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Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Background: Malignancies of the nasopharynx (NPC), the (para)nasal cavities, the salivary glands, and the thyroid gland are distinct to head and neck squamous cell carcinomas (HNSCC) in the oro-/hypopharynx and larynx in terms of etiology, tumor biology, and the therapeutic concept., Objective: The contributions to the 2024 American Society of Oncology (ASCO) Annual Meeting provide insight into the latest developments in these "special entities of the head and neck region.", Methods: Abstracts were examined for their clinical relevance and placed into context with current therapeutic concepts., Results and Conclusion: In the treatment of locally advanced NPC, a randomized phase III study showed equivalence of induction (ICT) and adjuvant therapy (AT; NCT03306121). PD-1 inhibitors have become established in the palliative therapy of NPC in recent years and could now also play an increasing role in curation: the phase III study "Dipper" showed a significantly better 3‑year event-free survival in patients adjuvantly treated with camrelizumab versus placebo after IT and definitive platinum-containing chemoradiotherapy (dRCT; 89% vs. 80%; NCT03427827). The phase III study "Beacon" showed complete remission in 30.5% of patients after IT with gemcitabine/cisplatin and the PD‑1 inhibitor tislelizumab (three cycles), a rate almost twice as high as with gemcitabine/cisplatin alone (NCT05211232). Intensification of dRCT in NPC using EGFR and VEGF inhibitors appears promising (NCT04447326). Abstracts on salivary gland and nasal and sinus cancers emphasize the importance of targeted therapies. In anaplastic thyroid carcinoma, the combination of a PD‑1 inhibitor and a CTLA4 inhibitor showed a 50% response., Competing Interests: Einhaltung ethischer Richtlinien Interessenkonflikt H.B. Zech hat Referentenhonorare von MSD, Merck, BMS, Sanofi und Regeneron erhalten. C.S. Betz gibt an, dass keine Interessenkonflikte vorliegen.Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Objective: Salivary gland carcinomas are rare and heterogeneous. More than 20 subtypes are recognized and risk factors are diverse. The aim of this work was to evaluate the subtype and other risk factors in a monocentric population from more than four decades., Material and Methods: 205 cases (diagnosis period 1972-2014) were retrospectively collected and analyzed with regard to the distribution of risk factors and their influence on overall survival (OS)., Results: 19/24 (79.2%) of the subtypes listed in the WHO classification occurred rarely in the cohort (< 5%). 10/24 (41.7%) of all subtypes were never diagnosed. With a total of 145/205 cases (70.7%), squamous cell carcinoma (PEC), adenocarcinoma (AdenoCa), acinar cell carcinoma (AcinarCa), mucoepidermoid carcinoma (MEC), and adenoid cystic carcinoma (ACC) were by far the most common subtypes. Risk factors are significantly different in these groups (e.g., lymphogenic metastasis and degree of differentiation in AdenoCa and age, T and UICC stage in PEC). The 5-year overall survival of all patients was 66.9% and differed significantly within the most common subtypes. An independent impact on overall survival was detectable for patient age (p<0.001), and T- (p=0.003) and N-stage (p=0.046) in multivariate analysis., Conclusions: Most subtypes occurred markedly rarely or not at all within decades. The most common diagnoses differ with respect to risk factors as well as OS and 3 risk groups can be defined based on histology. In conclusion, considering TNM alone is insufficient for prognosis estimation in salivary gland carcinoma., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Competing Interests: Frau Prof. Dr. Grosheva erhielt Referentenhonorare von den Firmen MDS, MedEL, Merz Pharmaceuticals

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Salivary gland tumors and tumor-like lesions in the pediatric population are uncommon. They comprise a heterogeneous group of infectious/inflammatory and neoplastic conditions. Pediatric salivary neoplasms include benign tumors of mesenchymal or epithelial origin as well as malignancies of epithelial (carcinomas), mesenchymal (sarcoma) or hematolymphoid (lymphoma) derivation. Infectious/inflammatory conditions and hematolymphoid malignancies may represent either genuine parenchymal pathology or conditions involving intraglandular lymph nodes of the parotid glands (intraglandular lymphadenopathy and intraglandular nodal lymphomas). Pediatric sialadenitis may be of diverse etiologies including viral (mumps, CMV, HIV, etc.), bacterial, autoimmune (juvenile Sjögren syndrome) or idiopathic (chronic recurrent juvenile sialectatic sialadenitis). Angiomatous lesions (juvenile capillary hemangioma, lymphangioma and vascular malformation) and pleomorphic adenomas represent the most common pediatric benign mesenchymal and benign epithelial tumors, respectively. The vast majority of salivary gland carcinomas in children and adolescents represent low-grade mucoepidermoid carcinomas followed by acinic cell and adenoid cystic carcinomas (together >80% of carcinomas). Other malignant neoplasms include (rhabdomyo-) sarcomas, malignant lymphomas and very rarely sialoblastomas. This long differential diagnosis list of etiologically and biologically highly heterogeneous entities, their shared clinical presentation as "salivary gland enlargement" and the significant differences in their therapeutic strategies and prognosis underline the need for careful assessment to identify the correct diagnosis. Diagnosis is mainly based on a set of typical clinical and imaging features, serological/microbiological findings and, in selected cases, histomorphological characteristics in biopsy specimens.

