Treatment Of Adenoid Cystic Carcinoma Research Articles

Current aspects of the diagnosis and treatment of adenoid cystic carcinoma of the trachea and larynx: a literature review

This review discusses current aspects of the diagnosis and treatment of adenoid cystic carcinoma of the trachea and larynx. It describes different variants of surgical treatment, radiotherapy, combination therapy, endotracheal interventions using endoscopic techniques and physical methods, grafting, tracheal transplantation, complications, and oncological and functional treatment outcomes. We also analyze clinical aspects of adenoid cystic carcinoma of the larynx, most common tumor location, difficulties associated with morphological verification, and controversial issues related to surgery volume, considering that this disease is rare and clinical experience is often insufficient.

Comparison of Clinical Outcomes of Definitive and Postoperative Radiotherapy for Adenoid Cystic Carcinoma of the Head and Neck: Can Definitive Radiotherapy Be a Treatment Option?

Simple SummaryAdenoid cystic carcinoma of the head and neck is a rare malignant tumor; thus, it is difficult to establish an optimal treatment based on clinical trials with a large number of enrolled patients. Retrospective analyses of a small number of cases have revealed that the standard treatment is surgical resection followed by postoperative radiotherapy, while definitive radiotherapy is considered inadequate. Previous studies have used classical techniques for radiotherapy and did not evaluate the efficacy of current radiotherapy techniques, which may have underestimated the efficacy of definitive radiotherapy. We retrospectively analyzed 44 cases of adenoid cystic carcinoma of the head and neck treated with current radiotherapy techniques. Our results show that definitive radiotherapy is comparable to surgical resection followed by postoperative radiotherapy with respect to overall survival and local control. The results suggest that definitive radiotherapy can be an effective treatment option for adenoid cystic carcinoma of the head and neck.Background: The standard treatment for adenoid cystic carcinoma of the head and neck is surgical resection followed by postoperative radiotherapy (PORT). Currently, definitive radiotherapy (defRT) is considered an inadequate treatment; however, its data are based on studies using classical radiotherapy techniques. Therefore, the therapeutic effects of current radiotherapy techniques have not been adequately evaluated, and it may have underestimated the efficacy of defRT. Methods: We retrospectively analyzed 44 adenoid cystic carcinoma patients treated with radiotherapy based on modern treatment techniques from 1993 to 2017. Results: Twenty-four patients underwent PORT and 20 patients underwent defRT. The 5-year overall survival rates for patients treated with PORT and defRT were 85.3% and 79.7%, respectively. The 5-year local control rates were 82.5% and 83.1%, respectively. There were no statistically significant differences in the overall survival and local control of patients treated with PORT and defRT (p = 0.4392 and p = 0.0904, respectively). Conclusion: Our results show that defRT is comparable to surgical resection followed by PORT with respect to overall survival and local control. The results suggest that defRT can be an effective treatment option for adenoid cystic carcinoma of the head and neck.

Treatment of adenoid cystic carcinoma of the breast: Is postoperative radiation getting its due credit?

IntroductionThe role of postoperative radiation (PR) in treating mammary ACC is poorly defined. This study evaluated the impact of PR on survival outcomes for mammary ACC and the extent of utilization. MethodsPatients who underwent surgery for mammary ACC from 2005 to 2015 in SEER database were analyzed. KM analyses of OS and DSS were done for PR versus no PR. Cox hazard regression models were used to determine predictors of OS and DSS. ResultsOf the 488 patients, 244 underwent PR. The PR group was younger, but other variables were similar between the 2 groups. OS was better for PR (p = 0.029). 10-year DSS was better for PR group by an absolute value of 6 % but did not reach statistical significance (p = 0.537). Age, radiation, nodal metastasis, and grade III/IV were independent predictors of OS while grade III/IV and AJCC stage III/IV independently predicted DSS. ConclusionPR improves OS for mammary ACC, but this study did not show increased utilization. Radiation should be considered after surgery for mammary ACC, particularly for patients with independent predictors of OS.

Adenoid cystic carcinoma. An indolent but aggressive tumour. Part B: treatment and prognosis.

