Immunohistological profiling confirms salivary gland-like nature of the tubarial glands and suggests closest resemblance to the palatal salivary glands.

BACKGROUND AND PURPOSE: High label uptake in 68 Ga-PSMA-11 PET/CT recently identified a bilateral nasopharyngeal structure as a salivary gland (SG)-like additional 'area of interest', to be considered in conditions affecting SGs. These structures were termed 'tubarial glands'. We aimed to further characterize their histological and immunohistochemical position compared to established SGs. METHODS: Tubarial gland tissue was compared with parotid, submandibular, sublingual, palatal and labial SGs tissue using immunohistological techniques. RESULTS: Expression of acinar cell-associated aquaporin-5 (AQP5) was detected in tubarial glands, in an apical location associated in control, established SGs with polarized, secretory acinar cells. Keratin14 (KRT14) expression in cells peripheral to AQP5+ clusters also suggested presence of myoepithelial cells. α-amylase, prolactin-induced protein, proline rich protein Haelll subfamily 2, and Muc5B expression suggests mucous acinar cell presence, and presence of muco-serous acinar cells peripheral to putative mucous acinar cells. Expression of adrenergic receptor-ß1 by acinar-like cells of the tubarial gland suggests ability to transduce sympathetic neuronal signaling. In terms of ductal architecture, tubarial glands contained large excretory-like ducts (similar to all other SGs), and squamous ducts, comprised of intermingled KRT14+ and KRT7+ cells. These squamous ducts were also observed in palatal, sublingual and labial SGs. No striated or intercalated ducts were observed, similar to palatal SGs. CONCLUSION: Based on histological and immunohistochemical analyses, the tubarial glands resemble SGs. They most convincingly echo characteristics of the palatal SGs in terms of ductal cells, and both the palatal and labial SGs when considering acinar cells.

Prognostic factors in acinic cell carcinoma of the head and neck: The Amsterdam experience.

INTRODUCTION: The aim was to analyse prognosticators in acinic cell carcinoma (AciCC) in two head and neck referral centers in Amsterdam, the Netherlands. MATERIALS AND METHODS: Eighty- nine cases of AciCC treated between 1979 and 2016 were retrospectively reviewed. Five, - 10 -and 20- year estimates of survival were executed as well as univariate analysis of prognosticators. RESULTS: The majority of AciCC were T1-T2; 89%. Two percent had nodal disease (2%). The most affected organ was the parotid gland (84%) with a female preponderance (67%). Mean age was 52 years with most cases diagnosed in the fourth to sixth decade. The majority of patients received adjuvant radiotherapy. Elective neck dissection (END) in the N0 neck showed no metastases. High grade transformation (HGT) was found in 21% of cases. Median follow up was 101.9 months. Median time to recurrence was 26 months. Nine patients developed distant metastases (DM) of whom 6 had HGT-AciCC. Median survival with DM was 7 months. Five,- ten -and twenty- year estimates were 84%, 81% and 81% for recurrence free survival respectively. Negative clinical features were advanced stage disease and tumour size > 2.6 cm. Negative histological features were a high mitotic rate, HGT, close and involved surgical margins and necrosis. CONCLUSION: AciCC- HGT excluded- of the head and neck has an excellent prognosis and shows acceptable long term results. END can be considered as part of the standard treatment due to the relative high incidence of HGT- AciCC and low accuracy of cytology.

Malignant transformation of salivary gland pleomorphic adenoma: proof of principle.

Supposed risk of malignant transformation of salivary gland pleomorphic adenoma (SGPA) is an important reason for aggressive retreatment in recurrent pleomorphic adenoma (RPA). However, although the diagnostic category 'carcinoma ex-pleomorphic adenoma' suggests that malignant transformation of a pleomorphic adenoma is a regular event, this has to date not been shown to occur in sequential lesions of one patient. Here, we show the molecular events in transformation to malignancy of a pleomorphic adenoma of the parotid gland. Detailed molecular analysis revealed an LIFR/PLAG1 translocation characteristic for pleomorphic adenoma and, next to this, a PIK3R1 frameshift mutation and several allelic imbalances. In subsequent malignant recurrences, the same LIFR/PLAG1 translocation, PIK3R1 frameshift mutation, and allelic imbalances were present in addition to TP53 mutations. Thus, this case not only shows malignant transformation of SGPA, but also demonstrates that molecular analysis can be of help in recognising malignancy in the rare instance of RPA.