The parapharyngeal space extends from the nasopharynx to the oropharynx. It is bordered medially by the pharyngeal wall and the constrictor pharyngis muscles, and laterally by the mandible. One distinguishes between a pre- and a poststyloid space. Tumors of the parapharyngeal space are rare and represent less than 1 % of all head and neck neoplasms. Benign (70-80 %) as well as malignant (20-30 %) tumors arise from different structures of the parapharyngeal space, mainly from salivary glands and nerve structures. Concerning salivary gland tumors, most are pleomorphic adenomas typically appearing in the prestyloid space, whereas the schwannomas that may also arise are located in the poststyloid space. The main symptom is dysphagia, with the tumor generally presenting as a visible bulking of the pharyngeal wall, in rare cases also as an externally visible cervical mass. Treatment is generally surgical resection, particularly in benign tumors, preferably via transcervical access. If R0 resection of malignancies is possible, this should be performed. In malignant lymphomas and nonresectable tumors, primary chemo-, radio-, or combination therapy should be considered after histologic confirmation. For neurogenic tumors, particularly vagal nerve schwannoma and especially in older patients, a wait-and-scan strategy is most favorable, since postoperative vagal palsy is unavoidable with surgical resection. Treatment planning for parapharyngeal space tumors requires good knowledge of topographic anatomy and careful evaluation of imaging findings.

Objective: Contrast-enhanced ultrasound (CEUS) allows analyzing perfusion of salivary gland tumors more precisely in addition to conventional sonography. The evaluation of tumor dignity can be improved by CEUS. Currently an analysis of comparing perfusion parameters of different regions of interest (ROI) inside salivary gland tumors has not been reported. Materials and Methods: In this study 25 patients with tumors of the salivary glands were examined by B-Mode- Sonography, Color Doppler Sonography and CEUS. The parameters diameter, echogenicity, demarcation and especially perfusion were measured. We describe a new method for analyzing perfusion in 6 peripheral and 2 central ROI which were standardized distributed in the entire salivary gland tumors. The parameters were compared between different tumor dignities and in particular between the standardized ROI inside the tumors. Results: The results showed a hotspot of perfusion in the deep peripheral ROI with special perfusion characteristics. The differences of perfusion between benign and malignant salivary gland tumors were significant. Conclusions: This new method seems to improve validity of CEUS in interpreting tumor dignity., (© Georg Thieme Verlag KG Stuttgart · New York.)

Salivary gland surgery is a common procedure in otorhinolaryngology. Parotidectomy and submandibulectomy represent the treatment of choice in benign and malignant tumors of the salivary glands. However, as to this point there are no guidelines are concerning diagnostic and therapeutic approaches of benign and malignant tumors of the salivary gland. Since the introduction of sialendoscopy there are new diagnostic and therapeutic procedures available in treating obstructive sialadenitis. The present article provides an overview of anatomical principles, diagnostic approaches and the most important salivary gland surgeries for future otorhinolaryngologists under specialist training., (© Georg Thieme Verlag KG Stuttgart · New York.)

Tumors of the head and neck form a heterogeneous group of benign and malignant neoplasms with significant differences in biological behavior and therapeutic strategies. Squamous cell carcinomas (SCC) of the larynx, pharynx and oral cavity represent the most frequent and, thus, clinically most important malignant neoplasms in this anatomical region. Similar to other neoplasms, grading of head and neck malignancies is based on evaluation of the tumor histology usually including both architectural and cytological features; however, the current consensus grading for head and neck SCC is of limited prognostic and therapeutic value and the reproducibility is low. Therefore, novel grading criteria have been proposed that are based on additional parameters, such as the type of tumor growth pattern at the invasive front (so-called tumor budding). These novel algorithms, however, have not yet been officially endorsed into guidelines. Salivary gland (SG) neoplasms, although less frequent, constitute a second important pathologically and clinically complex group of tumors at this location. In contrast to SCC, grading of these tumors is of high clinical importance. Based on the large variety of carcinoma entities of the SG, both entity-specific (e. g. mucoepidermoid carcinoma) algorithms but also algorithms, which are solely based on the recognition of a specific carcinoma variant with subsequent automatic assignment of the tumor grade (e. g. acinic cell carcinoma and salivary duct carcinoma) are in use. In the sinonasal tract, grading is important for non-intestinal type adenocarcinoma and esthesioneuroblastoma. In this article the most important grading schemes and criteria for head and neck malignancies are presented and their prognostic and therapeutic implications are discussed.

Benign papillary lesions originating from the ductal epithelium of the minor salivary glands of the oral cavity include intraductal papilloma, inverted ductal papilloma (IDP) and sialadenoma papilliferum.

Despite major discrepancies in basic microscopic anatomy, remarkable similarities are manifest within the wide spectrum of cutaneous adnexal and salivary gland tumors. In this study salivary gland and adnexal tumors were identified and investigated with respect to similarities in histology, terminology and pathogenesis. Histological similarities of certain types of salivary gland tumors relate to eccrine, apocrine and rarely sebaceous (but not trichofollicular) types of adnexal tumors. The most striking similarity was found with salivary gland pleomorphic adenoma and cutaneous mixed tumor. Multistep carcinogenesis starting with intraductal carcinoma, identified in carcinoma ex pleomorphic adenoma is identical to that found in cutaneous carcinoma ex spiradenoma. Further histological and terminological similarities are shown for mucinous and mucoepidermoid carcinoma, for lymphadenoma and lymphoepithelial carcinoma, for sebaceous adenoma and carcinoma, for adenoid-cystic carcinoma, as well as for salivary gland basal cell adenoma versus cutaneous spiradenoma. Manifest diagnostic problems related to histologically similar salivary gland and adnexal tumors are rare and are topographically limited to the parotid and oral areas.