SUMMARYThe purpose of this review is to analyse the very large number of studies (sometimes contradictory) on adenoid cystic carcinoma (ACC). This second part provides a critical analysis of various treatment described in the literature. Anywhere the primary tumour is located, the most common treatment for ACC is complete surgical resection, with or without post-operative radiotherapy (PORT), while conventional photon and/or electron radiotherapy alone and chemotherapy are commonly used in unresectable or metastatic disease. Fast neutron radiotherapy was used in the past with good local results, but the risk of late effects was high and tended to increase over time. Modern carbon-ion radiotherapy seems to be a valid option in selected cases. The quite universally accepted poor prognostic factors are advanced stage, perineural and intraneural invasion, involved margins, and initial presence or later development of neck metastases. The impact of histologic grade on prognosis is controversial. Owing to the long natural history of ACC, the follow-up for patients must be at least 10 years long.

Comparative Proteomic Analysis to Investigate the Pathogenesis of Oral Adenoid Cystic Carcinoma.

Adenoid cystic carcinoma (ACC) belongs to salivary gland malignancies commonly occurring in an oral cavity with a poor long-term prognosis. The potential biomarkers and cellular functions acting on local recurrences and distant metastases remain to be illustrated. Proteomics is the core content of precision medicine research, which provides accurate information for early detection of cancer, benign and malignant diagnosis, classification and personalized medication, efficacy monitoring, and prognosis judgment. To obtain a comprehensive regulation network and supply clues for the treatment of oral ACC (OACC), we utilized mass spectrometry-based quantitative proteomics to analyze the protein expression profile in paired tumor and adjacent normal tissues. We identified a total of 40,547 specific peptides and 4454 differentially expressed proteins (DEPs), in which HAPLN1 was the most upregulated protein and BPIFB1 was the most downregulated. Then, we annotated the functions and characteristics of DEPs in detail from the aspects of gene ontology, subcellular structural localization, KEGG, and protein domain to thoroughly understand the identified and quantified proteins. Glycosphingolipid biosynthesis and glycosaminoglycan degradation pathways showed the biggest difference according to KEGG analysis. Moreover, we confirmed 20 proteins from the ECM-receptor signaling pathway by a parallel reaction monitoring quantitative detection and 19 proteins were quantified. This study provides useful insights to analyze DEPs in OACC and guide in-depth thinking of the pathogenesis from a proteomics view for anticancer mechanisms and potential biomarkers.

Surgery combined with iodine-125 interstitial brachytherapy for treatment of parotid adenoid cystic carcinoma: A single-institution experience

PurposeThe purpose of this study was to analyze the effectiveness and safety of the combination of surgery plus postoperative iodine-125 interstitial brachytherapy for treatment of adenoid cystic carcinoma (ACC) of the parotid. Methods and MaterialsThis study included a retrospective analysis of the data of patients who underwent postoperative iodine-125 interstitial brachytherapy for histology-confirmed ACC of the parotid between January 2002 and November 2018 in Peking University Hospital of Stomatology. Acute and long-term radiation-related toxicities were assessed by the criteria of the Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer. Multivariate analysis was used to identify the factors affecting overall survival, disease-free survival (DFS), and distant metastasis–free survival (DMFS). ResultsA total of 86 patients (53 women; median age 50 years, SD = 13.1) were included. Median followup was for 45.5 months. About half the patients (44/86, 51.3%) had clinical stage IV disease. Local recurrence occurred in 11 of 86 (12.8%) patients. No patient had nodal metastases in the followup period. The five- and 10-year DFS rates were 74.8% and 66.6%, respectively. The mean DMFS was 60.6 months. On multivariate analysis, preoperative facial palsy, type of surgery, perineural spread (PNS), and distant metastases were independent prognostic factors for DFS; preoperative facial palsy, nodal metastases, and PNS were independent prognostic factors for overall survival; and preoperative facial palsy, type of surgery, PNS, and pathological type were independent prognostic factor for DMFS. ConclusionsThe combination of surgery and iodine-125 interstitial brachytherapy appears to be an effective and safe treatment for primary ACC of the parotid.

Clinicopathologic and survival analysis of patients with adenoid cystic carcinoma of vulva: single-institution experience.