Risk of breast cancer in women after a salivary gland carcinoma or pleomorphic adenoma in the Netherlands.

Salivary and mammary gland tumors show morphological similarities and share various characteristics, including frequent overexpression of hormone receptors and female preponderance. Although this may suggest a common etiology, it remains unclear whether patients with a salivary gland tumor carry an increased risk of breast cancer (BC). Our purpose was to determine the risk of BC in women diagnosed with salivary gland carcinoma (SGC) or pleomorphic adenoma (SGPA). BC incidence (invasive and in situ) was assessed in two nationwide cohorts: one comprising 1567 women diagnosed with SGC and one with 2083 women with SGPA. BC incidence was compared with general population rates using standardized incidence ratio (SIR). BC risk was assessed according to age at SGC/SGPA diagnosis, follow-up time and (for SGC patients) histological subtype. The mean follow-up was 7.0 years after SGC and 9.9 after SGPA diagnosis. During follow-up, 52 patients with SGC and 74 patients with SGPA developed BC. The median time to BC was 6 years after SGC and 7 after SGPA. The cumulative risk at 10 years of follow-up was 3.1% after SGC and 3.5% after SGPA (95% Confidence Interval (95%CI) 2.1%-4.7% and 2.6%-4.6%, respectively). BC incidence was 1.59 times (95%CI 1.19-2.09) higher in the SGC-cohort than expected based on incidence rates in the general population. SGPA-patients showed a 1.48 times (95%CI 1.16-1.86) higher incidence. Women with SGC or SGPA have a slightly increased risk of BC. The magnitude of risk justifies raising awareness, but is no reason for BC screening.

The tubarial salivary glands: A potential new organ at risk for radiotherapy.

INTRODUCTION: The presence of previously unnoticed bilateral macroscopic salivary gland locations in the human nasopharynx was suspected after visualization by positron emission tomography/computed tomography with prostate-specific membrane antigen ligands (PSMA PET/CT). We aimed to elucidate the characteristics of this unknown entity and its potential clinical implications for radiotherapy. MATERIALS AND METHODS: The presence and configuration of the PSMA-positive area was evaluated in a retrospective cohort of consecutively scanned patients with prostate or urethral gland cancer (n = 100). Morphological and histological characteristics were assessed in a human cadaver study (n = 2). The effect of radiotherapy (RT) on salivation and swallowing was retrospectively investigated using prospectively collected clinical data from a cohort of head-neck cancer patients (n = 723). With multivariable logistic regression analysis, the association between radiotherapy (RT) dose and xerostomia or dysphagia was evaluated. RESULTS: All 100 patients demonstrated a demarcated bilateral PSMA-positive area (average length 4 cm). Histology and 3D reconstruction confirmed the presence of PSMA-expressing, predominantly mucous glands with multiple draining ducts, predominantly near the torus tubarius. In the head-neck cancer patients, the mean RT dose to the gland area was significantly associated with physician-rated post-treatment xerostomia and dysphagia ≥ grade 2 at 12 months (0.019/gy, 95%CI 0.005-0.033, p = .007; 0.016/gy, 95%CI 0.001-0.031, p = .036). Follow-up at 24 months had similar results. CONCLUSION: The human body contains a pair of previously overlooked and clinically relevant macroscopic salivary gland locations, for which we propose the name tubarial glands. Sparing these glands in patients receiving RT may provide an opportunity to improve their quality of life.

Validated Prognostic Nomograms for Patients With Parotid Carcinoma Predicting 2- and 5-Year Tumor Recurrence-Free Interval Probability.