Warthin tumors (cystadenolymphoma, cystadenoma lymphomatosum papilliferum) account for approximately 10-15 % of all benign salivary gland tumors and are bilateral in approximately 10-15 %, as well as extraparotideal in approximately 8 % of cases. Nasopharyngeal Warthin tumors are extremely rare; however they should be borne in mind as a consideration of differential diagnostics. Furthermore, parotid glands and cervical lymph nodes should be examined as associated synchronous or metachronous manifestations are possible. Palpation, sonography and other radiological imaging of the cervical region, if applicable, might be required.

Xanthogranulomatous inflammation is an uncommon subtype of chronic inflammatory processes that has been mainly reported in the kidneys, gallbladder and other less common sites. Due to the presence of tumefactive mixed inflammatory infiltrates with variable involvement of surrounding soft tissues, this benign condition is often mistaken for a malignancy on clinical examination. In the salivary glands xanthogranulomatous inflammation is rare and mainly represents reactive changes secondary to a preexisting lesion, in particular infarcted Warthin tumors as well as ruptured ductal cysts and other sialectatic ductal changes. A special type of xanthogranulomatous salivary gland disease is represented by the rare primary (idiopathic) xanthogranulomatous sialadenitis without identifiable predisposing parenchymal or ductal lesions. The histological differential diagnosis is mainly based on the dominant histological pattern and encompasses among others inflammatory pseudotumors of various etiologies (e.g. inflammatory myofibroblastic tumor, IgG4-related disease and sarcoidosis), neoplastic and paraneoplastic xanthogranulomatosis, malignant lymphoma and carcinoma with secondary xanthogranulomatous reactions. Thus, identification of the underlying lesion is necessary for correct classification and to avoid overlooking more serious neoplastic or autoimmune diseases.

Warthin tumor is the second most frequently seen benign tumor of the salivary glands and is generally located in the parotid gland. Although extraparotideal manifestations in the small salivary glands are rare, the occurrence of cystic lesions in the area of the nasopharynx, eyelid, oral cavity or vestibular folds should include the Warthin tumor in the differential diagnosis. The therapy of choice is complete surgical tumor resection.

Due to their infrequency, diagnosis of salivary gland tumors remains a challenge for the practicing pathologist with respect to subtyping, grading and estimating patient prognosis. In a 3 center collaborative study of 288 cases with clinical follow-up information, it could be demonstrated that apart from clinical parameters like high patient's age, male sex and high tumor stage, the application of a 3-tiered grading system incorporating the histological tumor type is of high prognostic relevance. In immunohistochemical and molecular analyses overexpression of epidermal growth factor receptor (EGFR), high expression of human epidermal growth factor receptor 2 (HER2), amplification and gains of EGFR and HER2, absent expression of C-KIT, loss of maspin and of O(6)-methylguanine DNA-methyltransferase (MGMT) as well as MGMT promoter methylation turned out to be negative prognostic factors. In mucoepidermoid carcinomas the presence of a translocation t(11;19) was less relevant than recognizing different subtypes (classical type, eosinophilic, clear-cell and squamoid variants). Acinic cell carcinoma with mixed acinar-ductular differentiation as judged by expression of CK7 was characterized by a higher frequency of early relapse. The presented results underline the pathologist's role in the diagnosis and management of patients with salivary gland carcinomas.

We report a complex and rare combination of clinical and histological findings in a 59-year-old female patient: severe sicca-syndrome due to M. Sjögren, marginal zone B-cell lymphoma (MALT-type) in labial salivary glands with localized amyloid deposition, IgM-paraproteinemia, and Bence-Jones proteinuria. The causal association of these findings could only be elucidated by intense interdisciplinary correlation of all findings.

Significant progress in the diagnosis and therapy of salivary gland diseases has been made in recent years. The new technique of diagnostic and interventional sialendoscopy has made an important contribution and is indicated in every case of obstructive sialadenitis. The number of open resections of salivary glands due to stones will clearly decrease in the future in favor of endoscopic removal. Due to recent publications on the appropriate extent of salivary gland resection in benign tumors, more and more specimens with reduced cuffs of healthy salivary gland tissue will be sent to the pathologists. Ultrasound will stay the procedure of first choice for imaging of salivary gland diseases in Germany. In combination with fine-needle aspiration cytology high sensitivity and specificity for the assessment of salivary gland tumors can be achieved. Diffusion-weighted magnetic resonance imaging (MRI) is a new imaging tool and the power of distinction of pleomorphic adenoma from malignant tumors is promising. The use of botulinum toxin for salivary glands diseases is increasing. Intraglandular injections have been shown to induce salivary gland atrophy in animal experiments. The availability of biologicals is currently yielding new aspects for the treatment of Sjögren's disease.

In the majority of cases the diagnosis of pleomorphic adenoma (PA) is straightforward. In "monomorphic" types of PA problems may result: Epithelial-rich PA need to be distinguished from basal cell adenoma or canalicular adenoma. PA dominated by mesenchymal, spindle-shaped differentiation need to be distinguished from myoepithelioma or soft tissue tumours like schwannoma. Focal biphasic-tubular differentiation with CK7/18-positive ductal cells is good evidence for a tumour within the wide spectrum of PA. Focal peripheral pseudoinfiltration can represent physiological growth pattern of PA; this may render a difficult distinction from low-malignant carcinomas like adenoid-cystic or epithelial-myoepithelial carcinoma, harbouring also tubular structures. The different progression steps of carcinoma ex pleomorphic adenoma (CEPA), starting with intraductal carcinoma, are highly relevant with respect to prognosis and therapy. Early stages including CEPA with minor extracapsular invasion show favourable prognosis, while cases with extensive extracapsular invasion carry a dismal prognosis.