The purpose of this study was to elucidate our experience in the diagnosis and treatment of adenoid cystic carcinoma of the vulva (ACC-vulva) and to assess the clinicopathological characteristics and prognosis among ACC-vulva patients. A retrospective study of seventeen patients was performed to illustrate the demographic information, clinical performance, pathological characteristics, treatment modality, and development of local recurrence or distant metastasis, as well as the survival outcome. The median age at diagnosis was 56years (range, 26-71years). Radical local excision was performed on fifteen patients, and two patient received radical hemi-vulvectomy. Six patients received ipsilateral inguinal lymphadenectomy. Involvement of the resection margin was observed in six patients. The postoperative pathologic diagnosis showed no proof of inguinal lymph node metastasis in all the six patients receiving lymphadenectomy. However, the perineural invasion was observed in all patients. Postoperative adjuvant radiotherapy was applied to five patients who had positive resection margin. The mean survival time except for that in four patients (recent case) was 47.8months (range, 23-78months). Radical resection towards negative margins seems to be acceptable as initial treatment. Adjuvant radiotherapy is a preferable treatment modality for patients with high-risk factors pathologically or patients with local recurrence.

PD-L1 and PD-L2 Expression Levels Are Low in Primary and Secondary Adenoid Cystic Carcinomas of the Orbit: Therapeutic Implications.

To determine if there is a biologic rationale for using checkpoint inhibitor drugs targeting programmed cell death ligand 1 (PD-L1) and PD-L2 in the treatment of adenoid cystic carcinoma of the orbit. Twenty-three cases of adenoid cystic carcinoma involving the orbit (13 primary lacrimal gland, 5 secondarily extending into the orbit, and 5 unspecified) were examined histopathologically. Immunohistochemistry for PD-L1, PD-L2, and CD8 was performed. Charts were reviewed for clinical correlations. Expression of PD-L1 and of PD-L2 was overall low in adenoid cystic carcinoma (mean expression 1.4 ± 0.9 of 5 for PD-L1, mean 0.83 ± 1.1 of 5 for PD-L2), and tumor-infiltrating CD8-positive T-lymphocytes were sparse (mean 1.1 ± 0.51 of 3). Only 13 of the 23 (57%) cases expressed PD-L1 as a combined positive score ≥1 of cells. No associations were found between expression levels of these markers and patient sex, tumor site of origin, Tumor, Node, Metastasis stage, or patient outcome. A significant association was observed between stromal PD-L1 expression and tumor histopathologic subtype (p = 0.05), and between tumor PD-L1 expression and prior exposure to radiation (p = 0.03). Checkpoint inhibitor drugs may have limited impact in the treatment and clinical course of orbital adenoid cystic carcinoma based on the low frequency of CD8 infiltrate and low expression of PD-L1 and PD-L2. Pretreatment with radiation, however, may improve tumor response to checkpoint inhibitor drugs.

Adenoid cystic carcinoma of the lung — a case report

Adenoid cystic carcinoma (ACC) is a malignant neoplasm that frequently originates from the salivary glands of the head and neck. The majority of pulmonary adenoid cystic carcinomas develop centrally in the trachea. Primary ACC of the lung arising from the bronchial glands is a rare disease and accounts for only 0.09‑0.2% of all primary lung neoplasms [1]. Although their growth rate is often indolent, they sometimes show aggressive biologic behaviour. Local invasion with perineural infiltrations, and lymph node and hematogenous metastases have been reported for some of these neoplasms [2]. Treatment options for advanced disease are limited. We herein report a case of a 56-year-old male patient with adenoid cystic carcinoma of the lung, who received conventional chemotherapy and endobronchial irradiation. This review focuses on the palliative therapy in the treatment of metastatic ACC.

Case report of adenoid cystic carcinoma of the breast – a rare lesion with favorable prognosis

