Basal cell adenoma (BCA) is a benign salivary neoplasm that exhibits a divergent spectrum of growth patterns, including cribriform, tubular, trabecular, membranous, and solid. A subset of BCAs is characterized by the presence of abundant S100 protein-positive stroma, which makes this variant unique and potentially represents a hybrid lesion or an entity intermediate between BCA and pleomorphic adenoma (PA). From the authors' registry, we selected 17 cases of BCA with abundant S100 protein-positive stromal components and compared them with 7 cases of BCA without S100 protein-positive stroma, and 6 cases of myoepithelial cell-rich PAs. All cases were analyzed by immunohistochemistry (IHC) using antibodies to S100 protein, SOX10, PLAG1, HMGA2, p63/p40, cytokeratins, EMA, LEF1, and/or β-catenin. Next-generation sequencing (NGS), fluorescence in situ hybridization (FISH) for the rearrangement of PLAG1, and methylation analysis were performed. The BCA S100 protein stromal cell-rich group consisted of 7 males and 10 females with an average age of 62 years. Their tumors showed typical S100 protein-positive stroma, which was also positive for SOX10 in all cases. The stromal and/or epithelial components showed expression of LEF1 and β-catenin in 17 and 15 cases, respectively. HMGA2 IHC showed nuclear expression in one case while PLAG1 was negative in all cases. In 11 cases, one or more mutations were present, including CTNNB1 mutation (n = 11). The first control cohort of BCA without S100 protein-positive stroma consisted of 1 male and 6 females with an average age of 50 years. This group showed LEF1 and nuclear β-catenin expression in 1 and 2 cases, respectively. The second control group of PA (including 4 spindle-shaped cellular and 2 oncocytic PAs) was devoid of CTNNB1 mutations. Two cases presented with gene fusions, including MEG3::PLAG1 and ACTA2::PLAG1, and an additional two cases showed PLAG1 break. It has been proposed earlier that BCA is related to PA based on a shared biphasic nature and a divergent spectrum of growth patterns. Our findings suggest that BCAs with abundant S100 protein-positive stroma are tumors that morphologically display tricellular differentiation into inner (luminal) ductal epithelial cells, outer (abluminal) basaloid myoepithelial cells, and spindle-shaped stromal S100-positive cells (stromal abluminal). According to our investigation, BCAs with S100 protein-positive stroma represent a distinctive triphasic subset of BCA, which is substantially different from PA, both in immunoprofile and molecular underpinnings.

• Keywords
• Basal cell adenoma, Methylation analysis, Molecular diagnostics, Next-generation sequencing, S100 protein–positive stroma, Salivary gland,
• Publication type
• Journal Article MeSH

BACKGROUND: Primary oncocytic salivary gland tumors and oncocytic subtypes of traditionally non-oncocytic salivary gland neoplasms are occasionally encountered in fine needle aspiration specimens, biopsies, and resections. Oncocytes are cells, either non-neoplastic or neoplastic, containing increased numbers of mitochondria resulting in cells with abundant eosinophilic cytoplasm and a low N/C ratio. SUMMARY: A broad range of salivary gland tumors can be oncocytic including oncocytoma, Warthin tumor, mucoepidermoid carcinoma, salivary duct carcinoma, and others, especially those tumors where the oncocytic pattern represents a subtype of neoplasm; the oncocytic pattern can create a diagnostic challenge due to marked similarities in the oncocytic pattern of cells. KEY MESSAGES: While their microscopic cytologic and histologic features may be similar, these tumors differ intrinsically at the molecular level. Ancillary studies such as immunologic (e.g., androgen receptor for salivary duct carcinoma) and molecular analysis, e.g., FISH for detecting the MAML2 or PLAG1/HMGA2 gene alterations in mucoepidermoid carcinoma and pleomorphic adenoma, respectively, can be used to classify these oncocytic tumors in difficult cases.

