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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 2  |  Page : 834-839

Characterization and localization of c-kit and epidermal growth factor receptor in different patterns of adenoid cystic carcinoma


1 Department of Oral Pathology and Microbiology, I.T.S. CDSR, Muradnagar, Ghaziabad, Uttar Pradesh, India
2 Department of Oral and Maxillofacial Pathology, SDM College of Dental Sciences and Hospital, Dharwad, Karnataka, India

Date of Web Publication25-Jul-2016

Correspondence Address:
Anshi Jain
I.T.S. CDSR, Delhi-Meerut Road, Muradnagar, Ghaziabad, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.177504

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 > Abstract 


Introduction: Adenoid cystic carcinoma (ACC) is malignant neoplasm of the salivary glands. It accounts for most cases of minor salivary gland malignancies and a substantial proportion of parotid and submandibular gland malignancies. ACC is associated with a high mortality rate, and it often recurs after prolonged periods of time, and this occurs even when radical excision has been performed.
Aims: The present study was aimed to determine the localization of dual cell population and to analyze the potency of using a system of dual markers (c-kit and epidermal growth factor receptor [EGFR]) in enhancing the characterization of ACC.
Subject and Method: Three micrometer thin sections of adenoid cystic carcinoma were obtained. One set of slides was stained by hematoxylin and eosin for reconfirmation of histological diagnosis while the other two sets were stained for c-kit and EGFR using immunohistochemical method.
Statistical Analysis Used and Results: Show c-kit expression to be limited to the inner ductal epithelial cells and the EGFR expression mainly to the outer myoepithelial cells in the majority of tubular and cribriform patterns. In solid ACC, c-kit was uniformly positive while EGFR was consistently negative.
Conclusions: C-kit and EGFR biomarkers can be used to enhance the characterization of ACC and to determine the localization of dual cell population which could suggest the dual origin of ACC and provides evidence for the new therapeutic strategy in ACC.

Keywords: Adenoid cystic carcinoma, c-kit, epidermal growth factor receptor


How to cite this article:
Jain A, Shetty DC, Rathore AS, Kumar K. Characterization and localization of c-kit and epidermal growth factor receptor in different patterns of adenoid cystic carcinoma. J Can Res Ther 2016;12:834-9

How to cite this URL:
Jain A, Shetty DC, Rathore AS, Kumar K. Characterization and localization of c-kit and epidermal growth factor receptor in different patterns of adenoid cystic carcinoma. J Can Res Ther [serial online] 2016 [cited 2019 Dec 15];12:834-9. Available from: http://www.cancerjournal.net/text.asp?2016/12/2/834/177504




 > Introduction Top


The salivary gland tumors are the most histologically heterogeneous group of the tumor, despite their characteristically rather pronounced variation in histological appearance, all salivary gland tumors were simplistically separated only into infiltrating and encapsulated type.[1] The biological behavior or malignancy of salivary gland as a group is peculiar. Ackerman and Del Regato described salivary gland tumor as “the usual tumor of salivary gland is a tumor in which the benign variant is less benign than the usual benign tumor and the malignant variant is less malignant than the usual malignant tumor.”[2] The worldwide annual incidence of salivary gland tumor ranges from 0.4 to 13.5 cases per 100,000 people.[3] The annual incidence for malignant salivary gland tumors (MSGTs) varies from 0.4 to 2.6 cases per 100,000 populations.[4] MSGTs can be broadly categorized into low, intermediate, and high grade according to their behavior.[5] Salivary gland tumors, not uncommonly pose a problem in diagnosis since they exhibit a very broad morphological spectrum, but with overlapping features among different types.[3]

