Salivary gland tumours

Salivary gland tumours are a relatively rare and morphologically diverse group of lesions. Although most clinicians and pathologists will have encountered the more common benign neoplasms, few have experience of the full range of salivary cancers, which are best managed in specialist centres. This review considers some current areas of difficulty and controversy in the diagnosis and management of these neoplasms. The classification of these lesions is complex, encompassing nearly 40 different entities, but precise classification and terminology is essential for an accurate diagnosis and for the allocation of tumours to prognostic groups. For many salivary tumours diagnosis is straightforward but the wide range of morphological diversity between and within tumour types means that a diagnosis may not be possible on small incisional biopsies and careful consideration of the clinical and pathological features together is essential. Although tumour grading is important and helpful, it is not an independent prognostic indicator and must be considered in the context of stage. Large malignancies tend to have a poor prognosis regardless of grade and even high-grade neoplasms may do well when they are small. A helpful guide to management of salivary cancers is the '4 cm rule'.     

A clinicopathologic study of 196 intraoral minor salivary gland tumours

We present a retrospective study of 196 patients with intraoral minor salivary gland tumours, 128 malignant and 68 benign, diagnosed from 1954 to 1993 in the A.C. Camargo Hospital, São Paulo, Brazil. Sixty-five percent of the cases occurred in the palate, followed by tongue (9.7%) and retromolar area (6.1%). Pleomorphic adenoma was the most common benign tumour, and mucoepidermoid carcinoma was predominant among the malignant tumours. Surgery was the main treatment method and postoperative radiotherapy and radiotherapy alone were used in 40 and 15 patients, respectively. Local recurrence was observed in two patients with pleomorphic adenoma and in eight patients with malignant tumours. Regional lymph node metastases occurred in four cases and distant metastases in five. Forty-six of 47 patients with benigh tumours who were followed up from 1 to 7 years were alive without disease. Twenty-four of 79 patients with malignant tumours who were followed up for at least 5 years died due to the tumour and 47 were alive without disease.     

Salivary gland tumours: an epidemiological review of non-neoplastic and neoplastic pathology

Salivary gland tumours (SGT) demonstrate geographical variation. The primary objective of this study was to determine the types, frequency, distribution, and demographics of non-neoplastic and neoplastic salivary gland pathology at Waikato Hospital, New Zealand (NZ) over a 10-year period. Following this we conducted a 10-year retrospective review of SGT epidemiology from international literature. In total 825 patients were identified, 31% (256/825) with non-neoplastic salivary gland pathology, 34% (284/825) with benign neoplastic pathology, 14% (118/825) with primary malignant lesions, 18% (146/825) with metastatic SGTs, and 3% (21/825) with lymphoma. Patients had a mean (range) age of 58 (3–102) years, were predominantly male (58%, 476/825), and NZ European (65%, 536/825). Tumours were most prevalent in the parotid gland (85%, 484/569), of which 44% (211/484) were malignant. Pleomorphic adenoma was the most common benign (71%, 203/284) and overall (36%, 203/569) tumour, while mucoepidermoid carcinoma (25%, 29/118) and squamous cell carcinoma (SCC) (73%, 106/146) were the most common primary malignant and metastatic SGTs, respectively. Our literature review identified 18 studies consisting of 33,933 patients, of whom 71% (24,013/33,933) had benign SGTs. Pleomorphic adenoma (68%, 16404/24013) and mucoepidermoid carcinoma (29%, 2826/9621) were the most common benign and malignant SGTs, respectively. Low numbers of non-neoplastic and metastatic SGTs were reported in the literature. This research provides a greater understanding of differences in their global distribution. Consistent with previous literature, pleomorphic adenoma and mucoepidermoid carcinoma were the most common benign and malignant SGTs. In NZ, we found high rates of malignant SCC to the parotid gland, consistent with the epidemiology of non-melanoma skin cancer in the country.     

Expression of Mcm-2, Ki-67 and geminin in benign and malignant salivary gland tumours

Background:  Recent studies have proposed that minichromosome maintenance (Mcm) proteins may be sensitive proliferation markers and may serve as novel biomarkers for prognostication and diagnosis of various pre-malignant and malignant lesions. The aims of this study were to determine the expression of Mcm-2, Ki-67 and geminin in salivary gland (SG) tumours, and to evaluate their usefulness for diagnosis or for prediction of tumour behaviour.
Methods:  Tissue from 62 SG tumours was assembled in tissue microarray format. There were 13 adenoid cystic carcinomas (ACC), 10 carcinoma ex pleomorphic adenomas (CEPA), 10 mucoepidermoid carcinomas (MEC), 10 polymorphous low-grade adenocarcinomas (PLGA), 10 pleomorphic adenomas (PA) and nine acinic cell carcinomas (AcCC). Clinicopathological data were collected retrospectively and immunohistochemical analyses of Mcm-2, Ki-67 and geminin were performed on all lesions. Labelling index (LI) for each marker was determined by counting the percentage of positive cells in six random fields from three arrays per case.
Results:  Mcm-2 expression was higher than Ki-67 and geminin in all tumours studied. Mcm-2 LI was higher in ACC (28.2 ± 19.2%) than in CEPA, AcCC, MEC, PA and PLGA (5.3 ± 4.1%, P  = 0.001). Mcm-2 LI was higher in CEPA (20.4 ± 5.0%) than in PA (6.9 ± 5.0%, P  = 0.001). LI did not correlate to tumour grade or outcome for any of the markers or tumour types.
Conclusions:  The findings suggest that Mcm-2 may be a sensitive proliferation marker in SG tumours and may be useful for differential diagnosis between PA and CEPA, and ACC and PLGA. Further studies are warranted to assess the value of Mcm-2 as a predictor of recurrence and survival.     

Epidermal growth factor receptor immunoexpression evaluation in malignant salivary gland tumours

Objective:  The aim of this study was to determine epidermal growth factor receptor (EGFR) expression in malignant salivary gland tumours and its possible relationships with clinical and morphological findings, disease course and prognosis.
Patients and methods:  The study sample comprised 88 patients diagnosed and treated for primary malignant salivary gland tumours between January 1992 and December 2002. We analysed EGFR expression using immunohistochemistry on formalin-fixed, paraffin embedded surgical specimens of all patients. Statistical analysis was used to investigate possible relationships between EGFR expression and clinical findings, histological findings, disease course and patients survival.
Results:  Of all cases, 32 (36.4%) were EGFR positive. There was a statistically significant correlation between EGFR expression and histological grade. No other variable was correlated with EGFR expression including the overall and disease-free survival. Stage classification was the only parameter in multivariate analysis that was an independent predictor of low overall and disease-free survival.
Conclusion:  EGFR is not a useful indicator of prognosis in malignant salivary gland tumours. However, the EGFR expression in salivary gland cancers like adenocarcinomas, undifferentiated carcinomas, mucoepidermoid carcinomas or salivary duct carcinomas suggests that these tumours may be a candidate for therapy investigation directed at EGFR.     

Migration‐stimulating factor as a novel biomarker in salivary gland tumours

J Oral Pathol Med (2011) 40 : 747–754 Background: The identification of novel stratification biomarkers would benefit the clinical management of patients with salivary gland tumours. Migration‐stimulating factor (MSF) is a potent stimulator of cell invasion, matrix remodelling and angiogenesis. The aim of this study was to determine whether MSF was expressed in salivary gland tumours and its potential value as a diagnostic biomarker. Methods: Paraffin‐embedded archival specimens of small salivary gland tumours were stained with an MSF‐specific antibody. The specimens included 27 malignant and seven benign tumours; histologically normal salivary gland adjacent to the tumour was present in 16 specimens. MSF expression was assessed by consensus of 2–4 independent observers according to various indices, including ‘overall MSF grade’, ‘percentage of area stained’ and ‘intensity of the staining’. The motogenic effect of MSF on a salivary gland tumour cell line, HSG, was examined in the transmembrane assay. Results: Overall MSF expression increased significantly in a step‐wise fashion from normal salivary gland to benign and malignant tumours (P = 0.04–0.0001); with moderate/strong positive specimens representing 6%, 33% and 74% of the normal, benign and malignant specimens, respectively. MSF was heterogeneously expressed in both carcinoma and stromal cell compartments, its expression being higher in malignant than benign tumours regarding various MSF indices. In tissue culture studies, exogenous MSF stimulated the migration of HSG cells. Conclusions: These immunohistochemical and functional studies suggest that MSF expression is a potentially useful biomarker of salivary gland tumour progression.     

Immunolocalization of α2, α5, and α6 integrin subunits in salivary tissue and adenomas of the parotid gland

The localization of the integrin subunits α₂, α₅, α₆ was studied immunohistochemically in samples of normal salivary gland and in a series of 8 pleomorphic adenomas, 5 Warthin's tumors, and 2 basal cell adenomas. In normal salivary tissue, acinar and ductal cells expressed α₂ and α₆ chains at the basal cell pole facing the basement membrane. α₂ also localized at sites of cell-cell contact. No staining of the epithelial component was seen with α₅. The polarized expression of α₂ and α₆, subunits was retained in salivary adenomas. These subunits were present at the basal cell pole of solid nests, tubules and ducts of pleomorphic adenomas, as well as of the basal layer of the epithelium of Warthin's tumor, and of the trabecular structures of basal cell adenomas. The α₅ subunit was consistently expressed only by cells embedded in the myxoid or chondroid matrix of pleomorphic adenomas. We conclude that the pattern of a integrin subunit expression in salivary adenomas may be related to the "epithelial" or "mesenchymal" phenotype of the neoplastic cells.     

Immunolocalization of β1 integrins in human gingival epithelium and cultured keratinocytes

Beta 1 integrins are cell surface receptors for extracellular matrix binding. We have recently shown that these receptors may also play a role in cell-cell binding of human epidermal keratinocytes. In this study we used immunofluorescence and confocal laser scanning microscopy to localize beta 1 integrins in frozen sections of human gingiva and cultures of human gingival keratinocytes. The results show that beta 1 integrin polypeptides, localized by monoclonal and polyclonal antibodies, were detected mainly in the basal layer of the keratinized epithelium. There was also scattered staining in connective tissue fibroblasts, nerves, and blood vessel walls. In the basal layer, the integrins were found around the entire periphery of the basal keratinocytes. Furthermore, confocal laser scanning microscopy (CLSM) revealed that most of the staining was in fact localized in dot-like structures at the lateral cell membranes of neighboring basal cells. In cultured human gingival keratinocytes maintained in low calcium (0.15 mM) conditions β1 integrins were localized in several different structures: trails which were left behind when the cells moved in culture, dots underneath the cells, around the nucleus, and in cell-cell contacts. The trails were also found to contain fibronectin and type IV collagen but not laminin. Switching the keratinocytes to high calcium (1.2 mM) conditions induced the formation of cell-cell contacts which were strongly positive for β1 integrins. No fibronectin or type IV collagen was found in cell-cell contact sites. The results indicate that β1 integrins are localized to cell-cell junctions of human gingival keratinocytes both in vivo and in vitro. Cultured cells also express these receptors in cell-matrix contacts indicating a dual role for β1 integrins in cell-matrix and cell-cell contacts of human gingival keratinocytes.     

Primary epithelial salivary gland tumours in children and adolescents

Primary epithelial tumours of the salivary glands are very rare in paediatric patients. The aim of this study was to evaluate the clinical course, treatment, and outcomes of these uncommon neoplasms based on the authors’ experience and the recent literature. The medical charts of 12 female patients and seven male patients with primary epithelial salivary gland tumours were reviewed. All were under 19 years of age and underwent surgical treatment between 1994 and 2016. The results of this group of paediatric patients were compared with those of 621 adult patients. The two most common tumours in the paediatric patients were pleomorphic adenoma and mucoepidermoid carcinoma (89.4%; P = 0.004). The incidence of facial nerve palsy following surgery of the parotid tumours was similar in the two groups (P = 1.000). The most common primary cancer in the paediatric group was mucoepidermoid carcinoma (77.8%), while in the adult group, adenoid cystic carcinoma was most common (P < 0.001). The paediatric group had only low-grade cancers in early stages (P < 0.001), with an overall 5-year survival rate of 100%. These results show that the incidence of malignant salivary gland tumours is higher in paediatric patients than in adult patients. This should be taken into account during diagnosis and therapy.     

Intraoral Minor Salivary Gland Tumours: A Retrospective Study from a Dental and Maxillofacial Surgery Centre in Salem,Tamil Nadu

Abstract

Minor salivary gland tumors (MSGTs) constitute a heterogeneous group of neoplasms with variation in histopathology. These are rare neoplasms usually occurring in the palate. Dental examination may provide an opportunity for early detection.

Aim

This study was undertaken to do an epidemiological survey of minor salivary gland tumours reporting to a single dental and maxillofacial surgery centre and to determine the correlation of the histopathologic characteristics with the clinical features.

Materials and Methods

A retrospective survey of the histopathological findings of 1,020 consecutive biopsy reports in a single dental and maxillofacial surgery centre was done to identify cases of MSGT. The results were tabulated based on various criteria.

Results

In our study, only 8 tumors were benign (26.67 %), and 22 tumors were malignant (73.33 %). Mucoepidermoid carcinoma (MEC) was the most common tumor (15 of 30). Pleomorphic adenoma was most common benign MSGT in our series (7 of 30). This was followed by adenoid cystic carcinoma (6 of 30). Palate was the most common site (13 of 30) followed by buccal mucosa (5 of 30) and lip (4 of 30).

Conclusions

Unlike many previous studies, malignant salivary gland tumours were predominant. MEC was the most common malignant tumour in our study similar to many other studies. The palate was the most common site for minor salivary gland neoplasms.     

Maspin expression in normal and neoplastic salivary gland

BACKGROUND: Maspin inhibits cell motility, invasion and metastasis. Loss or reduction in maspin expression has been associated with tumoral progression. METHODS: The presence of maspin was studied immunohistochemically in salivary gland tumours presenting cells with myoepithelial differentiation in their composition, and in normal salivary gland. RESULTS: Pleomorphic adenoma (PA) presented high expression of maspin, except in the spindle cells and occasional luminal cells. Epithelial-myoepithelial carcinoma and tubular adenoid cystic carcinoma (ACC) showed intense expression in all cells. Cribriform ACC evidenced only few positive cells of the luminal type, while solid subtype showed rare positive cells. Normal salivary gland tissue has shown low levels of maspin positivity. CONCLUSIONS: Maspin has small participation in normal salivary gland, is increased in PA, and decreases as the histological malignancy raises. Hence, in salivary gland, its expression is not exclusive of myoepithelial cells; thus, it should not be used as a marker for this cell. Nevertheless, we believe it is an important marker of biological behaviour in these tumours.     

Expression of hMSH2 and hMLH1 proteins of the human DNA mismatch repair system in salivary gland tumors

BACKGROUND: The human DNA mismatch repair (hMMR) system plays an important role in reducing mutation and maintaining genomic stability. The MMR system in human cells is composed of at least six genes (hMSH2, hMLH1, hMSH3, hPMS1, hPMS2 and GTBP/hMSH6). In particular, hMSH2 and hMLH1 are expressed in cells undergoing rapid renewal; their reduced expression has been reported in several tumors. METHODS: We examined the expression of hMSH2 and hMLH1 by immunohistochemistry in tumor specimens from 43 patients with primary tumors. RESULTS: All carcinomas (n = 20) expressed these proteins. In addition, when compared to pleomorphic adenomas, malignant tumors contained significantly (P < 0.01) higher proportions of hMSH2 (56.1 +/- 31.5 vs. 31.1 +/- 22.6) and hMLH1 (27.9 +/- 26.0 vs. 14.0 +/- 12.6) positive cells. Warthin's tumors showed no specific nuclear staining of tumor cells for both hMSH2 and hMLH1. CONCLUSIONS: These data suggest a minor, if any, role for a defect in the hMMR system in the pathogenesis of malignant salivary gland tumors.     

4种涎腺肿瘤及人胚颌下腺免疫组化对比研究

目的：探讨涎腺肿瘤细胞的形态分化、组织发生及其异质性。方法：采用光镜、免疫组化技术对８例腺淋巴瘤、３例嗜酸性腺瘤、１２例多形性腺瘤及２例上皮－肌上皮癌进行研究,同时观察了５６例胚胎颌下腺组织作为对照。结果：多形性腺癌中导管样结构系肿瘤性闰管结构和肿瘤性分泌管结构;腺淋巴瘤和嗜酸性腺瘤中导管结构系肿瘤性分泌管结构;上皮－肌上皮癌中导管结构系肿瘤性闰管结构;涎腺肿瘤组织结构及抗原表达复杂多样,与人胚涎腺发生过程中结构及抗原表达有相似之处。结论：涎腺肿瘤的复杂性系致瘤因素作用于不同干细胞或同一干细胞不同分化阶段所致。     

DNA ploidy analysis in salivary gland tumours by image cytometry

AIM: To determine whether DNA ploidy by image cytometry is a good diagnostic tool to distinguish benign and malignant salivary gland tumours. METHODS: A total of 62 salivary gland tumours were studied. Cases were histologically diagnosed [haematoxylin and eosin (H&E)]. According to the World Health Organization (WHO) classification, there were 14 mucoepidermoid carcinomas (MEC), 11 adenoid cystic carcinomas (ACC), 10 pleomorphic adenomas (PA), 10 carcinoma ex PA (CEPA), 9 acinic cell carcinomas (ACCa), 3 polymorphous low-grade adenocarcinomas (PLGA), 2 papillary cystadenocarcinomas (PC), 1 myoepithelial carcinoma (MC), 1 undifferentiated carcinoma (UC) and 1 mucinous adenocarcinoma (MA). Paraffin sections (40 microm) were micro-dissected to isolate tumour areas; cell nuclei were extracted and Feulgen-stained cytospin monolayers were analysed using a DNA image cytometry system. For each case, DNA index (DI) was calculated relative to internal controls (lymphocytes; DI=1.0). Cases were categorized as diploid or aneuploid and the proportion of cells over 5c was also calculated. RESULTS: Fifty-three of 62 salivary gland tumours were uniformly diploid. Only nine cases were aneuploid: five CEPA, one low-grade MEC, one PC, one UC and one MA. CONCLUSIONS: The vast majority of salivary gland tumours were diploid. High-grade malignancies may be aneuploid, and ploidy may be useful to identify malignant change in atypical PA. Further, larger studies are needed to confirm our results and to further evaluate the usefulness of the technique in high-grade lesions.     

Immunohistochemical assessment of CD1a‐positive Langerhans cells and their relationship with E‐cadherin in minor salivary gland tumors

J Oral Pathol Med (2012) 41 : 47–53 Objective: The aim of this study was to investigate the presence of CD1a‐positive Langerhans cells and their relationship with E‐cadherin in minor salivary gland tumors. Methods: Twenty‐seven minor salivary gland tumors were investigated using immunohistochemistry for CD1a and E‐cadherin. Results: A significant difference regarding the mean density of CD1a‐positive Langerhans cells was observed between pleomorphic adenomas and malignant tumors studied (P = 0.001). No CD1a‐positive cells were detected in most cases (n = 5) of cystic adenoid carcinomas. CD1a‐positive cells were detected in one mucoepidermoid carcinoma case, and six low‐grade polymorphous adenocarcinomas cases. Comparison of the mean density of CD1a‐positive cells between the three malignant tumors showed no significant difference (P = 0.127). No significant difference was observed in the presence of E‐cadherin between tumors (P = 0.73), but it was detected in 24 cases. Conclusions: The lack of CD1a‐positive in malignant salivary gland tumors facilitates the neoplastic development and suggests that these cells might be useful as auxiliary diagnostic and prognostic tool in minor salivary gland tumors. Furthermore, it is suggested that E‐cadherin mediates cell adhesion in these tumors although we did not demonstrate significance.     

Salivary gland 99mTc-scintigraphy: a grading scale and correlation with major salivary gland flow rates

Sequential salivary gland scintigraphy with 99mTc-technetium pertechnetate (Tc-99) is a safe, minimally invasive test for study of major salivary glands. However, its relationship to salivary function has not been investigated in detail. We have investigated the relationship between major salivary gland flow rates and Tc-99 scans and developed a new rating scale using scans of a control group with normal salivary function. Salivary flow rates and Tc-99 scans were obtained from healthy, non-medicated subjects (n = 33) and from xerostomic patients (n = 22). There were significant differences between the groups for salivary flow rates and Tc-99 ratings. Significant correlations were found between salivary flow rates and Tc-99 ratings in the control and xerostomic groups. The Tc-99 rating scale proved reliable in assessing salivary dysfunction, and showed a high inter-examiner correlation. These results demonstrate the usefulness of salivary gland scintigraphy in assessing major salivary gland flow rates and the utility of a new rating scale.     

骨桥蛋白在涎腺良、恶性肿瘤中的表达及意义的研究

目的 探讨骨桥蛋白(OPN)在涎腺良、恶性肿瘤中的表达及意义。方法 采用免疫组化SP法检测OPN在68例涎腺肿瘤(多形性腺瘤20例、腺样囊性癌24例、Warthin瘤24例)和20例瘤旁正常涎腺组织中的表达。结果 OPN在多形性腺瘤和Warthin瘤中均较正常涎腺组织增高(P<0.05);在腺样囊性癌中较正常涎腺组织增高,但两组间比较差异无显著性(P>0.05)。结论 OPN在正常涎腺组织和腺样囊性癌中有弱表达,在多形性腺瘤和Warthin瘤中表达增高。     

Genetic analysis of DNA microsatellite loci in salivary gland tumours: comparison with immunohistochemical detection of hMSH2 and p53 proteins

To investigate genetic alterations in salivary gland tumours, microsatellite instability at eight representative loci and loss of heterozygosity (LOH) on chromosome 17 were analysed by polymerase chain reaction amplification. The results were compared with immunohistochemical expression of the hMSH2 and p53 proteins. Microsatellite instability and expression loss of hMSH2 protein were not recognized in the salivary gland tumours, suggesting a low frequency of abnormalities of the mismatch repair system. LOH associated with the p53 gene was detected in approximately one-half of pleomorphic adenomas and salivary carcinomas, which often showed strong p53 immunoreactivity. These features suggest that the p53 gene plays an important role in malignant transformation of salivary gland tumours. The genetic characteristics of pleomorphic adenomas might reflect a low-grade potential for malignant progression.