• Keywords
• Cytopathology, Fine needle aspiration, Histopathology, Molecular biology, Oncocytic tumor, Salivary gland,
• Publication type
• Journal Article MeSH
• Review MeSH

Primary squamous cell carcinoma of the parotid gland (pSCCP) has long been recognized as a separate entity and is included in the WHO classifications of salivary gland tumors. However, it is widely accepted among head and neck pathologists that pSCCP is exceptionally rare. Yet, there are many publications describing series of pSCCP and data from SEER and other cancer register databases indicate erroneously an increasing incidence of pSCCP. Importantly, pSCCP and metastatic (secondary) squamous cell carcinoma to the parotid gland (mSCCP) have nearly identical histological features, and the diagnosis of pSCCP should only be made after the exclusion of mSCCP. Moreover, all of the histological diagnostic criteria proposed to be in favor of pSCCP (such as, for example, dysplasia of ductal epithelium) can be encountered in unequivocal mSCCP, thereby representing secondary growth along preexistent ducts. Squamous cell differentiation has also been reported in rare genetically defined primary parotid carcinomas, either as unequivocal histological squamous features (e.g., NUT carcinoma, mucoepidermoid carcinoma), by immunohistochemistry (e.g., in NUT carcinoma, adamantinoma-like Ewing sarcoma, basal-type salivary duct carcinoma, mucoepidermoid carcinoma), or a combination of both. Another major issue in this context is that the International Classification of Diseases (ICD) coding system does not distinguish between primary or metastatic disease, resulting in a large number of patients with mSCCP being misclassified as pSCCP. Immunohistochemistry and new molecular biomarkers have significantly improved the accuracy of the diagnosis of many salivary gland neoplasms, but until recently there were no biomarkers that can accurately distinguish between mSCCP and pSCCP. However, recent genomic profiling studies have unequivocally demonstrated that almost all SCCP analyzed to date have an ultraviolet light (UV)-induced mutational signature typical of mSCCP of skin origin. Thus, mutational signature analysis can be a very useful tool in determining the cutaneous origin of these tumors. Additional molecular studies may shed new light on this old diagnostic and clinical problem. This review presents a critical view of head and neck experts on this topic.

• Keywords
• Cancer registration, Diagnostic misclassification, Metastatic cutaneous squamous cell carcinoma, Primary parotid squamous cell carcinoma, Salivary gland carcinoma, UV mutational signature,
• MeSH
• Squamous Cell Carcinoma of Head and Neck pathology   diagnosis   MeSH
• Humans MeSH
• Biomarkers, Tumor analysis   MeSH
• Skin Neoplasms * pathology   diagnosis   MeSH
• Parotid Neoplasms * pathology   diagnosis   MeSH
• Carcinoma, Squamous Cell * pathology   diagnosis   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Biomarkers, Tumor MeSH

Classification of head and neck tumors has evolved in recent decades including a widespread application of molecular testing in tumors of the salivary glands, sinonasal tract, oropharynx, nasopharynx, and soft tissue. Availability of new molecular techniques allowed for the definition of multiple novel tumor types unique to head and neck sites. Moreover, the expanding spectrum of immunohistochemical markers facilitates a rapid identification of diagnostic molecular abnormalities. As such, it is currently possible for head and neck pathologists to benefit from a molecularly defined classifications, while making diagnoses that are still based largely on histopathology and immunohistochemistry. This review highlights some principal molecular alterations in head and neck neoplasms presently available to assist pathologists in the practice of diagnosis, prognostication and prediction of response to treatment.

• Keywords
• Head and neck, Molecular diagnostics, Next-generation sequencing, Salivary gland, Sinonasal tumor, Soft tissue,
• MeSH
• Immunohistochemistry MeSH
• Humans MeSH
• Pathology, Molecular * MeSH
• Head and Neck Neoplasms * diagnosis   genetics   MeSH
• Pathologists MeSH
• Salivary Glands MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

• This ESMO–EURACAN Clinical Practice Guideline provides key recommendations for managing salivary gland cancer. • The guideline covers clinical and pathological diagnosis, staging and risk assessment, treatment and follow-up. • Treatment algorithms for parotid, submandibular, sublingual and minor salivary gland cancer are provided. • The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe. • Recommendations are based on available scientific data and the authors’ collective expert opinion.