Introduction: Salivary gland malignancies are rare tumors with a heterogenous histological and clinical appearance. Previously, we identified multiple prognostic factors in patients with parotid cancer and developed prognostic indices which have repeatedly been validated internationally, demonstrating their general applicability and lasting relevance. Recently, nomograms gained popularity as a prognostic tool. Thus, in this research we aimed to construct nomograms based on our previous validated prognostic models. Material and Methods: Nomograms were constructed using the previously reported dataset of 168 patients with parotid cancer which was used to develop pre- and postoperative prognostic scores, PS1 and PS2, respectively. Concordance indices for PS1 and PS2 were previously estimated at 0.74 and 0.71, respectively, and are in line with other, widely accepted oncological nomograms. Results: Pre- and postoperative nomograms predicting 2- and 5-year tumor recurrence-free survival probability are presented. All previously multivariately identified and validated prognostic factors, are incorporated (T size, N classification, pain, age at diagnosis, skin invasion, facial nerve dysfunction, perineural growth, and positive surgical margins). Examples of clinical application and interpretation are given. Conclusions: The presented prognostic nomograms for predicting 2- and 5-year tumor recurrence-free probability in patients with parotid cancer are powerful, user-friendly, visual tools and are based on internationally validated prognostic indices. They allow for a reliable prognostic assessment and result in a more individualized estimate of the risk for recurrence than the prognostic grouping based on PS1 and PS2. This facilitates assigning trial-patients to risk groups, and may assist in therapeutic decision making and determining appropriate follow-up intervals in clinical practice.

Prostate-specific membrane antigen (PSMA) expression in adenoid cystic carcinoma of the head and neck.

BACKGROUND: Treatment options for advanced head and neck adenoid cystic carcinoma (AdCC) are limited. Prostate-Specific Membrane Antigen (PSMA), a transmembrane protein that is known for its use in diagnostics and targeted therapy in prostate cancer, is also expressed by AdCC. This study aimed to analyse PSMA expression in a large cohort of primary, recurrent and metastasized AdCC of the head and neck. METHODS: One hundred ten consecutive patients with histologically confirmed AdCC in the period 1990-2017 were included. An analysis was made of clinical details, revised pathology and semiquantitative immunohistochemical expression of PSMA on tissue microarray and whole slides. Associations of PSMA expression with clinicopathological parameters were explored and survival was analysed by multivariate Cox-proportional Hazard analysis. RESULTS: PSMA expression was present in 94% of the 110 primary tumours, with a median of 31% positive cells (IQR 15-60%). Primary tumours (n = 18) that recurred (n = 15) and/or had metastases (n = 10) demonstrated 40, 60 and 23% expression respectively. Expression was not independently related to increased pathological stage, tumour grade, and the occurrence of locoregional recurrence or metastasis. After dichotomization, only primary tumour PSMA expression ≤10% appeared to be associated with reduced 10-years recurrence-free survival (HR 3.0, 95% CI 1.1-8.5, p = .04). CONCLUSIONS: PSMA is highly expressed in primary, recurrent and metastatic AdCC of the salivary and seromucous glands. PSMA expression has no value in predicting clinical behaviour of AdCC although low expression may indicate a reduced recurrence-free survival. This study provides supporting results to consider using PSMA as target for imaging and therapy when other diagnostic and palliative treatment options fail.

Natural history of recurrent pleomorphic adenoma: implications on management.

BACKGROUND: Treating recurrent pleomorphic adenoma (RPA) aims to reduce risk of malignant transformation (MT) while avoiding facial nerve injury. Our objective was to systematically investigate this natural history of RPA and address the current rational for its treatment. METHODS: The follow-up data of two nationwide series of PA was pooled with a focus on risk of MT and analyzed against the literature. RESULTS: The combined nationwide data (n = 9003 PA patients) showed 3.1% with first recurrence of which 6.2% were malignant. In the literature first RPA rate was >7% at 20 years follow-up. MT occurred in 0% to 7%, and facial nerve damage increased from with each surgery 3% to 16% at first RPA to 18% to 30% at second RPA. CONCLUSIONS: RPA showed a characteristic course with surgery being unreliable and damage to the facial nerve. The risk of MT was low. This might give flexibility towards a more conservative approach of management.

High CXCR4 expression in adenoid cystic carcinoma of the head and neck is associated with increased risk of locoregional recurrence.