Introduction: Adenoid cystic carcinoma (ACC) is a rare type of breast tumor – less than 0.1% of breast malignancies. Usually, ACC is triple-negative, with lymph node involvement not exceeding 2%, and metastases are uncommon. When localized, the disease is indolent with an excellent prognosis. Objective: To report a case of ACC of the breast and provide data for the medical literature. Method/Case report: J.S.M.S., 44 years old, had a 1 cm nodule in the right breast (RB) and free axillae. Mammography (MMG) showed focal asymmetry in the upper outer quadrant (UOQ) and BI-RADS 0. Ultrasound (US) revealed a solid, circumscribed, periareolar lesion with areas of cystic degeneration, 1.2 cm, BI-RADS 3. Fine-needle aspiration biopsy (FNAB) suggested fibroadenoma. Lesion resection led to the diagnosis of ACC, histological grade 1 (HG1), nuclear grade 1 (NG1), with associated ductal carcinoma in situ (DCIS), and sentinel lymph node with no neoplasia. Immunohistochemistry (IHC) revealed estrogen receptor-negative (ER-), progesterone receptor-negative (PR-), HER2 negative (HER2-), and Ki67 10%. Staging had no evidence of distant disease. The patient did not receive chemotherapy (CT) but underwent 18 sessions of radiotherapy (RT) in the breast with a boost to the tumor bed. She remains disease-free at 8 months of follow-up. Results/Discussion: ACC has low malignant potential with histology similar to that of primary ACC of the salivary gland (which is aggressive); in the breast, it represents 0.058% of all ACC cases. It is more common in Caucasian women aged 60 to 70 years and usually subareolar (approximately 50% of cases). Imaging tests are nonspecific. ACC has lymph node involvement in about 2% of cases. Histology shows epithelial and myoepithelial cells distributed in the classic tubular or cribriform architecture. IHC reveals epithelial cells positive for CD117 and myoepithelial cells positive for smooth muscle actin, calponin, and p63. ACC of the breast expresses proto-oncogene c-KIT and a chromosomal translocation similar to its salivary counterpart: t (6; 9) (q22-23; p23-24). Treatment consists of surgery with free margins. Axillary dissection, CT, and RT have a questionable role due to the indolent course of the disease. Until now, small studies have not suggested a benefit in overall survival when adding adjuvant CT. Although triple-negative, its prognosis is favorable. Local recurrence is approximately 3–18%, and 10-year survival is above 90%. Conclusion: The rarity of these tumors and their favorable course raise questions about the best treatment for ACC. The benefit of axillary dissection, CT, or RT remains unknown because the prognosis seems very favorable with only surgery, despite its triple-negative status. Further studies are necessary to adopt the optimal strategy for these tumors.

외이도에 발생한 선양낭성암종 1예

Adenoid cystic carcinoma (ACC) is thought as a tumor usually found in salivary gland and it is hard to find in external auditory canal. ACC has a slow progression feature and few early symptoms so it is not easy to diagnosis in early stage. ACC is often involved perineural invasion but hardly found in lymph node metastasis. Because of these features, patients with ACC have symptoms such as otalgia, otorrhea and ear canal mass. ACC has 3 different histologic patterns and each patterns have different prognosis. The treatment of ACC is nowdays surgery and postoperative radiotherapy. We report a ACC case in ear canal with a review of other literatures. (J Clinical Otolaryngol 2019;30:232-236)

Accumulated cytotoxicity of CDK inhibitor dinaciclib with first-line chemotherapy drugs in salivary adenoid cystic carcinoma cells.

Adenoid cystic carcinoma (ACC) is one of the most common salivary gland malignant tumors. Its treatment failure is partly due to the limitations of chemotherapeutic agents and their adverse effects. The objective of this study was to determine the potential additive anti-cancer effect of a novel CDK inhibitor dinaciclib with first-line chemotherapy drugs in ACC. Protein expression of phosphorylated CDK2 (p-CDK2) in paraffin-embedded tissue specimens of ACC from 17 patients was investigated by immunohistochemistry (IHC). Cell Counting Kit (CCK-8), clone formation assay, and flow cytometry were used to test the proliferation and apoptosis of ACC-2 cells treated with dinaciclib with or without other first-line chemotherapy drugs. Protein expression was also determined by Western blot. Interestingly, we discovered that p-CDK2 protein was expressed in both cytoplasmic and nucleus in salivary ACC tissues, which was higher than that in normal salivary tissues, indicating that agents targeting CDK2 may be potential therapeutic strategies against this type of tumor. As expected, CDK inhibitor dinaciclib significantly induced ACC-2 cells apoptosis. Moreover, it sensitized cells to the chemotherapeutic agents such as cisplatin, pemetrexed, and etoposide (VP-16), and this effect by dinaciclib may induce cell cycle arrest via abrogating CDK2 activity. Therefore, combinational therapy of CDK inhibitor dinaciclib with first-line chemotherapy drugs may be a promising strategy in the treatment of salivary ACC.