• Keywords
• ESMO–EURACAN Clinical Practice Guideline, diagnosis, follow-up, salivary gland cancer, treatment,
• MeSH
• Adult MeSH
• Medical Oncology MeSH
• Humans MeSH
• Salivary Gland Neoplasms * diagnosis   therapy   MeSH
• Follow-Up Studies MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Practice Guideline MeSH
• Geographicals
• Europe MeSH

This review gives a brief history of the development of head and neck pathology in Europe from a humble beginning in the 1930s to the explosive activities the last 15 years. During the decades before the introduction of immunohistochemistry in the 1980s, head and neck pathology grew as a subspeciality in many European countries. In the late 1940s, the Institute of Laryngology and Otology with its own pathology laboratory was founded in London, and in 1964 the World Health Organization (WHO) International Reference Centre for the Histological Classification of Salivary Tumours was established at the Bland-Sutton Institute of Pathology, also in London. International collaboration, and very much so in Europe, led to the publication of the first WHO Classification of Salivary Gland Tumours in 1972. In the 1960s, a salivary gland register was organised in Hamburg and in Cologne the microlaryngoscopy was invented enabling microscopic endoscopic examination and rather shortly afterwards a carbon dioxide laser attached to the microscope became established and laryngeal lesions could be treated by laser vaporisation. During the last three decades, the use of immunohistochemistry supplemented with cytogenetic and refined molecular techniques has greatly facilitated the pathological diagnostics of head and neck lesions and has had a huge impact on research. Collaboration between different European centres has drastically increased partly due to establishment of scientific societies such as the Head and Neck Working Group (HNWG) within the European Society of Pathology and the International Head and Neck Scientific Group (IHNSG). A very large number of European pathologists have contributed to the 2nd, 3rd and 4th WHO books, and are involved in the upcoming 5th edition. Accredited educational meetings and courses are nowadays regularly arranged in Europe. Numerous textbooks on head and neck pathology have been written and edited by European pathologists. The increased collaboration has created larger series of tumours for research and new entities, mainly defined by their genetic abnormalities, are continuously emerging from Europe, particularly regarding salivary gland neoplasms and "undifferentiated" sinonasal tumours. These findings have led to a better and more precise classification and open the possibilities for new treatment strategies.

• Keywords
• Cancer, Head and neck pathology, History of European head and neck pathology, Laryngeal neoplasms, Salivary neoplasms, Sinonasal neoplasms,
• MeSH
• Humans MeSH
• Head and Neck Neoplasms * diagnosis   MeSH
• Salivary Gland Neoplasms * MeSH
• Salivary Glands MeSH
• World Health Organization MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Geographicals
• Europe MeSH

The salivary gland section in the 5th edition of the World Health Organization Classification of Head and Neck Tumours features a description and inclusion of several new entities, including sclerosing polycystic adenoma, keratocystoma, intercalated duct adenoma, and striated duct adenoma among the benign neoplasms; and microsecretory adenocarcinoma and sclerosing microcystic adenocarcinoma as the new malignant entities. The new entry also includes mucinous adenocarcinoma subdivided into papillary, colloid, signet ring, and mixed subtypes with recurrent AKT1 E17K mutations across patterns suggesting that mucin-producing salivary adenocarcinomas represent a histologically diverse single entity that may be related to salivary intraductal papillary mucinous neoplasm (IPMN). Importantly, the number of entities in the salivary chapter has been reduced by omitting tumors or lesions if they do not occur exclusively or predominantly in salivary glands, including hemangioma, lipoma, nodular fasciitis and hematolymphoid tumors. They are now discussed in detail elsewhere in the book. Cribriform adenocarcinoma of salivary gland origin (CASG) now represents a distinctive subtype of polymorphous adenocarcinoma (PAC). PAC is defined as a clinically, histologically and molecularly heterogeneous disease group. Whether CASG is a different diagnostic category or a variant of PAC is still controversial. Poorly differentiated carcinomas and oncocytic carcinomas are discussed in the category "Salivary carcinoma not otherwise specified (NOS) and emerging entities". New defining genomic alterations have been characterized in many salivary gland tumors. In particular, they include gene fusions, which have shown to be tightly tumor-type specific, and thus valuable for use in diagnostically challenging cases. The recurrent molecular alterations were included in the definition of mucoepidermoid carcinoma, adenoid cystic carcinoma, secretory carcinoma, polymorphous adenocarcinoma, hyalinizing clear cell carcinoma, mucinous adenocarcinoma, and microsecretory adenocarcinoma.

