Myoepithelial cells in salivary gland tumors. An immunohistochemical study

Normal salivary glands and 55 salivary gland tumors were examined by immunostaining (immunoperoxidase [IMP] and immunofluorescence [IMF]) to identify myoepithelial cells (MCs) and speculate on their role in the histogenesis of the tumors. The classic (C) MCs of normal salivary glands stained by IMP with antibodies to cytokeratin and S100 protein and stained by IMF with the same antibodies and with antibodies to vimentin and actin. Modified (M) MCs of pleomorphic adenomas stained positively by IMP and IMF with all of the preceding antibodies. In many mucoepidermoid carcinomas, adenoid cystic carcinomas, and basal cell adenomas, variable numbers of CMCs and MMCs stained positively by IMP with anti-cytokeratin and anti-S100 protein antibodies. No MCs were detected in adenolymphomas or acinic cell carcinomas. We believe that MCs play a major role in the histogenesis of pleomorphic adenomas and may also be important in many mucoepidermoid carcinomas, adenoid cystic carcinomas, and basal cell adenomas.     

Lymphadenoma of the salivary gland: clinicopathological and immunohistochemical analysis of 33 tumors

Lymphadenomas (LADs) are rare salivary gland tumors. Their clinicopathologic characteristics and etiopathogenesis are poorly understood. We examined 33 LADs in 31 patients (17 women and 14 men) aged 11-79 years (median 65 years). There were 22 sebaceous LADs in 21 patients (9 women and 12 men) and 11 non-sebaceous LADs in 10 patients (8 women and 2 men). Two patients had synchronous double tumors. Twenty-six tumors (79%) arose in parotid, three in the neck, and two each in submandibular gland and oral cavity. Extraparotid tumors were seen in 2 of 21 (10%) patients with sebaceous and 4 of 10 (40%) patients with non-sebaceous LADs. Seven of twenty-three (30%) patients had immunosuppressive therapy for unrelated diseases. The tumors were well circumscribed, encapsulated (n=28, 84%) painless masses, varying in size from 0.6 to 6 cm (median 2.2). The cut surfaces were gray-tan to yellow, homogeneous and multicystic (n=24, 72%). The epithelial cells were basaloid, squamous and glandular, forming solid nests, cords, tubules, and cysts. Sebaceous differentiation was restricted to sebaceous lymphadenoma. The epithelial cells expressed basal cell markers (p63, 34BE12, and/or CK5/6, 18/18, 100%) and the luminal glandular cells expressed CK7 (12/12, 100%). Myoepithelial cells were absent (n=10/16, 63%) or focal. The lymphoid stroma was reactive, with germinal centers in 28 (84%). There was no evidence of HPV (0/11), EBV (0/7), and HHV-8 (0/8). Malignant transformation to sebaceous and basal cell adenocarcinoma was seen in one patient each. None of the 11 patients with follow-up (1-8 years) recurred. In summary, sebaceous and non-sebaceous LADs are benign, encapsulated, solid and cystic tumors affecting older adults. Non-sebaceous LADs affect women and extraparotid sites more frequently than sebaceous LADs. Altered immune status may have a role in their etiopathogenesis. Multiple synchronous tumors, origin in buccal mucosa, and malignant transformation may rarely occur.     

Light microscopic, ultrastructural and immunocytochemical spectrum of malignant lacrimal and salivary gland tumors, including malignant mixed tumors.

Ten malignant myoepithelial tumors of the salivary glands and one of lacrimal gland origin were studied by light, electron microscopy and immunocytochemistry. The light microscopic appearance of the tumors varied from primarily spindle cell neoplasms (two cases), to others with predominantly epithelial components (four cases) and mixed varieties (five cases). Therefore, they can be confused with other epithelial and mesenchymal neoplasms. The electron microscopic spectrum varied from tumors with widespread and typical myoepithelial differentiation (i.e. myofilament bundles at the cell periphery, attachment plaques and intercellular junctions) to some with diffusely distributed filaments, without associated spindle densities but with attachment plaques, and others with evidence of duct formation and containing scattered cells showing intracytoplasmic tonofilaments. Often the tumors revealed mixed ultrastructural features; the relative numbers of the different cellular components was variable. The eleven neoplasms were S-100 protein, actin and keratin positive, either focally or diffusely, with varying degrees of intensity. Ten of the eleven tumors were positive for vimentin and nine of ten tested expressed carcinoembryonic antigen. Only two of nine were focally positive for glial fibrillary acidic protein. The study emphasizes the variable light microscopic appearances of these neoplasms and their immunocytochemical and ultrastructural spectrum. Accurate determination of myoepithelial differentiation sometimes requires careful evaluation of the light, ultrastructural and immunocytochemical findings. If all three diagnostic modalities are not utilized, it is likely that some of these neoplasms will be improperly classified.     