AIM: Treatment options for head and neck adenoid cystic carcinoma (AdCC) are limited in advanced disease. Chemokine receptor type 4 (CXCR4) is present in various tumour types, including AdCC. Upregulation is associated with tumour recurrence and metastasis. New CXCR4-specific diagnostic and therapeutic target agents have recently been available. This study aimed to analyse CXCR4 expression in a cohort of primary head and neck AdCC. METHODS: After histopathological revision, tumour tissues of 73 consecutive patients with AdCC over 1990-2016 were sampled on a tissue microarray. Slides were immunohistochemically stained for CXCR4 and semiquantitatively scored. Associations between protein expression and cliniopathological parameters were tested. HRs were calculated using a Cox proportional hazard model. RESULTS: Sixty-six tumours could be analysed. CXCR4 expression was present in 81% of the tumours with a median of 29% (IQR 1-70) positive cells. Expression was univariately correlated to perineural growth (Spearman ρ .26, p=0.04) and bone invasion (Spearman ρ .32, p=0.01), but not with tumour grade.CXCR4 expression in the primary tumour was significantly higher in tumours that recurred as compared with those that did not recur (median 60%, IQR 33-72 vs 12%, IQR 1-70, Kruskal-Wallis p=0.01). After dichotomisation, >25% of CXCR4 expressions proved an independent prognosticator for a reduced recurrence-free survival (RFS) (HR 7.2, 95% CI 1.5 to 72.4, p=0.04). CONCLUSION: CXCR4 is expressed in the majority of primary AdCCs and independently correlated to worse RFS, suggesting CXCR4 as a target for imaging and therapy purposes in patients with advanced AdCC.

Prostate-specific membrane antigen positron emission tomography/computed tomography as a potential tool to assess and guide salivary gland irradiation.

Evaluation of salivary gland damage after head and neck radiotherapy (RT) is difficult with current tools, such as subjective patient-reported outcome measures. We demonstrate the use of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) as an objective non-invasive tool to visualize damage to salivary glands resulting from RT. In three clinical cases, the PSMA-ligand distribution correlates to the RT dose distribution including intra-gland dose gradients and matches patient-reported toxicity, suggesting a dose-response relation. These findings support further exploration of PSMA PET/CT to guide and evaluate RT, with the ultimate aim to reduce salivary gland toxicity.

Physiologic distribution of PSMA-ligand in salivary glands and seromucous glands of the head and neck on PET/CT.

OBJECTIVES: Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is used for detection and (re)staging of prostate cancer. However, healthy salivary, seromucous, and lacrimal glands also have high PSMA-ligand uptake. This study aimed to describe physiologic PSMA-ligand uptake distribution characteristics in the head and neck to aid in PSMA PET/CT interpretation and to identify possible new clinical applications for PSMA-ligand imaging. STUDY DESIGN: Thirty consecutive patients who underwent PSMA PET/CT for prostate cancer were evaluated. Tracer maximum standardized uptake values (SUVmax) in the salivary, seromucous, and lacrimal glands were determined visually and quantitatively. Overall and intraindividual variations were reported. RESULTS: All gland locations had increased tracer uptake. The mean SUVmax ± standard deviation varied: parotid 12.3 ± 3.9; submandibular 11.7 ± 3.5; sublingual 4.5 ± 1.9; soft palate 2.4 ± 0.5; pharyngeal wall 4.3 ± 1.3; nasal mucosa 3.4 ± 0.9; supraglottic larynx 2.7 ± 0.7; and lacrimal 6.2 ± 2.2. The parotid had the largest overall variation in SUVmax (5.2-22.9), and the sublingual glands had the largest mean intraindividual difference (18.1%). CONCLUSIONS: Major and minor salivary and seromucous glands consistently have high PSMA-ligand uptake. Minor gland locations can be selectively visualized by this technique for the first time. This provides potential new applications such as quantification of present salivary gland tissues and individualization of radiotherapy for head and neck cancer or lutetium-177-PSMA radionuclide treatment.

Interpretation of treatment outcome in the clinically node-negative neck in primary parotid carcinoma: a systematic review of the literature.

BACKGROUND: Critical evaluation of outcome of primary parotid carcinoma treatment is limited by pathologic diversity and low incidence numbers. Scientific evidence for the optimal management of the N0-neck is scarce and was, therefore, investigated in a systematic literature review. METHODS: The articles included were published in English between 1997 and 2007 and describe populations with the definitive pathology, staging, and treatment. Of 1104 articles, 19 were selected, describing 2703 patients. RESULTS: Of eligible populations, 83% were clinically N0. Pathology reporting of elective lymph node dissection (ELND) had limitations, but 23% showed occult metastases. Regional recurrence occurred in 5% of patients. CONCLUSION: The discrepancy between the relatively high percentage of occult metastases and reported low regional recurrence rates may indicate the efficacy of treatment, being either ELND or radiotherapy of the neck. Pooling, standardized collection, and reporting of data are essential in comparing outcomes in populations to determine optimal treatment.