• Keywords
• Classification, Gene fusion, Neoplasm, Salivary gland, WHO, World Health Organization,
• MeSH
• Adenocarcinoma * pathology   MeSH
• Adenoma * genetics   pathology   MeSH
• Humans MeSH
• Adenocarcinoma, Mucinous * MeSH
• Biomarkers, Tumor genetics   MeSH
• Salivary Gland Neoplasms * genetics   pathology   MeSH
• Salivary Glands pathology   MeSH
• World Health Organization MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers, Tumor MeSH

Diagnosis of salivary gland neoplasms is often challenging due to their high morphological diversity and overlaps. Several recurrent molecular alterations have been described recently, which can serve as powerful diagnostic tools and potential therapeutic targets (e.g. NTRK or RET fusions). However, current sequential molecular testing can be expensive and time consuming. In order to facilitate the diagnosis of salivary gland neoplasms, we designed an all-in-one RNA-based next generation sequencing panel suitable for the detection of mutations, fusions and gene expression levels (including NR4A3) of 27 genes involved in salivary gland neoplasms. Here we present the validation of the "SalvGlandDx" panel on FFPE histological specimen including fine needle aspiration (FNA) cell block material, against the standard methods currently used at our institution. In a second part we describe selected unique cases in which the SalvGlandDx panel allowed proper diagnosis and new insights into special molecular characteristics of selected salivary gland tumors. We characterize a unique salivary gland adenocarcinoma harboring a ZCCHC7-NTRK2 fusion, a highly uncommon spindle cell and pseudoangiomatoid adenoid-cystic carcinoma with MYBL1-NFIB fusion, and a purely oncocytic mucoepidermoid carcinoma, whereas diagnosis could be made by detection of a CRTC3-MAML2 rearrangement on the cell block specimen of the FNA. Further, a rare case of a SS18-ZBTB7A rearranged low-grade adenocarcinoma previously described as potential spectrum of microsecretory adenocarcinoma, is reported. In addition, features of six cases within the spectrum of polymorphous adenocarcinoma / cribriform adenocarcinoma of salivary gland including PRKD1 p.E710D mutations and novel fusions involving PRKAR2A-PRKD1, SNX9-PRKD1 and ATL2-PRKD3, are described.

• Keywords
• Biopsy, Comprehensive, FNA, Molecular, Salivary gland neoplasm, Testing,
• MeSH
• Biopsy MeSH
• Oncogene Proteins, Fusion genetics   metabolism   MeSH
• In Situ Hybridization, Fluorescence MeSH
• Immunohistochemistry methods   MeSH
• Humans MeSH
• Mutation MeSH
• Biomarkers, Tumor * MeSH
• Cell Line, Tumor MeSH
• Salivary Gland Neoplasms diagnosis   drug therapy   genetics   MeSH
• Neoplasm Staging MeSH
• Gene Expression Profiling * methods   MeSH
• Neoplasm Grading MeSH
• High-Throughput Nucleotide Sequencing * methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Oncogene Proteins, Fusion MeSH
• Biomarkers, Tumor * MeSH