Adenoid cystic carcinoma (ACC) is the second most frequent malignancy of the major and minor salivary glands and clinically and pathologically well-defined malignant epithelial tumor with peak incidence occurs predominantly among women between fifth and sixth decade of life which develops primarily in the major salivary glands and relatively frequent in minor salivary glands, particularly in palate.[6] The widespread distribution in the upper alimentary and respiratory tracts underlines its origin more particularly in the mucosa as compared with major salivary glands.[7] This well-recognized tumor was first described by Theodor Billroth in 1856 under the name “Zylindrome.” However, the WHO subcommittee on the classification of tumors recommended adoption of the term ACC, which was first used by Reid in 1952.[8],[9] ACC is defined as an invasive neoplasm composed of basaloid cells with predominant myoepithelial/basal cell differentiation, accompanied by some interspersed ductal structures [Figure 1].[3] The role of the myoepithelial cells in the production of ACC remains controversial as it does in other SGT. The light microscopic features have been well documented by Thackray and Lucas in 1960 cribriform pattern is of sovereign importance not only because its presence is essential to the histological diagnosis but because its pathogenesis offers a clue to the natural clinical behavior.
Figure 1: H and E section of cribriform pattern of adenoid cystic carcinoma (×400)

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The transmembrane tyrosine kinase receptor c-kit (CD117) is a 145- to 165 kD proto-oncogene, that maps to the long arm of chromosome 4 and encodes a transmembrane receptor-type tyrosine kinase, KIT, that is structurally and functionally related to (platelet-derived growth factor) and colony stimulating factor-1 receptors.[10] After binding to its ligand, alternatively known as stem cell factor, mast cell growth factor, or steel factor, it is activated by receptor dimerization on stimulation by its ligand. Recent studies indicate that KIT is expressed in ACC raising the possibility that KIT might be useful as an ancillary marker for this tumor.[11] C-kit expression is limited to the inner ductal cells and is negative in the myoepithelial cells in ACC.

Epidermal growth factor receptor (EGFR), a 170 kDa transmembrane glycoprotein receptor with tyrosine kinase activity composed of an extracellular ligand-binding domain, a hydrophobic region, and a cytoplasmic region that contain tyrosine kinase domain.[12] It causes increased proliferation, decreased apoptosis, enhanced tumor cell motility, neoangiogenesis, and survival of cancer cells. Overexpression of EGFR has been associated with advanced disease, development of a metastatic phenotype, and poor prognosis in a variety of human carcinomas.[13] Recently, its role is been studied in ACC where EGFR expression is noted mainly in myoepithelial cells and negative in ductal cells of both tubular and cribriform tumors.

Expression of c-kit and EGFR has been predominantly seen in ACC where c-kit is noted in inner ductal cells, and EGFR is expressed in myoepithelial cells. Since the role of myoepithelial cells in the histogenesis of ACC is a controversy, the present study was aimed to determine the localization of ductal and myoepithelial cells using c-kit and EGFR immunostaining in different histological patterns of ACC, to assess qualitatively and quantitatively the differential expressions of c-kit and EGFR immunostaining within and between different patterns of ACC and to objectively analyze the potency of using a system of dual markers (c-kit and EGFR) in enhancing the characterization of ACC.


 > Subjects and Methods Top


Tissue specimens were retrieved from the archives of 30 histopathologically confirmed ACC cases. The selected specimens consisted of 10 cases each of different patterns (cribriform, tubular, and solid pattern) of ACC. The tissue specimens were fixed in 10% neutral buffered formalin. From each of the formalin fixed paraffin embedded tissue blocks, three 3 µm sections were obtained using a rotary microtome. One set of slides was stained by hematoxylin and eosin (H and E) for reconfirmation of histological diagnosis while the other two sets were stained for c-kit and EGFRusing the immunohistochemical method. Histopathologically, at least, two distinctive patterns of ACC's within and between cores of the same case tumor was observed. A predominant pattern was determined based on the presence of >60% of a given pattern in a tumor. Solid pattern was determined on the presence of more than 30% of a given pattern in a tumor.[3]

Immunohistochemical procedure

Immunohistochemical analysis for c-kit and EGFR was performed on 3 µm paraffin sections were obtained using a rotary microtome. In brief, following dewaxing, washing, and rehydration of the slides through xylene and graded alcohol concentrations, citrate buffer at pH 6.0–6.2 was used for antigen retrieval. Slides were subsequently treated with 3% hydrogen peroxide to block endogenous peroxidase. Following incubation with the primary antibodies, c-kit (Biogenex) and EGFR (Biogenex), the secondary conjugate antibody was applied and followed by chromogen DAB and counterstaining with Mayer's hematoxylin.

Positive control

Poorly differentiated breast cell carcinoma tissues were selected as a positive control and immunostained in the same manner as other study cases.

Immunohistochemical analysis

Immunohistochemical analysis for c-kit and EGFR was performed for ACC tissue sections. All the immunostained sections were observed under a light microscope at ×10 and ×40 magnification. Membranous and cytoplasmic staining was assessed qualitatively and quantitatively compared with normal salivary gland control samples as mentioned below.

Quantitative analysis of c-kit and epidermal growth factor receptor expression

In study cases of cribriform and tubular pattern, three random fields were analyzed with a minimum of three ductal structures per field at ×40. Continuous 10 inner ductal cells and continuous 10 cells below luminal cells were counted for both c-kit and EGFR staining.

In study cases of solid pattern, 3 random fields at ×40 were observed. Thirty random cells in solid sheets equivalent to total number of cell in the cribriform and tubular pattern were counted for both c-kit and EGFR staining.

Mean number of positive cells in between each pattern and within each pattern were tabulated and analyzed statistically.

Qualitative analysis (intensity) of c-kit and epidermal growth factor receptor expression

Whole section was observed under ×40 for c-kit and EGFR staining and graded as mentioned below and compared with control cases.



  1. 1+ = Low or negative of immunostaining
  2. 2+ = Intermediate immunostaining
  3. 3+ = High immunostaining.


Mean percentage of positive cells and extent of immunostaining under different patterns and within each pattern, were tabulated and statistically analyzed.

Statistical analysis

Descriptive statistics including the mean values, standard deviations, and ranges (minimum and maximum) were calculated for each variable.

The resulting data were analyzed using SPSS software. Data have been expressed as mean and standard deviation. Differences between the different variables were analyzed using ANOVA test and post hoc test followed by Bonferroni test.

The significance, i.e., P < 0.05 was considered to be significant.


 > Results Top


The results were analyzed using ANOVA followed by post hoc comparison with Bonferroni method and Pearson Chi-square test wherever applicable.

Quantitative assessment of c-kit expression between different patterns of ACC shows that c-kit expression was lowest in the cribriform pattern (73.20 ± 6.61), followed by a gradual increase in tubular pattern (73.90 ± 8.93) and maximum in solid pattern (83.50 ± 7.53). Therefore, as the severity of the patterns increased, there was an increase in the expression of c-kit which was significant statistically (P < 0.05). Quantitative assessment of EGFR expression between different patterns of ACC shows that the EGFR expression was highest in cribriform pattern (71.70 ± 10.6), followed by a gradual decrease in the tubular pattern (67.90 ± 12.87) and minimum in solid pattern (20.50 ± 5.29). Therefore, as the severity of the patterns increased, there was decrease in the expression of EGFR, which was significant statistically (P < 0.05).

Quantitative assessment of differential expressionc-kit and EGFRwithin cribriform pattern of ACC shows that c-kit expression was 73.2 ± 6.61 and expression of EGFR was 71.7 ± 10.6. Therefore, within the cribriform pattern of ACC, the differential expression of c-kit and EGFR was statistically nonsignificant (P > 0.05). Quantitative assessment of differential expressionc-kit and EGFRwithin tubular pattern of ACC shows that c-kit expression was 73.90 ± 8.93 and expression of EGFR was 67.90 ± 12.8. Therefore, in tubular pattern of ACC, the differential expression of c-kit and EGFR was statistically nonsignificant (P > 0.05). Quantitative assessment of differential expressionc-kit and EGFRwithin solid pattern of ACC shows that c-kit expression was 83.50 ± 7.53 and expression of EGFR was 20.50 ± 5.29. Therefore, in a solid pattern of ACC, the differential expression of c-kit and EGFR was statistically significant (P < 0.05).

Qualitative comparison of c-kit between three patterns of ACC which shows statistically significant results (P < 0.05). Qualitative comparison of EGFR between three patterns of ACC which shows statistically highly significant results (P < 0.05). Qualitative assessment ofc-kit and EGFRwithin cribriform and tubular pattern shows statistically nonsignificant results (P > 0.05) while solid pattern shows statistically significant results (P < 0.05).

Quantitative post hoc comparison of all patterns of ACC using c-kit shows that the mean difference in number of cells in cribriform and tubular pattern of ACC was −7.00 which was statistically nonsignificant (P > 0.05). Similarly, mean difference between tubular and solid pattern of ACC was −9.6 which was statistically significant (P < 0.05). Finally, the mean difference between cribriform and solid pattern of ACC was calculated as −10.3, which was statistically highly significant (P < 0.05). Thus, as the severity of pattern increases in ACC, there was an increase in the number of inner ductal cells which causes increase c-kit expression.

Quantitative post hoc comparison of all patterns of ACC using EGFR shows that the mean difference in number of cells showing EGFR expression in cribriform and tubular pattern of ACC was 4.30 which was statistically nonsignificant (P > 0.05). Similarly, mean difference between tubular and solid pattern of ACC was 59.90 which was statistically highly significant (P < 0.05). Finally, the mean difference between cribriform and solid pattern of ACC was calculated as 63.80 which was statistically highly significant (P < 0.05). Thus, as the severity of pattern increases in ACC, there was a marked decrease in the number of myoepithelial cells which causes a decrease in EGFR expression.


 > Discussion Top


This immunohistochemical study was conducted to analyze the potency of using the system of dual biomarkers (c-kit and EGFR immunostaining) in enhancing the characterization of ACC. The present study shows that c-kit biomarker is specific for inner ductal, or luminal cells and EGFR is a marker for abluminal cells. In the cribriform pattern of ACC, c-kit stained inner ductal cells which are cuboidal in shape and surrounds small and sometimes indistinct lumina [Figure 2] and [Figure 3]. Foci of ductal cells are present within the myoepithelial areas. EGFR stained abluminal cells (myoepithelial cells) which are elongated and flattened cells attached to the surrounding basal lamina and are present below the luminal cells as a single cell layer [Figure 4]. In tubular pattern of ACC, double cell layered, c-kit expression remains confined to the inner cell layer and EGFR stained outer cell layer which is composed of abluminal or myoepithelial cells [Figure 5], [Figure 6], [Figure 7]. In solid pattern of ACC, there is sheets and nest of basaloid cells, c-kit biomarker stained intensely, and diffusely all neoplastic cells, on contrary EGFR biomarkers did not show any expression in a solid pattern which signifies the absence of myoepithelial cells in this pattern of ACC [Figure 8]. Hence, it can be put forth the importance of using the system of dual biomarkers (c-kit and EGFR) immunostaining which help in identifying and the localization of dual cell population (ductal and myoepithelial cells) in a different histological pattern of ACC which is problematic at a light microscopic level under conventional H and E.[14]
Figure 2: Cribriform pattern of adenoid cystic carcinoma showing c-kit immunopositivity in inner ductal cells (×400)

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Figure 3: Cribriform pattern of adenoid cystic carcinoma showing c-kit immunopositivity in inner ductal cells (×400)

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Figure 4: Cribriform pattern of adenoid cystic carcinoma showing epidermal growth factor receptor immunopositivity in outer myoepithelial cells

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Figure 5: Tubular pattern of adenoid cystic carcinoma showing c-kit immunopositivity in inner ductal cells (×400)

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Figure 6: Tubular pattern of adenoid cystic carcinoma showing c-kit immunopositivity in inner ductal cells (×400)

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Figure 7: Tubular pattern of adenoid cystic carcinoma showing epidermal growth factor receptor immunopositivity in outer myoepithelial cells (×400)

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Figure 8: Solid pattern of adenoid cystic carcinoma showing c-kit immunopositivity in all neoplastic cells (×100)

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In this study, it was observed that as the severity of the histological patterns of ACC increased, there was an increase in the expression of c-kit which was significant statistically (P < 0.05). This suggested that myoepithelial cells did not express c-kit as abluminal cells did not stain. This was in accordance with study of Aslan et al. demonstrated that c-kit expression was present in 80% to 100% of ACC where solid pattern showed more diffuse and intense staining, whereas cribriform pattern showed staining in the luminally differentiated cells only, he concluded that c-kit expression could not be substantiate as a prognostic or predictive marker in ACC.[15] Bell et al. investigated the differential localization and expression of the c-kit protein in different histologic subtypes of ACC and demonstrated that c-kit expression was limited to the inner ductal epithelial cells whereas in solid ACCs, c-kit uniformly was positive hence concluded that the current findings underscored the importance of cellular subtype localization of biomarker in the clinical and therapeutic stratification of patients with ACC.[8] Our results and different studies are based on the fact that this difference in the expression of c-kit in tubular and cribriform pattern of ACC, as compared to solid variant of ACC, suggests a loss of cellular heterogeneity in solid variants, with differentiation primarily along the line of the luminal cell layers, and may correlate with the worse clinical course of the solid variant of ACC.[16],[17] Mino et al. and Edwards et al. demonstrated that the distinction of ACC from other head and neck salivary gland neoplasms such as polymorphous low-grade adenocarcinoma, monomorphic adenomas including canalicular adenomas, trabecular adenomas, and basal cell adenomas can occasionally be problematic, particularly in small biopsies. Expression of c-kit in other benign and malignant head and neck neoplasms, including those that mimic ACC has not been well studied. However, their results have concluded that the expression of c-kit within a majority of ACC and few other head and neck neoplasm suggests that c-kit is potentially useful in the diagnostic evaluation of ACC.[11],[18]

Quantitative analysis of EGFR expression was done to determine the presence of myoepithelial cells in different histological patterns of ACC. Our results revealed that as the severity of histological patterns of ACC increased, the mean number of myoepithelial cells decrease, thus the mean expression of EGFRdecreased which was significant statistically (P < 0.05) as in solid pattern there is the presence of nests/sheets of basaloid cells instead of myoepithelial cells. Where myoepithelial cells and basal cells differ concerns the rich complement of muscle-specific actin in myoepithelial cells and its apparent absence in basal cells. These results are in accordance with the study of Bell et al.[8] Based on these results, it may be concluded that differentiation is along the line of intercalated ductal cells with less differentiation toward myoepithelial cells. Hence, myoepithelial cells are confined in association with acinar-intercalated units, intercalated duct-like structures, and tubular configurations but not in solid areas.[19],[20]

Results of our study demonstrate variation in the differential expression of c-kit and EGFR within three patterns of ACC which could be hypothesized that cribriform and tubular pattern of ACC, dual cell population, i.e. number of inner ductal cells surrounding pseudocystic spaces and around all true glandular lumens respectively and number of myoepithelial cells around basal lamina are almost same, but there is marked increase in the number of inner ductal cell or luminal cells as the severity of patterns of ACC increases (solid pattern), and there is noticeable decrease in number of myoepithelial cells in solid pattern of ACC.

When qualitative analysis of c-kit expression was done in between different patterns of ACC, cytoplasmic and membranous staining was scored. The difference in immunostaining in different patterns of ACC is partly associated with the distribution of solid, cribriform and tubular pattern, results are in accordance with the study of Aslan et al. (2005) who demonstrated that c-kit expression was present in 80% to 100% of ACC and expression was lower in ACC arising in the nose and paranasal sinuses.[18]

While doing a qualitative analysis of EGFR expression between different patterns of ACC, it was observed that intensity of immunostaining decrease as the severity of pattern of ACC increases as there is a decrease in number of myoepithelial cells, with a complete absence of myoepithelial cells in solid pattern of ACC. Our results are in accordance with the study of Vered et al. and Bell et al. who demonstrated that EGFR expression was noted mainly in myoepithelial cells and was negative or weakly cytoplasmic positive in ductal cells of both tubular tumors and cribriform tumors. EGFR immunoreactivity was restricted to the myoepithelial cells of tubular tumors and cribriform tumors. EGFR staining was negative in the solid type tumors.[8],[21]


 > Conclusions Top


ACC is an MSGT with a deceptively benign histologic appearance characterized by indolent, locally invasive growth with high propensity for local recurrences and distant metastasis. C-kit and EGFR biomarkers can be used to enhance the characterization of ACC and to determine the localization of dual cell population which could suggest the dual origin of ACC. Differential expression of c-kit and EGFR in ductal cells and in myoepithelial respectively provides evidence for the new therapeutic strategy in ACC, which may benefit patients who have tumors with tubular and cribriform patterns, and patients with solid type tumors may be responsive to a single agent. Thus, the assessment of the study in analyzing the histogenesis and pathogenesis of ACC has led to a new dimension of its intricacies associated with the differentiation and treatment modalities which could be employed. This synergistic action of c-kit and EGFR of being commendably used in the diagnosis, pathogenetic aspect, progression of disease, and treatment planning is a new avenue for further research. This system of dual markers can be a boon to those salivary gland neoplasms which have a wide range of diversification in their behavior and biological activities.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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Pearson FG, Thompson DW, Weissberg D, Simpson WJ, Kergin FG. Adenoid cystic carcinoma of the trachea. Experience with 16 patients managed by tracheal resection. Ann Thorac Surg 1974;18:16-29.  Back to cited text no. 5
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Soares EC, Carreiro Filho FP, Costa FW, Vieira AC, Alves AP. Adenoid cystic carcinoma of the tongue: Case report and literature review. Med Oral Patol Oral Cir Bucal 2008;13:E475-8.  Back to cited text no. 6
    
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Aslan DL, Oprea GM, Jagush SM, Gulbahce HE, Adams GL, Gaffney PM, et al. C-kit expression in adenoid cystic carcinoma does not have an impact on local or distant tumor recurrence. Head Neck 2005;27:1028-34.  Back to cited text no. 15
    
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Ahmed MM, Abo-Hager EA. Differential expression of c-kit and CD43 in histological subtypes of adenoid cystic carcinoma of salivary gland. Saudi Dent J 2010;22:27-34.  Back to cited text no. 16
    
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Zhou Q, Chang H, Zhang H, Han Y, Liu H. Increased numbers of P63-positive/CD117-positive cells in advanced adenoid cystic carcinoma give a poorer prognosis. Diagn Pathol 2012;7:119.  Back to cited text no. 17
    
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Edwards PC, Bhuiya T, Kelsch RD. C-kit expression in the salivary gland neoplasms adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma, and monomorphic adenoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:586-93.  Back to cited text no. 18
    
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Chaudhry AP, Leifer C, Cutler LS, Satchidanand S, Labay GR, Yamane GM. Histogenesis of adenoid cystic carcinoma of the salivary glands. Light and electronmicroscopic study. Cancer 1986;58:72-82.  Back to cited text no. 19
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Vered M, Braunstein E, Buchner A. Immunohistochemical study of epidermal growth factor receptor in adenoid cystic carcinoma of salivary gland origin. Head Neck 2002;24:632-6.  Back to cited text no. 21
    


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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]



 

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