Definitive Radiotherapy and Postoperative Radiotherapy for Adenoid Cystic Carcinoma in the Head and Neck: A Propensity Score Analysis

The mainstay radical treatment of adenoid cystic carcinoma in the head and neck (HNACC) is surgery. The outcome of definite radiotherapy (RT) and surgery combined with postoperative radiotherapy (PORT) has not been properly compared due to the rarity of disease and imbalances of characteristics between patients receiving either treatment. The present study aims to compare outcomes of definitive RT versus surgery + PORT for HNACC using adjustment with propensity scores (PS). A retrospective review of medical records was performed in patients who underwent definitive RT (n=47) or surgery + PORT (n=145) for newly diagnosed nonmetastatic HNACC between January 1981 and December 2016. A median follow-up period was 4.9 years (range, 0.34 to 27.6 years). PS was estimated using factors including age, sex, T stage, N stage, radiotherapy techniques and primary sites. Propensity score (PS) matching and inverse probability of treatment weighting (IPTW) were used to estimate and compare survival outcomes. Five-year overall survival (OS), disease-free survival (DFS), locoregional control (LRC), distant metastasis-free survival (DMFS) of unmodified cohort were 75.7%, 31.4%, 66.3%, 34.2% (definitive RT) and 86.8%, 49.5%, 79.7%, 55.9% (surgery + PORT). These treatment outcomes were significantly different between two groups (p<0.05). In the PS-matched cohort, differences between the treatment outcomes were not significant. Five-year OS, DFS, LRC, DMFS of PS-matched cohort were 72.6%, 37.8%, 74.4%, 39.5% (definitive RT) and 89.3%, 48.2%, 79.0%, 52.1% (surgery + PORT). Also in the IPTW-adjusted cohort, the differences were not significant. Five-year OS, DFS, LRC, DMFS of IPTW-adjusted cohort were 77.9%, 51.7%, 81.9%, 53.6% (definitive RT) and 86.8%, 48.9%, 79.9%, 53.7% (surgery + PORT). Two analyses using PS showed there were no differences in treatment outcomes after balancing patient characteristics. Definitive RT would actually give better treatment results than those reported in previous studies. These results ultimately need be explored in a randomized trial.

The role of organ- and function-preserving radiotherapy in the treatment of adenoid cystic carcinoma of the larynx.

To evaluate clinical outcome and functional larynx preservation after radiotherapy (RT) for adenoid cystic carcinoma (ACC) of the larynx. Eleven patients with primary ACC of the larynx, who received RT definitely (n = 5/11) or postoperatively (n = 6/11), were analyzed regarding survival and treatment-related toxicity with the focus on functional larynx preservation. Median follow-up was 45 months. RT offered an excellent 5-year local control (LC) rate of 100%. Eight of 11 patients were treated with a laryngeal preservation approach (LPA). At last follow-up, only one of these eight patients developed a local recurrence requiring a total laryngectomy 11 years after treatment. Severe toxicity was uncommon, with only one patient with LPA, requiring a temporary tracheostomy during therapy. RT is an effective treatment method for laryngeal ACC with excellent LC rates, preservation of the laryngeal function and voice formation, representing a valuable therapy alternative to total laryngectomy.

Prise en charge médico-chirurgicale d’un carcinome adénoïde kystique trachéal : l’union fait la force

Adenoid cystic carcinoma or cylindroma is a rare tumor of the trachea which arises from mucous secreting cells. Its evolution and growth are slow but it is often fatal in the absence of radical treatment. The latter relies on a surgical sleeve resection of the pathological area, with a tracheo-tracheal anastomosis. Therapeutic bronchoscopy plays a crucial role in the clinical improvement of patients before surgery which will be performed under better conditions. For inoperable patients, radiotherapy has proved its efficacy, unlike conventional chemotherapy. The finding of biomarkers expressed by tumor cells could lead to target therapies. This case report illustrates the efficient combination of therapeutic bronchoscopy and surgery for the treatment of adenoid cystic carcinoma affecting central airways.

Clinical diagnosis and treatment of adenoid cystic carcinoma of the external auditory canal

Objective:To discuss the clinical diagnosis, therapies and prognosis of adenoid cystic carcinoma of external auditory canal.Method:Eleven patients with adenoid cystic carcinoma of external auditory canal, who had been admitted to West China hospital, Sichuan university from April 2009 to October 2015 were recruited and a retrospective analysis was performed.Result:All the 11 patients were treated with surgery except one elderly with T1 stage who was only treated with radiotherapy(RT),1 of the 10 patients treated with surgery were added on radiotherapy after surgery. Following up for 12-104 months,the patient who was treated with RT alone has survived with carcinoma for 51 months by now,among the remainder stage T1 patients,one was reoperated for local recurrence 95 months after surgery, and therefore survived without recurrence.The other 2 patients all survived with free-disease;in the stage T2 patients,one was lost to follow-up after identified local recurrence with pulmonary masses 12 months after surgery, another one committed suicide because of family problems 56 months after operation,and the other one survived without recurrence for 57 months after surgery; the stage T3 patient survived without recurrence for 26 months at present;in the T4 patients, one died after gamma knife therapy for local recurrent disease with brain metastasis 22 months after surgery, another one died from pulmonary metastasis 17 months after surgery,and the other one survived without recurrence for 56 months.Conclusion:Adenoid cystic carcinoma of external auditory canal is a rare disease with high misdiagnosis rate and progresses slowly.Surgery is the preferred therapy.The prognosis is closely related to disease clinical stage at presentation type of pathology and surgical approaches. Adenoid cystic carcinoma of external auditory canal is characteristically susceptible to local recurrence and distant metastasis,inaddition to routine re-exam of ear,the patients should be reviewed carefully to exclude of pulmonary,brain and kidney metastasis during follow-up.

Bimodality treatment of patients with pelvic adenoid cystic carcinoma with photon intensity-modulated radiotherapy plus carbon ion boost: a case series.

BackgroundTreatment of patients with pelvic adenoid cystic carcinoma (ACC) remains a challenge owing to the rarity of the disease, the lack of data, and the relative radioresistance of these tumors.Case reportsThis case series presents the results of three patients with recurrent or inoperable pelvic ACC treated with intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost. Patients received C12 therapy at a dose of 3 Gray equivalents (GyE) (relative biological effectiveness [RBE]) per fraction up to 24 GyE RBE, followed by 50 GyE of photon IMRT in 25 fractions.ConclusionIMRT plus C12 ion boost as a definitive or adjuvant treatment for pelvic ACCs seems to be a promising therapeutic option. No unexpected toxicity was detected and the observed toxicity remained consistently low. The initial treatment response is promising and similar to that experienced for head and neck ACCs.

Multicenter Study of Carbon-Ion Radiation Therapy for Adenoid Cystic Carcinoma of the Head and Neck: Subanalysis of the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS) Study (1402 HN)

Toretrospectively analyze the treatment outcomes of carbon-ion radiation therapy for adenoid cystic carcinoma (ACC) of the head and neck at 4 active carbon-ion facilities in Japan. A total of 289 patients who underwent carbon-ion radiation therapy for histology-proven ACC of the head and neck at 4 institutions in Japan between November 2003 and December 2014 were included in this study. Median patient age was 58years (range, 12-83years). Tumor sites included the nasal cavity and paranasal sinuses (42%), nasopharynx and oropharynx (19%), oral cavity (12%), major salivary glands (12%), and others (15%). Tumor classifications were T4 in 200 (69%) patients, T3 in 45 (16%), T2 in 22 (8%), T1 in 15 (5%), and unclassified in 7 (2%). The median total dose was 64Gy (relative biological effectiveness [RBE]; range, 55.2-70.4Gy [RBE]) in 16 fractions (range, 12-32 fractions). Median follow-up time was 30months (range, 2-118months). The 2-year overall survival, progression-free survival, and local control rates were 94%, 68%, and 88%, respectively. Estimated 5-year overall survival, progression-free survival, and local control rates were 74%, 44%, and 68%, respectively. In all, 43 patients (15%) experienced grade ≥3 late toxicity, of which osteonecrosis of the jaw bone was the most common. Two patients treated for nasopharyngeal ACC died from a bleeding ulcer at the tumor site (grade 5 toxicity). Carbon-ion radiation therapy seems to be a promising treatment for ACC of the head and neck.

Role of Postoperative Radiotherapy in the Treatment of Adenoid Cystic Carcinoma of the Trachea and Bronchus with Positive Surgical Margin: Rethinking about the Resection Range

Adenoid Cystic carcinoma (ACC) of the tracheobronchial tree is quite uncommon. The experience regarding their treatment and long-term outcome is limited. The aim of this study was to evaluate the role of postoperative radiotherapy in the treatment of ACC of the trachea and bronchus with positive surgical margin. Operated patients were enrolled in this study with pathologically confirmed trachea or bronchus ACC in Shanghai Chest Hospital. Clinical, pathologic and radiotherapeutic data were retrospectively reviewed. Survival analysis was performed using the Kaplan-Meier and log-rank tests. Multivariate analysis was performed using the Cox regression model. Meanwhile, the chi-square test was applied to analyze the failure pattern among different groups (R0/0: negative margin resection without postoperative radiotherapy; R1/0: positive margin resection without postoperative radiotherapy and R1/1: positive margin resection with postoperative radiotherapy). From January 2001 to December 2014, 77 patients were eligible for the study. The median follow-up time was 67 months (range, 16-203). The 5-year and 10- year OS rates in R0/0, R1/1, R1/0 patients were 100.0%, 98.9%, 90.0% and 85.7%, 89.9%, 59.1%, respectively(P = 0.086). Pairwise comparisons showed OS of group R1/1 was similar to group R0/0 (P = 0.438), although much better than group R1/0 (P = 0.032). The 5-year and 10- year local PFS rates in R0/0, R1/1, R1/0 patients were 85.9%, 98.0%, 78.8% and 43.0%, 98.0%, 33.8%, respectively (P = 0.003). Pairwise comparisons showed a difference between group R1/1 and R0/0 (P = 0.023) and between group R1/1 and R1/0 (P = 0.001). Cox multivariate analysis of patients with positive surgical margin identified the radiologic appearance (P = 0.012) and postoperative radiotherapy (P = 0.006) as significantly favorable prognostic factors for local PFS, and only postoperative radiotherapy as the corresponding variable for OS. Thirty-two patients had experienced recurrence by the end of follow-up, including local recurrence (n = 3), local recurrence with metastases (n = 5), pure pulmonary metastases (n = 16), pure bone metastases (n = 1) and multiple metastases (n = 7). Chi-square test suggested patients without postoperative radiotherapy were more prone to local recurrence than those received postoperative radiotherapy (P = 0.001). Similar outcome was not demonstrated for distant metastases (P = 1.000). For patients with positive surgical margin, postoperative radiotherapy can significantly prolong local PFS and OS, thus achieving similar survival to those with complete resection. Patients without postoperative radiotherapy are more likely to relapse instead of metastasize. These results suggest that postoperative radiotherapy provide an effective complement to operation with positive surgical margin. Appropriate resection range of ACC of trachea and bronchus should be rethinking.

Targeting the Oncogenic Transcriptional Regulator MYB in Adenoid Cystic Carcinoma by Inhibition of IGF1R/AKT Signaling.

Adenoid cystic carcinoma (ACC) is an aggressive cancer with no curative treatment for patients with recurrent/metastatic disease. The MYB-NFIB gene fusion is the main genomic hallmark and a potential therapeutic target. Oncogenic signaling pathways were studied in cultured cells and/or tumors from 15 ACC patients. Phospho-receptor tyrosine kinase (RTK) arrays were used to study the activity of RTKs. Effects of RTK inhibition on cell proliferation were analyzed with AlamarBlue, sphere assays, and two ACC xenograft models (n = 4-9 mice per group). The molecular effects of MYB-NFIB knockdown and IGF1R inhibition were studied with quantitative polymerase chain reaction, immunoblot, and gene expression microarrays. All statistical tests were two-sided. The MYB-NFIB fusion drives proliferation of ACC cells and is crucial for spherogenesis. Intriguingly, the fusion is regulated through AKT-dependent signaling induced by IGF1R overexpression and is downregulated upon IGF1R-inhibition (% expression of control ± SD = 27.2 ± 1.3, P < .001). MYB-NFIB regulates genes involved in cell cycle control, DNA replication/repair, and RNA processing. The transcriptional program induced by MYB-NFIB affects critical oncogenic mediators normally controlled by MYC and is reversed by pharmacological inhibition of IGF1R. Co-activation of epidermal growth factor receptor (EGFR) and MET promoted proliferation of ACC cells, and combined targeting of IGFR1/EGFR/MET induced differentiation and synergistically inhibited the growth of patient-derived xenografted ACCs (ACCX5M1, % growth of control ± SD = 34.9 ± 20.3, P = .006; ACCX6, % growth of control ± SD = 24.1 ± 17.5, P = .04). MYB-NFIB is an oncogenic driver and a key therapeutic target in ACC that is regulated by AKT-dependent IGF1R signaling. Our studies uncover a new strategy to target an oncogenic transcriptional master regulator and provide new important insights into the biology and treatment of ACC.