BACKGROUND: Adenoid cystic carcinoma (AdCC) is a rare and relatively heterogenous salivary gland malignancy, for which there is debate regarding grading, and clinical prognostic factors, including the role of adjuvant radiotherapy. METHODS: Surveillance, Epidemiology, and End Results (SEER) data were reviewed for AdCC cases from 2000 to 2018. RESULTS: A total of 1978 patients with AdCC were identified. Most patients were between 50 and 59 years of age (21.4 %), female (59.9 %), and Caucasian (76.8 %). Most tumors were localized at presentation (44.3 %), and moderately differentiated (or grade II) (43.7 %). Overall and DSS 5-year survival rates were 70.7 % (95 % CI, 69.9-78.8), and 78.6 % (95 % CI, 77.6-79.6). The best overall 5-year survival rate was observed for those treated with surgery plus radiation, 76.8 % (95 % CI, 75.5-78.1). Multivariate analysis revealed male sex, age > 65 (H.R. 2.659 (95 % CI,2.291-3.098), p < .001), grade III/IV (H.R.5.172 (95 % CI, 3.418-7.824), p < .001), nodal metastasis, distant metastasis (H.R. 2.400 (95 % CI, 2.178-2.645), p < .001), chemotherapy only, and combination therapy as negative prognostic factors, and receiving surgery plus radiation therapy (H.R.0.586 (95 % CI, 0.505-0.679), p < .001) as a positive prognostic factor. When limited just to the lungs, had much better survival than those patients with distant metastases to other sites such as the bones and liver (p < .001). CONCLUSION: This SEER study identifies grade, particularly III and IV, to be the strongest single predictor of worse survival. Patients did best when treated with surgery and postoperative radiotherapy. These results can inform future management of patients with this challenging cancer type.

The tumor microenvironment of benign and malignant salivary gland tumors.

BACKGROUND: Treatment of salivary gland tumors (SGTs) remains challenging. Little is known about the immune landscape of SGTs. We aimed to characterize the tumor microenvironment in benign and malignant SGTs. METHODS: Eleven benign and nine malignant tumors were collected from patients undergoing curative intent surgery. Specimens were analyzed using mass cytometry by time-of-flight. Immune cell populations were manually gated, and T cells were clustered using the FlowSOM algorithm. Population frequencies were compared between high-grade and low-grade malignancies, corrected for multiple hypothesis testing. RESULTS: There were trends towards increased CD4+ and CD8+ T cells among malignant tumors. High-grade malignancies exhibited trends towards higher frequencies of CD8+ PD-1+ CD39+ CD103+ exhausted T cells, CD4+ FoxP3+ TCF-1+ CD127- Tregs, and CD69+ CD25- CD4+ T cells compared to low-grade malignancies. CONCLUSION: SGTs exhibit significant immunologic diversity. High-grade malignancies tended to have greater infiltration of exhausted CD8+ T cells and Tregs, which may guide future studies for immunotherapy strategies.

Surgical Resection Improves Overall Survival in cT4b Major Salivary Gland Cancer.

OBJECTIVE: To compare surgical and nonsurgical definitive treatment in cT4b major salivary gland cancer (MSGC). STUDY DESIGN: Retrospective cohort study. SETTING: The 2004 to 2019 National Cancer Database. METHODS: The NCDB was queried for patients with cT4b MSGC (N = 976). Patients undergoing definitive treatment with (1) surgical resection + adjuvant therapy, (2) radiotherapy (RT) alone, or (3) chemoradiotherapy (CRT) were included in Kaplan-Meier and Cox survival analyses. RESULTS: Of 219 patients undergoing definitive treatment, 148 (67.6%) underwent surgical resection + adjuvant therapy and 71 (32.4%) underwent RT or CRT. There were no documented mortalities within 90 days of surgical resection. Tumor diameter and nodal metastasis were associated with decreased odds of undergoing definitive treatment (P < 0.025). Patients with positive surgical margins (PSM) had higher 5-year overall survival (OS) than those undergoing definitive RT or CRT (48.5% vs 30.1%, P = 0.018) and similar 5-year OS as those with negative margins (48.5% vs 54.0%, P = 0.205). Surgical resection + adjuvant therapy (adjusted hazard ratio: 0.55, 95% confidence interval [CI]: 0.37-0.84) was associated with higher OS than definitive RT or CRT (P < 0.025). A separate cohort of 961 patients with cT4a tumors undergoing surgical resection + adjuvant therapy was created; cT4a and cT4b (hazard ratio: 1.02, 95% CI: 0.80-1.29, P = 0.896) tumors had similar OS. CONCLUSION: A minority of patients with cT4b MSGC undergo definitive treatment. Surgical resection + adjuvant therapy was safe and associated with higher OS than definitive RT or CRT, despite high rate of PSM. In the absence of clinical trial data, appropriately selected patients with cT4b MSGC may benefit from surgical resection.

Adenoid Cystic Carcinoma, Clinical Presentation, Current Treatment and Approaches Towards Novel Therapies.

Adenoid cystic carcinoma (AdCC) is a rare cancer originating from secretory glands with unknown aetiology. It is one of the most dominant malignant salivary tumours (MST). However, it can arise in other areas of the head and neck region and in secretory glands outside this area. It occurs at all ages, but is more frequent between 50-70 years of age and more common in females than in males. The symptoms of AdCC are generally unspecific and the clinical diagnosis of AdCC maybe challenging, partially due to its heterogenous histopathology and indolent growth. Moreover, there is a lack of good prognostic markers, and due to its rarity, it is difficult to predict which therapeutic methods are the most optimal for each patient, especially since very late recurrences occur. This review presents some major characteristics of AdCC and some current treatments for this disease.

Molecular Profiling and the Impact of Treatment on Outcomes in Adenoid Cystic Carcinoma Type I and II.

PURPOSE: Adenoid cystic carcinoma (ACC) is an uncommon salivary gland cancer with no approved therapies available to treat advanced, incurable disease. 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. EXPERIMENTAL DESIGN: This retrospective observational cohort study involved de-identified samples from 438 patients with ACC with tumor samples sent for commercially-available molecular profiling (Caris Life Sciences). Next-generation whole-exome and whole-transcriptomic sequencing was performed on primary and metastatic samples. Immunostaining for PD-L1 and RNA deconvolution (quanTIseq) was used to explore the tumor immune microenvironment (TME). Real-world clinical and survival outcome metrics were extracted from insurance claims data. RESULTS: MYC expression was 1.61-fold higher (39.8 vs. 24.7; P < 0.0001) among NOTCH1-mutant ACC-I tumors, whereas MYB/L1 fusion rates were similar among ACC-I/II. The median B-cell fraction in the TME was higher among ACC-II (7.1% vs. 5.8%; P < 0.01), although infiltrating T cells subsets were low among either ACC subgroup (both <1%). 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. CONCLUSIONS: We confirmed the previously reported associations with MYC and TP63 in the prognostically relevant subgroups of ACC-I and -II, respectively, and report immunologic differences among these subtypes. Survival outcomes are comparatively worse in ACC-I regardless of treatment type.

Salivary gland carcinoma: Towards a more personalised approach.

Salivary Gland carcinomas (SGCs) are rare tumors accounting for less than 1% of all cancers with 21 histologically diverse subtypes. The rarity of the disease presents a challenge for clinicians to conduct large size randomized controlled trials. Surgery and radiotherapy remain the only curative treatment for localized disease, whereas treatments for recurrent and metastatic disease remain more challenging with very disappointing results for chemotherapy. The different histological subtypes harbor various genetic alterations, some pathognomonic with a diagnostic impact for pathologists in confirming a difficult diagnosis and others with therapeutic implications regardless of the histologic subtype. Current international guidelines urge pathologists to identify androgen receptor status, HER-2 expression that could be determined by immunohistochemistry, and TRK status in patients with non-adenoid cystic salivary gland carcinoma that are eligible to initiate a systemic treatment, in order to offer them available targeted therapies or refer them to clinical trials based on their mutational profile. A more advanced molecular profiling by next generation sequencing would offer a larger panel of molecular alterations with possible therapeutic implications such as NOTCH, PI3K, BRAF, MYB, and EGFR. In the following review, we present the most common genetic alterations in SGCs as well as actionable mutations with the latest available data on therapeutic options and upcoming clinical trials.