Adenoid cystic carcinoma (AdCC) of the salivary glands is characterized by MYB-NFIB or MYBL1-NFIB fusion, prolonged but relentlessly progressive clinical course with frequent recurrences, and development of distant metastasis resulting in high long-term mortality. Currently, no effective therapy is available for patients with advanced non-resectable and/or metastatic disease. Complicating the clinical management of this patient group is the lack of prognostic markers. The purpose of this study is to investigate the prognostic value of 1p36 loss in patients with AdCC. The presence of 1p36 deletion and gene fusions involving the MYB, NFIB, and MYBL1 genes in a cohort of 93 salivary gland AdCCs was studied using fluorescence in situ hybridization. These results were statistically correlated with clinical data and outcome. Deletion of 1p36 in AdCC was identified in 13 of 85 analyzable cases (15.29%). MYB-NFIB fusion was detected in 57/85 (67.1%), MYBL1-NFIB fusion in 12/85 (14.1%), MYB-X fusion in 4/85 (4.7%), MYBL1-X in 4/85 (4.7%), and NFIB-X in 2/85 (2.4%) of AdCC cases. None of the 1p36-deleted samples showed MYBL1 rearrangement. Statistical analysis demonstrated a significant correlation between 1p36 deletion and advanced tumor stage and solid histology (p = 0.0061 and 0.0007, respectively). Kaplan-Meier survival curves showed statistically significant correlations between 1p36 deletion and decreased overall survival, disease-specific survival, recurrence-free interval, and recurrence-free survival, all of which were maintained in multivariate analysis. We demonstrate that 1p36 deletion can serve as an indicator of unfavorable outcome of patients with salivary gland AdCC.

• Keywords
• 1p36 locus deletion, Adenoid cystic carcinoma, MYB-NFIB, Prognosis, Salivary gland,
• MeSH
• Carcinoma, Adenoid Cystic genetics   mortality   secondary   therapy   MeSH
• Time Factors MeSH
• Chromosome Deletion * MeSH
• Adult MeSH
• Phenotype MeSH
• Gene Fusion MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Genetic Predisposition to Disease MeSH
• In Situ Hybridization, Fluorescence MeSH
• Immunohistochemistry MeSH
• Kaplan-Meier Estimate MeSH
• Middle Aged MeSH
• Humans MeSH
• Chromosomes, Human, Pair 1 * MeSH
• Neoplasm Recurrence, Local MeSH
• Adolescent MeSH
• Young Adult MeSH
• Biomarkers, Tumor genetics   MeSH
• Salivary Gland Neoplasms genetics   mortality   pathology   therapy   MeSH
• Disease-Free Survival MeSH
• Disease Progression MeSH
• Proportional Hazards Models MeSH
• Proto-Oncogene Proteins genetics   MeSH
• Risk Factors MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Neoplasm Staging MeSH
• Neoplasm Grading MeSH
• Trans-Activators genetics   MeSH
• NFI Transcription Factors genetics   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Oncogene Proteins, Fusion MeSH
• MYB-NFIB fusion protein, human MeSH Browser
• MYBL1 protein, human MeSH Browser
• Biomarkers, Tumor MeSH
• NFIB protein, human MeSH Browser
• Proto-Oncogene Proteins MeSH
• Trans-Activators MeSH
• NFI Transcription Factors MeSH

Although relatively rare, polymorphous adenocarcinoma (PAC) is likely the second most common malignancy of the minor salivary glands (MiSG). The diagnosis is mainly based on an incisional biopsy. The optimal treatment comprises wide surgical excision, often with adjuvant radiotherapy. In general, PAC has a good prognosis. Previously, PAC was referred to as polymorphous low-grade adenocarcinoma (PLGA), but the new WHO classification of salivary gland tumours has also included under the PAC subheading, the so-called cribriform adenocarcinoma of minor salivary glands (CAMSG). This approach raised controversy, predominantly because of possible differences in clinical behaviour. For example, PLGA (PAC, classical variant) only rarely metastasizes, whereas CAMSG often shows metastases to the neck lymph nodes. Given the controversy, this review reappraises the definition, epidemiology, clinical presentation, diagnostic work-up, genetics, treatment modalities, and prognosis of PAC of the salivary glands with a particular focus on contrasting differences with CAMSG.

• Keywords
• Cribriform adenocarcinoma of minor salivary glands, Pathology, Polymorphous adenocarcinoma, Polymorphous low-grade adenocarcinoma, Prognosis, Salivary glands, Therapy,
• MeSH
• Adenocarcinoma pathology   surgery   therapy   MeSH
• Humans MeSH
• Salivary Glands, Minor * MeSH
• Salivary Gland Neoplasms pathology   therapy   MeSH
• Prognosis MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH