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Fine-Needle Aspiration Biopsy of Salivary Gland Lesions.

Masses or cystic lesions of salivary glands have a wide range of differential diagnoses, from inflammatory response to neoplasm and to less common causes of infection. (1) The World Health Organization has described 45 morphologic types of primary salivary gland tumors. (2) Fine-needle aspiration (FNA) is a well-established diagnostic approach for salivary gland lesions. Zbaren et al (3) have noted accuracy, sensitivity, and specificity rates for salivary gland FNA of 79% (87 of 110), 74% (50 of 68), and 88% (37 of 42), respectively. Fine-needle aspiration has a higher sensitivity/specificity for benign masses than for malignancy. (4) Carrillo et al (5) also noted that FNA has the potential to change the clinical approach for up to one-third of patients. Salivary lesions remain, however, one of the most challenging entities in cytopathology, mainly because of the diversity of histologic subtypes and the often overlapping morphologic features of the lesions. (1, 6)

Indeterminate diagnosis despite cellular adequacy even in the hands of an experienced cytopathologist is not an uncommon finding in salivary gland FNA. It was noted that indeterminate cytology may be present in greater than 31.3% (115 of 317) of parotid FNA cases. (7) Fundakowski et al (7) also demonstrated that an indeterminate interpretation may be associated with a nearly 2-fold increased likelihood of malignancy on final diagnosis as compared to overall group (all patients underwent FNA and parotidectomy). Indeterminate category perhaps is a true reflection of the nature of salivary gland tumors. They may share similar morphology and/or FNA may sample an area of the tumor that inherently may not show diagnostic morphology. An example includes a tumor of basaloid morphology, for which the differential diagnoses include basal cell adenoma, basal cell adenocarcinoma, and adenoid cystic carcinoma. In one study, (8) greater than 30% (13 of 42) of basal cell adenomas were incorrectly diagnosed on FNA and 17% (7 of 42) were interpreted as suggestive of or positive for malignancy. Similarly, mucoepidermoid carcinoma can have varied morphologic appearance, whereby the differential diagnosis may include necrotizing sialometaplasia, inverted papilloma, cystadenoma, and various carcinomas with squamous or clear cell features. As a consequence, to distinguish low-grade mucoepidermoid carcinoma from cystadenoma is notoriously difficult, particularly with limited cellularity as obtained on FNA. (9)

While there are inherent limits of the FNA technique with regard to the inability to capture histologic architecture for salivary pathologic processes, improvements can definitely be made for better objectivity of reporting. To date, however, there is neither a standard system of terminology nor a classification for salivary neoplasms. This results in variable terminologies being used between institutions as well as by individual cytopathologists. The relatively high frequency of uncertainty in diagnosis is likely partly responsible for current confusion in the interpretation of these samples.

In recent years much effort has been made to achieve accurate diagnosis of salivary gland lesions. To that end, while preoperative diagnosis based on morphologic characteristics can be achieved in a significant number of cases, the impact, utilization, and ever-increasing role of ancillary studies cannot be overlooked. Impressive advances have been made in recent years in the understanding of molecular pathogenesis of salivary gland tumors. These molecular changes, including several recurrent chromosome translocations, have been identified in many common subtypes of salivary gland tumors. (10) While validation of these newly identified genetic changes and development of targeted therapies are still ongoing, applications for these genetic changes (including tumor-type specific gene fusion network) have been introduced into daily practice in several institutions. (11) This information may assist in the placement of patients with salivary tumors into clinical trials with targeted therapies. (12) Other technologies, including the use of antibodies for tissue microarrays, provide other sets of diagnostic markers for more accurate classification of salivary gland tumors. (3)

This review will highlight 2 areas in salivary gland neoplasms that are increasingly being investigated: (1) classifying salivary gland neoplasm on FNA samples; and (2) evolving molecular markers in various salivary gland tumors.

PROPOSED CLASSIFICATION OF SALIVARY GLAND FNA SAMPLES

Fundakowski et al (7) conducted a study to determine if FNA diagnosis could guide ear, nose and throat surgeons in the management of their patients. The authors (7) categorized cytology diagnosis from a likelihood analysis to help clinical teams further their management of patients. We modified their categorization and propose the Temple classification system for better concordance with cytology practices. We reviewed 107 consecutive cases of salivary gland lesions from our archives, of which 57 had corresponding available excision material to validate the newly proposed classification. In our review, the sensitivity, specificity, positive predictive value, and negative predictive value were 92.7% (13 of 14), 100% (43 of 43), 100% (13 of 13), and 97.7% (43 of 44), respectively. In our practice, we have noted that the new classification is easily adopted by cytopathologists and has higher interrater reliability. We feel this classification provides a systematic means of reporting salivary gland FNA samples. It provides necessary objective categorization with the potential to (1) improve communication between cytopathologists; (2) improve communication between cytopathologists and surgeons; and (3) eventually provide risk stratification data by category, which may be used to improve clinical decision making and preoperative counseling.

Proposed 6-Tier Classification

We propose the following diagnostic terms to classify salivary gland fine-needle aspirates: unsatisfactory; negative for neoplasm; lesion of unknown significance; positive for neoplasm; suggestive of malignancy; and positive for malignancy (Table 1).

Category Descriptions.--The detailed description for each category is provided in Table 1.