Human salivary gland morphogenesis: myoepithelial cell maturation assessed by immunohistochemical markers

Ianez R F, Buim M E, Coutinho‐Camillo C M, Schultz R, Soares F A & Lourenço S V
(2010) Histopathology 57 , 410–417
Human salivary gland morphogenesis: myoepithelial cell maturation assessed by immunohistochemical markers Aims: Myoepithelial cells are important components of salivary gland structure, aiding the expulsion of saliva from acinar lobules. The aim was to evaluate the expression of smooth muscle actin (SMA), calponin, caldesmon, CD10, CD29, S100 protein, glial fibrillary acidic protein (GFAP) and p63 in myoepithelial cells during salivary gland morphogenesis to understand the maturation process of these cells and their possible use in the diagnosis of salivary gland lesions. Methods and results: Major and minor human salivary glands at various stages of development, derived from fetuses at 8–26 weeks of gestation, were studied immunohistochemically. Fully developed salivary glands were used as controls. The protein p63 was present in all stages of salivary gland morphogenesis from initial bud to terminal bud stage. CD29, S100 and calponin were detected increasingly as salivary gland structure matured and in fully developed salivary gland. Proteins GFAP, CD10 and caldesmon were not observed in myoepithelial cells of salivary glands. Conclusions: The proteins SMA, calponin, CD29, S100 and p63, which are present from the earliest stages of salivary gland maturation, are valuable myoepithelial markers but, although very specific, are not exclusive markers for this cell type.     

Nucleolar organizer regions in malignant salivary gland tumors.

Proliferative activity of carcinomas arising from salivary glands was analyzed by enumeration of argyrophilic nucleolar organizer regions (AgNORs). The mean numbers of AgNORs in the various tumors were as follows: mucoepidermoid carcinoma, 2.20; acinic cell carcinoma, 2.51; adenoid cystic carcinoma (ACC), 2.57; carcinoma in pleomorphic adenoma, 1.00 (benign component) and 3.99 (cancer-bearing area); salivary duct carcinoma, 4.49; polymorphous low-grade adenocarcinoma, 3.37; sebaceous carcinoma, 2.57; oncocytic carcinoma, 4.63; adenocarcinoma, 4.53. Cells of most tumors showed heterogeneous activity within the same tumor. In mucoepidermoid carcinoma, the mucous cells had suppressed activity in comparison with the epidermoid cells and intermediate cells. In ACC, the activity of the tumor cells increased according to growth pattern in the order tubular, glandular and solid. In carcinoma in pleomorphic adenoma, vigorous proliferative activity was observed in the malignant component, whereas less active cells were seen in the myxoid or chondroid matrix. AgNOR staining was useful for distinguishing benign from malignant regions in carcinoma in pleomorphic adenoma. Our results suggest that mucoepidermoid carcinoma, acinic cell carcinoma and ACC, except for that with a solid growth pattern, may be considered as low-grade malignancies, whereas solid-type ACC, the cancer component in carcinoma in pleomorphic adenoma and some of the other carcinomas have high-grade malignant behavior.     

Prognostic factors in malignant gastrointestinal stromal tumors

Gastrointestinal stromal tumors are a heterogeneous group of mesenchymal neoplasms of the gastrointestinal tract in which routine histopathological evaluation fails to reveal definitive evidence of differentiation. Given the heterogeneity in clinical presentation and the frequent morphological overlap, the biological behavior of these neoplasms is difficult to predict. We have evaluated, by Cox Proportional Hazards Regression Analysis, the clinicopathological features of 51 malignant gastrointestinal stromal tumors to identify predictors of survival. In the univariate analysis, survival inversely correlated with size, number of mitoses, and patient's age. In the multivariate analysis, only the degree of necrosis and phenotypic differentiation toward smooth muscle were found to be indicators of poor prognosis. Based on these results, a simple classification scheme for gastrointestinal stromal tumors is proposed. This classification appears to have great prognostic value for these tumors, and may be useful in guiding therapeutic management.     

Observer variation in histologic classification of malignant and borderline ovarian tumors

Eight hundred sixty-nine primary malignant or borderline ovarian tumors reported to the Norwegian Cancer Registry were reviewed. The histologic slides were randomly distributed to six observers and classified according to the World Health Organization classification of ovarian tumors. By rotation of slides, each tumor was successively reviewed by three observers. Each observer was given approximately 40 duplicates of slides he or she had typed before, mixed in with the slides for the third review. A contracted version of the classification with 27 entries was used in the analysis. Mean intraobserver reproducibility was 62% (kappa, 0.53), varying from 50% to 75% (kappa, 0.34 to 0.70) for the individual observers. The mean rate of agreement between two observers was 56% (kappa, 0.46), varying from 46% to 65% for the individual pairs of observers. The rate of full agreement among three observers was 41%. The most common disagreements were between different specific types of carcinoma, between undifferentiated and differentiated carcinoma, between borderline and malignant tumors, between unclassified and classified carcinoma, and between mixed and pure types of carcinoma. Very low reproducibility was obtained for mixed and unclassified carcinoma.     

Non-sebaceous lymphadenoma of the salivary gland: case report with immunohistochemical investigation

Non-sebaceous lymphadenoma (NSL) is a rare, recently described, benign salivary gland tumor characterized by a dense lymphoid infiltrate and absence of sebaceous differentiation. To our knowledge, only seven previous cases have been reported. In this paper, we describe an additional example of NSL along with an extensive analysis of its keratin (CK) profile. The patient was a 50-year-old woman presenting with a slowly growing painless mass in the right parotid gland. The tumor was encapsulated and measured 3 × 2 × 2 cm. Microscopically, the tumor comprised islands of epithelial cells with centrally located duct-like structures within a dense lymphoid stroma. Immunohistochemically, the tumor regularly expressed CKs 7, 8/18, and 19, which are typical for columnar differentiation and CKs 17 and 5/6, which are most typically expressed in basal cells of complex epithelia. CK14 was only expressed in rare scattered cells and eventually in groups of cells. The expression of CK10/13, which correlates with squamous differentiation, was negative. Additionally, immunostaining for smooth muscle actin, vimentin, and S-100 was also performed. The immunohistochemical findings in the neoplastic epithelial component of our case suggest a differentiation of “intercalated duct phenotype” without myoepithelial cell participation.     

Evolving concepts and new entities in the 2017 WHO classification of salivary gland tumors

For the past decades, many new salivary gland entities have been described which are somewhat related to the discovery of unique molecular alterations in these tumors. The 4th edition of World Health Organization (WHO) classification of head and neck tumors has included several new entities, e.g. secretory carcinoma, sclerosing polycystic adenosis and intercalated duct lesions and modified several carcinomas, e.g. clear cell carcinoma, intraductal carcinoma and polymorphous adenocarcinoma. In addition, in the 4th edition, the concept of high grade transformation has been introduced. In this review, we aimed to illustrate the major changes in the WHO classification, focusing on the rationale behind these changes, the morphologic features of the new described entities and the ancillary diagnostic tools that may help with the differential diagnoses of salivary gland neoplasms.     

Fine-needle sampling of salivary gland lesions V: Cytology of 22 cases of acinic cell carcinoma with histologic correlation

Fine-needle sampling (FNS) of 22 acinic cell carcinomas, including 17 primary tumors, 4 local recurrences, and 1 lymph node metastasis was performed preoperatively in 17 patients. Cytologic diagnoses were concordant with histology in 3 (13.7%) cases, whereas 15 (68.2%) cases were cytologically classified as malignant, 2 (9.1%) as suspicious, and 1 (4.5%) as benign (pleomorphic adenoma). The material was unsatisfactory for cytologic evaluation in 1 (4.5%) case. Preoperative FNS technique is, therefore, useful in acinic cell carcinoma with a concordant malignant/suspicious rate of 91%. Diagn. Cytopathol. 1997;17:347–352. © 1997 Wiley-Liss, Inc.     

Expression of the ERBB2 protein in benign and malignant salivary gland tumors.

Fifty-two primary human salivary gland tumors were analyzed for expression of the p185ERBB2 protein using immunohistochemical and immunoblotting techniques. About 63% (33/52) of the tumors expressed the ERBB2 protein. The highest expression levels were detected among the carcinomas, where 32% of the tumors showed intense membrane staining in 25-100% of the tumor cells. In benign pleomorphic adenomas, the corresponding figure was only 12%. Clinical follow-up data available for 18 of the 19 patients with carcinomas suggested an association between high ERBB2 protein levels and poor prognosis as measured by recurrence of disease and/or the appearance of metastases. These results indicate that ERBB2 activation and overexpression could be an important genetic event with possible prognostic implications in a subset of malignant salivary gland tumors.     

人乳头状瘤病毒与涎腺肿瘤相关性的系统评价

目的 系统评价人乳头状瘤病毒(human papillomavirus,HPV)感染与涎腺肿瘤(salivarygland tumors,SGT)之间的相关性.方法 检索Pubmed、web of science、Cochrane Library、EMbase、中国学术期刊全文数据库(CNKI)、中国生物医学文献数据库(CBM)、万方、重庆维普网等数据库,纳入符合条件的相关研究.HPV感染与SGT的关系采用合并比值比(odds ratios,ORs)和相应的95％可信区间(confidence intervals,CIs)进行评价.使用Stata 11.0进行数据分析.根据研究间的异质性,采用固定或随机效应模型进行计算.发表偏倚采用漏斗图进行分析.结果共纳入8个符合条件的研究,包含142例恶性肿瘤患者、220例良性肿瘤患者和37例正常对照,分析结果显示:恶性SGT与良性SGT患者相比有更高HPV感染率(OR=2.46,95％CI l.40～4.33,P＜0.001),差异有统计学意义;SGT患者与健康人群相比,HPV感染率更高(OR=19.24,95％CI 4.08～90.79,P＜0.001),差异有统计学意义.结论基于现有数据分析,感染HPV是SGT的危险因素,并且可能增加恶性SGT的患病风险.未来有待纳入更多高质量的文献,以对HPV与SGT的关系开展进一步的研究.     

Immunohistochemical expression of cytokeratins 7 and 20 in malignant salivary gland tumors.

On the basis of the heterogeneity of cytokeratins 7 and 20 expression in malignant epithelial tumors, the cytokeratin 7/20 immunophenotype has served as a useful diagnostic tool for discrimination of primary and/or metastatic carcinomas of unknown origin. However, the expression pattern of these cytokeratins in malignant salivary gland tumors has not been thoroughly studied. Our study material was composed of 84 malignant tumors of primary major or minor salivary gland origin. Nine histologic types of carcinoma were represented, including mucoepidermoid (26 cases), adenoid cystic (25), polymorphous low grade (11), salivary duct (8), acinic cell (4), ex mixed tumor (3), not otherwise specified (3), clear cell (2), and basal cell (2). In all, 13 cases of primary skin or mucosal squamous cell carcinoma with secondary salivary gland involvement were also examined. Immunoreactivity for cytokeratin 7 was evident in all malignant salivary gland tumors; the staining pattern was diffuse and strong in 62 cases, and focal and strong in 22 cases. In contrast, 78 cases were negative for cytokeratin 20, whereas only six cases (two mucoepidermoid, one adenoid cystic, and three salivary duct) displayed focal weak positivity. Overall, 92.9% of malignant salivary gland tumors were characterized by a cytokeratin 7 positive/20 negative immunoprofile, the remaining 7.1% of cases being positive for both cytokeratins. The latter phenotype was more common in salivary duct carcinomas (P< or =0.05). On the other hand, most squamous cell carcinomas (69%) were negative for both cytokeratins, while the remaining cases (31%) were negative for cytokeratin 20 and focally weakly positive for cytokeratin 7. We suggest that assessment of cytokeratin 7/20 immunoprofile may facilitate the differential diagnosis of (a) primary malignant salivary gland tumors from metastatic tumors, (b) metastatic salivary gland tumors, (c) primary salivary gland tumors, especially mucoepidermoid carcinomas, from squamous cell carcinomas, and (d) salivary duct carcinomas from other malignant salivary gland tumors.     

Gastric mixed adenoneuroendocrine carcinoma: correlation of histologic characteristics with prognosis

Gastric mixed adenoneuroendocrine carcinomas (MANECs) are rare, with both the exocrine and neuroendocrine components exceeding 30% volume. Several classifications for MANECs have been proposed, yet they have not been clinically evaluated. The aim of this study was to evaluate the correlation between tumor grade, histologic characteristics, and prognosis of gastric MANECs. We collected eligible 14 cases in our series and 31 cases in the literature and compared the prognostic difference among gastric MANECs with different histologic characteristics. Gastric MANECs could be divided into subgroups according to tumor grade of the neuroendocrine component and adenocarcinoma types. The high grade and large proportion of neuroendocrine component correlated with aggressive behavior and a tendency of poor clinical outcome. Gastric MANECs with a poorly differentiated adenocarcinoma showed a significant lower survival rate than did MANECs with a differentiated adenocarcinoma or mucin-producing carcinoma (P = .0008). Gastric MANECs were a heterogeneous group with different tumor grades, histologic subtypes, combination patterns, and patient outcomes. Previous classifications were evaluated. This study proves that histologic characteristics correlate with clinical outcomes. Our findings are complements to the latest prognostic classification.     

Fine-needle sampling of salivary gland lesions IV. Review of 50 cases of mucoepidermoid carcinoma with histologic correlation

Fine-needle sampling (FNS) of 50 mucoepidermoid carcinomas, including 44 primary tumors, five local recurrences, and one lymph node metastasis, was performed preoperatively in 44 patients. Concordant cytologic diagnoses were established in only 19 (38%) tumors, whereas 15 (30%) were classified as carcinoma, five (10%) as suspicious, and six (12%) as benign tumors. The material was insufficient for cytologic evaluation in five (10%) cases. The tumors were classified histologically as high-, intermediate-, and low-grade in 15, 13, and 22 cases, respectively. The quality of diagnosis did not vary between high- and intermediate-grade, but was lower in low-grade tumors: Malignancy was diagnosed or suspected in 13 (87%) high-grade tumors, 11 (85%) intermediate-grade tumors, and 15 (68%) low-grade tumors. In conclusion, FNS is an accurate technique in high- or intermediate-grade mucoepidermoid carcinomas, but quite unsatisfactory in low-grade tumors. Diagn. Cytopathol. 17:92–98, 1997. © 1997 Wiley-Liss, Inc.     

Expression of androgen,estrogen, and progesterone receptors in salivary gland tumors. Frequent expression of androgen receptor in a subset of malignant salivary gland tumors

The expression of sex hormone receptors in some tumors suggests a role for these receptors in tumor pathogenesis and therapy. Previous studies of the expression of estrogen and progesterone receptors in salivary gland tumors have reported conflicting results. We evaluated the immunohistochemical expression of androgen, estrogen, and progesterone receptors (AR, ER, and PR) in a series of 78 formalin-fixed, paraffin-embedded salivary gland tumors. Immunoreactivity for AR was seen in 14 of 14 carcinoma ex pleomorphic adenomas, 6 of 6 salivary duct carcinomas, and 2 of 2 basal cell adenocarcinomas but in only 2 of 10 acinic cell carcinomas, mucoepidermoid carcinomas, and adenoid cystic carcinomas each. AR expression was distributed evenly between the sexes. ER and PR were expressed in only a few cases of salivary gland tumors. All 26 benign salivary gland tumors were negative for AR, ER, and PR. The uniform expression of AR exclusively in a subset of malignant salivary gland tumors suggests a possible role for AR in the histogenesis and possibly in the clinical management of these malignant salivary gland tumors.     

Localization of prostate-specific antigen-like immunoreactivity in human salivary gland and salivary gland tumors

Immunoreactivity of prostate-specific antigen (PSA), a kallikrein-like enzyme present in the seminal plasma, was demonstrated by indirect immunoperoxidase staining using a PSA antiserum in the apical cytoplasm along the luminal border of small-sized duct epithelial cells of the major salivary (parotid and submandibular) gland of both sexes (56/56, 100%). No PSA-like immunoreactivity was seen in large-sized duct epithelial cells and acinar cells. Minor salivary gland ducts were negative. When inflammatory and atrophic changes were observed, ductal expression of PSA-like immunoreactivity was decreased (12/37, 32%) and the site of intracellular localization often became diffusely cytoplasmic. The immunoreactivity was absorbed by human seminal plasma. Immunoreactivities of prostatic acid phosphatase and sex hormone receptors were undetectable in the salivary gland. Twenty-nine (34%) of 86 salivary gland tumors with ductal differentiation were immunoreactive for PSA mainly in the cytoplasm. A PSA monoclonal antibody ER-PR8 detected immunoreactivity in the prostate but not in the salivary glands or their tumors. Prostate-specific antigen-like immunoreactivity in small-sized (intercalated) duct epithelial cells of the major salivary gland and their tumors may be due to cross-reactivity of the antiserum with kallikrein-like substances.