Salivary Gland Secretory Carcinoma; Review of 13 Years World-Wide Experience and Meta-Analysis.

OBJECTIVES: Secretory Carcinoma is a malignant salivary gland tumor, initially described in 2010. This rare tumor is associated with the translocation t(12;15) (p13;q25), resulting in the fusion gene ETV6-NTRK3. Since this tumor is quite rare, most publications describe only small cohorts of patients. We aimed to investigate the clinical, pathological, and prognostic features of this newly defined malignant entity. DATA SOURCES: Pubmed, Google Scholar, and Web of Science databases. REVIEW METHODS: All published articles between 2010 and 2023 were reviewed. Search terms included the terms "Mammary Analogue Secretory Carcinoma" and "Secretory Carcinoma". All articles published in English reporting on Secretory Carcinoma of salivary glands were retrieved. RESULTS: One-hundred and 12 retrospective articles reporting a total of 674 patients were included, with 52% males and a mean age of 44.9 ± 18.9. The event rate for patients with advanced-stage disease (Stage 3/4) at presentation was 24.1% (95% CI 17.6%-31.9%, I2 = 9.2%), 14.6% for regional metastases (95% CI 10.5%-20%, I2 = 12%), and the event rate of distant metastasis was 8.4% (95% CI 5.5%-12.7%, I2 = 4.2%). Adjuvant radiotherapy was administered for 30.3% of patients (95% CI 24.1%-37.2%, I2 = 21.5%). The recurrence rate was 19% (95% CI 15.1%-23.8%, I2 = 5%). Survival outcomes showed a 17.2% death of disease rate for Secretory Carcinoma patients (95% CI 13.5%-21.8%, I2 = 7.3%). CONCLUSIONS: Secretory Carcinoma is a rare and relatively newly defined entity arising in the parotid gland most commonly. Characterized as a low-grade tumor, the majority of patients are diagnosed at an early stage, without regional or distant disease, and the prognosis is relatively good. LEVEL OF EVIDENCE: NA Laryngoscope, 134:1716-1724, 2024.

Current diagnosis and treatment of salivary gland-type tumors of the lung.

Salivary gland-type tumors of the lung are thought to originate from the submucosal exocrine glands of the large airways. Due to their rare occurrence, reports of their study are limited to small-scale or case reports. Therefore, daily clinical practices often require a search for previous reports. In the last 20 years, several genetic rearrangements have been identified, such as MYB::NF1B rearrangements in adenoid cystic carcinoma, CRTC1::MAML2 rearrangements in mucoepidermoid carcinoma, EWSR1::ATF1 rearrangements in hyalinizing clear cell carcinoma and rearrangements of the EWSR1 locus or FUS (TLS) locus in myoepithelioma and myoepithelial carcinoma. These molecular alterations have been useful in diagnosing these tumors, although they have not yet been linked to molecularly targeted therapies. The morphologic, immunophenotypic, and molecular characteristics of these tumors are similar to those of their counterparts of extrapulmonary origin, so clinical and radiologic differential diagnosis is required to distinguish between primary and metastatic disease of other primary sites. However, these molecular alterations can be useful in differentiating them from other primary lung cancer histologic types. The management of these tumors requires broad knowledge of the latest diagnostics, surgery, radiotherapy, bronchoscopic interventions, chemotherapy, immunotherapy as well as therapeutic agents in development, including molecularly targeted agents. This review provides a comprehensive overview of the current diagnosis and treatment of pulmonary salivary gland tumors, with a focus on adenoid cystic carcinoma and mucoepidermoid carcinoma, which are the two most common subtypes.