The molecular genetic background of salivary gland neoplasms has not been characterized in detail to date. However, interesting target genes which could be used as prognostic and diagnostic molecular biomarkers have already been identified, e.g. CRTC1-MAML2 in mucoepidermoid carcinoma, or PLAG1 and HMGA2 in pleomorphic adenoma. In particular, CRTC1-MAML2 has shown strong diagnostic and prognostic potential in recent years. One of the major advantages of molecular tumor markers is that valid results are obtained on minute cell and/or tissue samples. Due to high-throughput techniques like comparative genome hybridization (CGH), micro- or gene profiling array detection of new marker genes can be expected in the future. This is also true for the most frequent malignant salivary gland tumors after the mucoepidermoid carcinoma, i.e. adenoid cystic carcinomas and acinic cell carcinomas.

The prototype of a salivary lymphoepithelial lesion is the autoimmune disease Sjögren's syndrome with the characteristic lymphoepithelial duct lesions (LEL). The distinction of Sjögren's syndrome from cases with initial transformation into associated marginal zone B-cell lymphoma (MALT type) can be very challenging, whereby the presence of small "halos" can lead to over-diagnosis. The HIV-associated cystic lymphoepithelial lesion can be histologically almost identical to Sjögren's syndrome and often needs clinical correlation. The sporadic lymphoepithelial cyst of the parotid gland is a frequent finding and has no clinical consequence; however, this entity needs to be identified and distinguished from the above-mentioned entities. The most frequent diagnosis in resected submandibular glands is chronic-fibrosing sialadenitis, so-called Küttner's tumour. Altogether, there is a wide spectrum of lymphoepithelial interaction in the area of salivary glands, including biphasic lymphoepithelial tumours with an obligate lymphoid component, epithelial tumours with facultative tumour-associated lymphoid proliferation, and different processes of intraparotid lymph nodes. The immunohistological reaction for pan-keratin can be very helpful for a thorough pattern analysis of the different lymphoepithelial lesions. The relative frequency of the lesions in different salivary glands can also be diagnostically helpful.

Background: Pleomorphic adenomas of the small salivary glands are very rare and usually arise from the hard palate., Case Report: We present a female patient who was referred to our Department because of a bleeding enoral tumor, which persisted for 35 years. Histopathological examination after complete tumor excision showed a pleomorphic adenoma., Conclusion: Pleomorphic adenomas are an important differential diagnosis for tumors of the hard palatine. The therapy of choice is surgical excision.

This review gives a short survey of cytological criteria of the most common salivary gland tumours. The emphasis is on a short and precise as well as practicable summary of the most important cytological criteria and comprehensive presentation without claiming completeness. In addition our own results were compared with other international data and publications.

DNA ploidy and S-Phase fraction (SPF) of 279 salivary gland tumours were analysed using high-resolution DNA flow cytometry. All 229 benign neoplasms were diploid while 12 of 50 malignant tumours showed cell populations with aneuploid DNA content. The SPF values of diploid malignancies were significantly higher if compared with pleomorphic adenomas but did not differ from that of the zystadenolymphoma (Warthin tumour) group. While aneuploidy represents a distinct indicator of malignancy SPF values are of minor relevance for dignity assessment in salivary gland tumours.

Sialadenoma papilliferum is a rare tumour of the salivary glands that usually occurs in the oral cavity. Following the course of the salivary glands of the oral mucosa, the hard and soft palate are the most common locations of this tumor. In the international literature, only a few case reports about this entity can be found. We present a 63-year-old patient with a sialadenoma papilliferum accidentally found during diagnostic procedures for progredient dysphagia. Suffering from infrabifurcal cancer of the oesophagus, the patient had undergone partial oesophagectomy 1 year before. Histological verification was performed with a tumor biopsy at the border of hard and soft palate, on the right side. This case is compared with 39 further cases reported in the literature. The therapy of choice is resection of the tumor. Because of the high frequency of recurrence, in sano resection should be planned.

A subset of rare benign and malignant breast tumors with and without myoepithelial differentiation are morphologically and histogenetically similar to salivary gland tumors, but may differ in incidence and clinical behavior. The clinicopathological, immunohistochemical, molecular and prognostic features of ten salivary gland-like tumor entities of the breast are discussed and compared with their respective counterparts in the salivary glands.

Rationale: Pleomorphic adenoma is the most common neoplasm of major and minor salivary gland origin, followed by infectious reasons and sialolithiasis. Less common are adenocarcinomas presented. The salivary duct carcinoma represents a rare variant of the group of adenocarcinomas originated from the salivary glands, especially extremely rare from minor salivary gland origin., Case Report: We report about a 52 year old male patient presenting with painless, non-ulcerating tumor at the floor of the mouth. Since 2 weeks ingestion was painful. Further ENT-investigations including endoscopy and scans (MRT, ultrasound) showed no pathology. In particular, growth of cervical lymph nodes and distant metastases were not revealed. A biopsy showed a rare salivary duct carcinoma of comedo-type originated from the left sublingual salivary gland. The patient underwent an operation: the tumor was extirpated in toto, and, as the pathohistological investigation confirmed, in sano. Additionally a neck dissection at the left side was performed, followed by the radiation of the tumor region and the lymphatic neck regions, after sufficient reconvalescence. The tumor-classification was pT3, pN0. Since 3 years no recurrence of the tumor was confirmed., Discussion: Salivary duct carcinoma is a rare, high-grade malignant epithelial neoplasm, which occurs almost exclusively in the parotid. As presented, it can also occur in minor salivary glands. Histologically it is composed of structures that resemble expanded salivary glands. Comedonecrosis of these structures is a frequent feature. There is some histologic similarity to intraductal carcinoma of the breast. Differential diagnosis comprises adenoid cystic carcinoma, metastases of other adenocarcinomas, such as the carcinoma of the thyroid gland and the comedocarcinoma of the breast. Because of its poor prognosis a rapid and radical therapy is recommended., Conclusion: A rare case of a salivary duct carcinoma of sublingual salivary gland origin is presented. Usually the prognosis is poor. The adequate therapy is the complete surgical extirpation including the surgery of the regional lymphatic nodes and the additional radiotherapy.

Salivary duct carcinomas (SDC) are high grade neoplasms morphologically reminiscent of breast ductal carcinomas. Whereas the latter are well characterized, the body of immunophenotypic and cytogenetic data on SDC is limited. We studied 23 SDC by conventional histology, immunohistology, in situ hybridization, and comparative genomic hybridization (CGH). Data were subjected to biomathematical analysis in comparison to previously characterized breast ductal carcinomas in situ and invasive ductal carcinoma cases. Most SDC stained for cytokeratins (Ck) Ck 8/18 (77 %) or Ck 5/6 (30 %), 30 % of cases expressed the androgen receptor (AR), 14 cases (63 %) expressed c-erbB2, and one case stained for prostate specific antigen. Except for two cases, Ck 8/18 and Ck 5/6 were not coexpressed. Ck 8/18 expression positively correlated with presence of c-erbB2 and AR. At variance, Ck 5/6 correlated positively with p63 and inversely with both AR and c-erbB2 expression. Ck 5/6 and p 63 co-expression was also found in a distinct population of ductal epithelial cells of normal salivary glands. CGH analysis of SDC revealed increasing numbers of alterations in correlation with advanced diseases, but no recurrent alterations. Cluster analysis of phenotypic and genotypic markers assigned both salivary and breast carcinomas to numerous clusters independent of the primary tumour site. Although undistinguishable by conventional histology, SDC are heterogeneous, comprising at least two immunophenotypically distinct subgroups of neoplasms. Cluster analysis suggests several distinct patterns of gene expression common to both primary sites explaining morphologic parallels between SDC and high grade breast cancer.

Salivary gland carcinomas comprise a rare group of malignant tumors which are difficult to diagnose and treat due to their histopathologic diversity, variable clinical course and anatomic location, particularly with respect to the facial nerve. The present paper summarizes important features of these tumors, including recent advances in their management, i.e., diagnosis, surgery of the primary tumor, neck dissection, radiation therapy, and updates risk factors, criteria of malignancy, and prognostic variables, taking into account the relevant literature. Additionally, the present paper highlights briefly the survival rates of patients suffering from salivary gland carcinomas. The present overview is divided into two parts: the first is focused on epidemiology, etiology, criteria of malignancy, prognostic factors, and tumor classification, while part II discusses the diagnosis and therapy of salivary gland carcinomas.

Chromosome translocations in tumors frequently give rise to fusion genes encoding proteins with oncogenic activities. Mucoepidermoid carcinomas (MEC) are characterized by a t(11;19)(q21-22;p13) translocation found in approximately 60% of the tumors. This t(11;19) translocation results in a fusion gene consisting of exon 1 of the MECT 1 gene and exons 2-5 of the MAML 2 gene. As a result of the t(11;19) a fusion protein is generated which, independent of NOTCH-ligands, activates the transcription of the NOTCH target gene HES 1. The altered function of MAML 2 causes a disruption of NOTCH signalling which suggests a novel mechanism of tumorigenesis. Pending the elucidation of the t(11;19) at the molecular level of an apparently identical chromosomal translocation in Warthin's tumor, the identification of the translocation in MEC by FISH- and/or RT-PCR-analyses may become important in diagnosis and might have prognostic relevance. Warthin's tumors are benign salivary gland neoplasms with a distinctive histomorphology and histogenesis completely different from MEC.

This tutorial focuses on myoepithelial tumors of salivary glands, an entity with heterogeneous cytomorphology and inconsistent immunophenotype. Moreover, the clinical course cannot be predicted reliably from cytomorphological and immunophenotypic analysis. This heterogeneity causes problems in routine diagnostic, so that diagnosis ultimately rests on conventional histology. In a representative series of myoepitheliomas and malignant myoepitheliomas, antibodies against cytokeratins 5/6, S 100 protein and vimentin produced the most consistent reactivity profile. Staining for cytokeratins 5/6 is a useful addition to the established immunohistologic marker panel in the work-up of myoepitheliomas, because of its reliable expression in most cases and because it may underline the epithelial nature of the lesion. Comparative genomic hybridisation (CGH) profiles of myoepitheliomas and myoepithelial carcinomas showed no chromosomal aberration in less than 50% of myoepithelial carcinomas, so that CGH is of limited help in a given case. In a case that was represented in three separately localized manifestations of the disease that differed in their CGH profiles, gross genetic aberrations suggest to be acquired during tumor progression and should raise the suspicion of malignancy. Thus, diagnosis of myoepithelial tumors of salivary glands has to rest on morphological grounds with support of a restricted panel of immunohistologic markers.

Systematic analysis of gene expression in salivary gland tumors is necessary to identify genes associated with specific tumor types. From the salivary gland register of the University Hospital Hamburg-Eppendorf sufficient samples of various tumors were available to generate Tissue Micro-Arrays (TMA). In light of the considerable heterogeneity of salivary gland tumors, this study was aimed at evaluating the suitability of TMA in salivary gland diagnostics and research. Epithelial antigens are not sufficient for a tumor-type-specific characterization. Myoepithelial markers are suitable for distinguishing biphasic tumor types from purely epithelial tumors. The detection of amylase in acinic cell carcinomas, and the detection of steroid hormone receptors in these and other malignant salivary gland tumors particularly in combination with the expression of transcription factors, oncogenes and proliferation associated antigens result in characteristic expression profiles. These may prove to be valuable for further investigations, especially on the molecular level.

This tutorial focuses on salivary duct carcinoma (SDC), a rare, high grade neoplasm mainly of major salivary glands. The clinical course of these tumors is characterised by extended local disease, early distant metastasis, and poor outcome. The morphology of SDC is reminiscent of breast ductal carcinomas and may occasionally cause diagnostic problems. In spite of mimicry with ductal carcinoma in situ of the breast and an in situ component, that is evident in most tumors by immunohistology with antibodies directed against high molecular weight cytokeratins (Ck), SDC is always an invasive carcinoma. By immunohistology, most tumors show reactivity with antibodies directed against Ck 7, Ck 8/18 and Ck 19 whereas a morphologically indistinguishable subgroup expresses Ck 5/6 in tumor cells in addition to residual basal epithelia. Carcinoembryonic antigen, GCDFP-15 and androgen receptor are other helpful markers in routine diagnosis of SDC. Prostate-specific antigen is detectable in some cases. Abnormal p53 expression seems to indicate an adverse prognosis. Expression of c-erbB2, the over-expression of which is associated with a poor prognosis, may form the basis for a targeted therapeutic approach for selected cases of SDC.

Myoepitheliomas of the salivary glands are rare benign tumors composed of spindle-shaped myoepithelial cells, but may show plasmacytoid, epitheloid and clear cell-types that principally exhibit myoepithelial but not ductal differentiation. These tumors are mainly located in the major salivary glands and have sometimes abundant, acellular, mucoid or hyaline stroma but lack chondroid and myxochondroid foci, probably representing the one end of the spectrum of pleomorphic adenoma. Lipomatosis in the form of isolated small islands or scattered single lipocytes, is quite uncommon, and a large amount of adipose tissue in a pleomorphic adenoma and myoepithelioma is a rarity and only described in major salivary glands. We present the case report of a 38-year old man with a myoepithelioma of the minor palatinal salivary glands with extensive lipomatosis as an example of this rare phenomena.

Purpose: In this retrospective study we give a clinical review of our experience with different tumor entities of salivary gland cancer., Patients: Between January 1983 and December 2002, a total of 155 patients with carcinomas of the salivary glands received initial treatment at the Department of Oral and Maxillofacial Surgery, Hanover Medical School., Results: There were 51.0% adenoid cystic carcinomas, 27.1% mucoepidermoid carcinomas, 7.7% adenocarcinomas, 6.5% polymorphous adenocarcinomas, and altogether 7.7% other less frequent tumor entities. Complete resection was achieved for 63.5% of patients with high-grade carcinomas and for 80.0% of patients with low-grade carcinomas. Postoperative radiation was administered to 26.2% of patients with high-grade carcinomas and 13.3% of patients with low-grade carcinomas. Overall local control rates at 5, 10, and 15 years were 77.5%, 66.2%, and 59.0%. Overall regional control rates at 5, 10, and 15 years were 93.5%, 87.6%, and 85,4%. Overall distant control rates at 5, 10, and 15 years were 85.9%, 77,2%, and 73,6%. Overall survival rates at 5, 10, and 15 years were 65,9%, 48,0%, and 39,8%. There was a significant difference between patients with low-grade and high-grade carcinomas. Polymorphous adenocarcinomas showed the best prognosis, followed by low-grade mucoepidermoid carcinomas, adenoid cystic carcinomas, adenocarcinomas, and high-grade mucoepidermoid carcinomas. The number of the remaining tumor entities was too small to be divided into independent subgroups for statistical analysis. Tumor entity, tumor stage, and margin status significantly influenced prognosis. Statistically, we were not able to demonstrate a positive effect for postoperative radiation., Conclusion: Grading is important, but should be considered in the context of stage. In the future, patients with salivary gland carcinomas should be randomized for prospective multicenter clinical trials, which could provide reliable information about adjuvant treatment modalities and their results even for rare subtypes of salivary gland cancer.

This tutorial focuses on malignant lymphomas and inflammatory conditions as potential precursors of primary malignant lymphomas in salivary glands. Salivary glands display a mucosa-associated lymphoid tissue and are often associated with intra- and periglandular lymph nodes. Inflammation of the glands may variably produce duct ectasia, lymphoepithelial lesions, atrophy, and fibrosis. Primary lymphomas of the salivary glands may develop on the basis of autoimmune sialadenitis and comprise most frequently marginal zone lymphomas, less often monocytoid lymphomas or other lymphoma entities. In a large proportion of cases, lymphoma infiltrates are attributable to extraglandular lymphomas either as a leukemic infiltrate with diffuse enlargement or as a localized manifestation of primary nodal non-Hodgkin lymphomas. Diagnosis is based on conventional histology and immunohistology.

The diagnosis of basaloid tumors of the salivary glands can be challenging. In most cases, conventional histologic examination, if carried out meticulously, will be sufficient. Yet, immunohistochemistry will be of help for the definition of purely myoepithelial tumors, basaloid squamous cell carcinomas, and canalicular adenomas. The differential diagnosis of canalicular adenoma, basal cell adenoma and basal cell adenocarcinoma, adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, myoepithelial tumors, epithelial-myoepithelial carcinoma, and basaloid squamous cell carcinoma is discussed.

Benign and malignant skin adnexal neoplasms, especially glandular lesions, show morphologically striking similarities to salivary gland tumors. On the other hand, histological and clinical differences are evident, and knowledge of their existence is important for adequate treatment and reliable prognostication. In this review similarities and differences of selected entities are briefly described and discussed. The following entities are reviewed: cylindroma (vs. membranous variant of basal cell adenoma), sebaceoma (vs. sebaceous adenoma), syringocystadenoma papilliferum (vs. sialadenoma papilliferum), chondroid syringoma (vs. pleomorphic adenoma), cutaneous myoepithelioma (vs. myoepithelioma of salivary glands), cutaneous malignant myoepithelioma (vs. malignant myoepithelioma of salivary glands), cutaneous adenoid cystic carcinoma (vs. adenoid cystic carcinoma of salivary glands), and mucinous eccrine carcinoma (vs. mucous carcinoma of salivary glands).

Undifferentiated salivary gland carcinomas may be divided into small cell and large cell types. Among large cell undifferentiated carcinomas, lymphoepithelial carcinomas have to be distinguished, the latter of which are endemic in the Arctic regions and southern China where virtually all cases of these tumors are associated with the Epstein-Barr virus (EBV). Association with EBV may also be observed in sporadic cases, and detection of EBV gene products may aid their diagnosis. Immunohistology may be employed to resolve the differential diagnosis of undifferentiated salivary gland carcinomas, comprising malignant lymphomas, amelanotic melanomas, Merkel cell carcinomas, and adenoid cystic carcinomas, in particular in small biopsy materials. Because of the rarity of undifferentiated salivary gland carcinomas, the differential diagnosis should always include metastases of undifferentiated carcinomas arising at other primary sites, particularly when expressing the thyroid transcription factor-1 (TTF-1).

In addition to staging, histological typing and grading provide important information for prognosis and adequate treatment of salivary gland cancers. Current classification and grading systems for mucoepidermoid carcinoma, adenoid cystic carcinoma, and malignant mixed tumor (carcinoma ex pleomorphic adenoma) are discussed.

Purpose: In this study we give a clinical review of our experience with adenoid cystic carcinoma (ACC) and compare our results with those reported in the literature., Patients: Between 1981 and 2000, 74 patients with ACC of the head and neck were treated at the Department of Oral and Maxillofacial Surgery, Hannover Medical School., Results: The average age at diagnosis was 58 years. There were 38 men and 36 women. The primary site was the parotid gland in 4 cases, the submandibular and sublingual gland in 21 cases, the lacrimal gland in 1 case, the minor salivary glands of the oral cavity and oropharynx in 44 cases, and the nasal cavity and maxillary sinus in 4 cases. There were 19 T1, 15 T2, 9 T3, and 31 T4 tumors with perineural invasion of 32 tumors. R0 resection was performed in 45 cases. Fourteen patients received postoperative radiation. There were only five N1 and two N2b necks. All patients were staged M0 at presentation. Local control rates at 5, 10, and 15 years were 64%, 56%, and 52% with a mean local control time of 11.1 years. Tumor size ( p< or =0.001), margin status ( p< or =0.001), and perineural invasion ( p

Introduction: The salivary duct carcinoma (sdc) represents a rare variant of the group of adeno-carcinomas of the salivary glands. Histopathologically, it is marked by solid and cribriform cell nests with central necrosis, displaying distinct similarity with the ductal carcinoma of the breast, where prognosis can be correlated with Her-2 gene-amplification. Based on this histopathological similarity, the prognostic value of Her-2 gene amplification in SDC was examined in the presented pilot-study., Patients and Methods: Four own patients with different clinical courses were examined in regard to their histopathological features, Her-2 gene-amplification and proliferation (Ki67)., Results: Three of the four patients died tumor related 2.4, 5.5 and 8.2 years after initial diagnosis. The remaining patient died tumor-free 6 year after diagnosis (myocardial infarct). The two patients with an early recurrent disease and distant metastasis showed a high Her-2 expression and proliferation (Ki67), compared to the other two patients., Conclusion: In the presented pilot-study a distinct correlation between Her2-gene-amplification, proliferation (Ki67) and clinical course could be observed. Additional analysis to evaluate this aspect seems rectified, especially under recognition of therapy decisions.

Background: Adenoid cystic carcinoma (ACC) of the salivary gland is a generally slow-growing but highly malignant neoplasm with a remarkable capacity for recurrence. Prognosis is greatly influenced by the histological subtype (tubular, cribriform or solid), presence of tumour at the margins, anatomic size, and lymph node metastases. However, none of these parameters has proven to be an unequivocal predictor of disease activity. Therefore, the current study was undertaken to investigate the prognostic value of molecular markers., Patients and Methods: Samples from 22 patients, including 4 patients with recurrent disease, were included in the study. By means of immunohistochemistry, the staining pattern of p53, bcl-2, P-glycoprotein, glutathione S-transferase, and topoisomerase as well as sequence analyses of p53 were performed. These molecules were chosen because of their proven association with poor prognosis and therapy resistance in other malignancies., Results: Homozygous p53 mutations were found in all of the 4 recurrent tumors. The other proteins were detected in some tumors, but showed no correlation with histological subtype or recurrence of tumor., Conclusion: The results of the current study emphasize the prognostic value of a p53 alteration as an independent prognostic marker. Further, it could be demonstrated for the first time that proteins known for their association with radio- and chemotherapy resistance can be overexpressed in some ACCs suggesting that those molecules could influence the outcome of new therapeutical approaches., (Copyright 2001 S. Karger GmbH, Freiburg)

Tyrosine-rich crystalloids in tumors of the salivary glands are rare and have been reported mainly in specimens from Black African patients. The pathogenesis of these structures is still unclear, but pathological secretion by neoplastic myoepithelial cells is supposed. Millon's staining and ultrastructural examinations are used for confirming the diagnosis. We present the case report of a 59-year-old woman with a myoepithelioma of the minor salivary glands in the smooth palate containing tyrosine-rich crystalloids as an example of this rare phenomenon.

Background: To evaluate alternative treatment regimen e.g. neutron therapy determination of treatment efficacy as well as side effects is important. Sensitivity of computed tomography (CT) in detecting changes of connective tissue after neutron therapy was examined., Patients and Methods: In the course of their follow-up period (median 45 months) 12 patients with malignant salivary gland tumors who had postoperatively received neutron (1/12) or photon/neutron therapy (11/12) were examined by means of CT densitometry on 3 representative scans in the area of radiotherapy. In 3 ROI (regions of interest) in subcutaneous fatty tissue the density at the irradiated and the non-irradiated side was determined according to Hounsfield units (HU) and the average density was calculated. The average density of both sides was compared and correlated with the clinical grade of fibrosis according to LENT SOMA., Results: All CT measurements (216 ROI, 18 ROI per patient) showed higher density levels on the irradiated side than on the non-irradiated side. The average density on the irradiated side was -57.7 +/- 4.7 HU and on the non-irradiated side -69.4 +/- 5.8 HU (p = 0.002). In 3/12 patients a clinical fibrosis was not seen; however, the relative density measured on the irradiated and non-irradiated side deviated by up to 8%. This could have been caused by minimal changes not being noticed by either patient and examiner. In patients with determined fibrosis Grade 1 (8/12) the relative density deviation was 4 to 39%. In 1/12 patients with determined fibrosis Grade 2 the relative density deviation was 50% (Figures 1a and 1b). Fibrosis Grade 3 and 4 did not occur (Table 1)., Conclusions: Fibrosis is correlated with an increasing value of HU of the tissue density in CT. With the described method it is possible to graduate radiation induced subcutaneous fibrosis in correlation to the clinical fibrosis grade according to LENT SOMA. In the patients we examined subcutaneous fibroses after photon/neutron therapy were moderate. Especially in characterising subclinical or slight changes of connective tissue after radiotherapy computed tomography is of value.

Background: Compared to the typical carcinomas of the upper aerodigestive tract the benign tumours of the salivary glands show significant histological diversity. Therefore correct histological diagnosis might be difficult even for the pathologist. Basal cell adenoma may have a multifocal origin and can be associated with cylindromas of the skin., Patients: In 17 patients with an average age of 65.8 a basal cell adenoma of a major salivary gland was diagnosed with a slight preponderance of the female sex (10:7)., Results: One male patient showed a bilateral basal cell adenoma of the parotid gland and simultaneously multiple cylindromas of the skin in the head and neck region. There might be a syndromal coincidence, since histology revealed similar features of the salivary gland tumours compared to the skin neoplasias. The patient's history gave hints of a familial occurrence of the dermal cylindromas., Conclusions: In rare cases a basal cell adenoma of the dermal type may be associated with cylindromas of the skin suggesting a common histogenesis. Due to possible multifocal origin and the menacing risk of malignant transformation a thorough follow-up of the patients after surgical treatment is mandatory.

Background: The origin of recurrences of pleomorphic adenomas after initial surgical treatment is discussed. In this study mesenchymal and epithelial tumorcomponents were immunhistochemically stained in recurrent and nonrecurrent adenoma. In addition the proliferation activity was assessed., Methods: Twelve nonrecurrent adenomas (10 of the parotid gland, 2 of the submandibular gland) and 18 recurrent adenomas (15 of the parotid gland, 3 of the submandibular gland) were immunhistochemically stained with a MIB1 antibody against the cell proliferation associated nuclear antigen (Ki-67 antigen). The proliferation index (MIB1 positive cells per 100 cells) was calculated separately for each tumor component., Results: The mean value (x) of the proliferation indices of the component with epithelial differentiation was 4.67 (recurrent group, standard deviation [SD]: 3.14) and x = 2.34 respectively (nonrecurrent group, SD = 1.83). The difference between the mean values was significant (p = 0.028). For the component with mesenchymal differentiation the values were x = 0.33 (for recurrent adenomas, SD = 0.59) and x = 0.17 (nonrecurrent adenomas, SD = 0.39) respectively. The difference was not significant., Conclusions: Proliferation activity is markedly higher in components with epithelial differentiation of recurrent adenomas compared to nonrecurrent tumors. The results demonstrate the tumor component with epithelial differentiation as a possible origin for recurrence.