1. Unsatisfactory. Lack of cellularity, obscuring cells will result in utilization of this category. The exact number of cells that constitute "adequate" remains to be settled. In our practice, we regard a salivary gland FNA sample "adequate" if (1) 4 clusters or more of epithelial and/or mesenchymal cells are present, each cluster consisting of at least 10 cells; (2) 200 cells or more are present when only hematopoietic cells are observed. However, if the aspirate contains only fluid, keratin debris, or other extracellular deposits, the finding should be communicated with radiologists and the treating clinical team. In this situation, adequacy is categorized from morphologic changes in conjunction with clinical and/or radiologic changes of the lesion (change in size).

2. Negative for neoplasm. Fine-needle aspiration samples of this entity contain no neoplastic cells. Efforts to subcategorize should be made from the diagnostic material in the smears and cell block (Figure 1).

3. Lesion of unknown significance. This entity refers to lesions when clear cellular atypia is present; however, reactive versus neoplastic processes cannot be clearly identified. Every effort should be made to reduce the frequency of this category.

4. Positive for neoplasm. Combined cytologic features of epithelial cells, myoepithelial cells, mesenchymal cells, stroma, and smear background clearly indicate neoplastic process. These features include but are not limited to high cellularity, cellular crowding in the same cluster, nuclear pleomorphism, hyperchromasia, and nuclear contour irregularities (Figure 2).

5. Suggestive of malignancy. Certain features of malignancy are present in the specimen, but the findings are not sufficient to make a conclusive diagnosis.

6. Positive for malignancy. Combined cytologic features in epithelial cells, myoepithelial cells, and/or mesenchymal cells clearly indicate malignant neoplasm. The features include, but are not limited to, crowding and disorientation of cells in the same cluster, significantly increased nuclear to cytoplasmic ratio, uneven distribution of nuclear chromatin, irregular nuclear contour, nuclear pleomorphism, and prominent nucleoli. Certain features in the smear background, such as necrosis, may also help to establish malignant diagnosis (Figures 3 and 4).

With the newly acquired diagnostic tools, including recently identified fusion genes and immunohistochemical markers, significant improvement in diagnostic accuracy of salivary gland FNA samples can certainly be expected. (13) So, while we hone in on the new classification system to make it better with modifications as suggested by our group, an understanding of new markers may further aid in reducing the indeterminate category. As a part of this review we provide an update on molecular and immunohistochemical studies for salivary gland neoplasms. It is important to note that not all types of tumors have their distinct molecular or immunohistochemical markers. The most common chromosome translocations are summarized in Table 2 and the immunohistochemical markers, in Table 3.

REVIEW OF ANCILLARY FINDINGS IN VARIOUS SALIVARY GLAND NEOPLASMS

Pleomorphic Adenoma and Carcinoma Ex Pleomorphic Adenoma

Pleomorphic adenoma (PA) is the most common salivary gland tumor in both children and adults. (14) Fine-needle aspiration is highly accurate in diagnosing PA. Diagnostic difficulties may arise in (1) cellular specimens with sparse or absent matrix; (2) lesions with adenoid cysticlike areas; (3) lesions with focal cytologic atypia; and (4) lesions with squamous and/or mucinous metaplasia. (15)

Cytogenetic studies (16, 17) have shown PAs are characterized by recurrent translocations or intrachromosomal rearrangement with breakpoints preferentially affecting 8q12 (> 25% cases, 56 of 220) and 12q14-15 (13.2% cases, 29 of 220). The translocations/rearrangements result in gene fusions involving the transcription factor-encoding genes pleomorphic adenoma gene 1(PLAG1) and high-mobility group AT-hook 2 (HMGA2). PLAG1 encodes a DNA-binding zinc finger protein, controls PLAG1 target genes and insulin-like growth factor 2 signaling pathways. HMGA2 is an architectural transcription factor; its target genes include cell cycle regulators cyclin A1 and cyclin B2. Over-expression of PLAG1 is due to promoter swapping with at least 1 of 4 other genes (catenin p1, leukemia inhibitory factor receptor, coiled-coil-helix-coiled-coil-helix domain-containing 7, transcription elongation factor A1). (18) Rearrangements of HMGA2 are due to fusion of 3' parts of HMGA2 with 3' parts of nuclear factor 1/B (NF1B), WNT inhibitory factor 1 gene, or fragile histidine triad genes. (19, 20) Of note, the PLAG1 and HMGA2 fusions are present only in PA and carcinoma ex pleomorphic adenoma (CA-ex-PA) and have not been encountered in any other types of salivary gland neoplasms. (21) Compared to PA, subsets of Ca-ex-PA also show amplification of human homolog of mouse double minute 2 gene, mutations of tumor protein p53 gene (TP53), and amplification of human epidermal growth factor receptor 2 gene (HER2/neu) as molecular markers of malignant transformation. (22) Changes in the expression levels of Ki-67, cyclin E, and p63 are also proposed to differentiate PA from Ca-ex-PA. (23)

Mucoepidermoid Carcinoma

Mucoepidermoid carcinoma (MEC) is the most common salivary gland carcinoma in children and adults, more frequently affecting females (female to male ratio, 3:1). (24) Morphologically, MEC is characterized by mixed epidermoid, mucus-secreting, and intermediate cells. The proportion of the different cell types and their architectural configuration (including cyst formation) vary significantly between tumors. Mucin and high-molecular-weight keratin (8-11, 20) are useful when mucous or epidermoid cells, respectively, are rare. Mucoepidermoid carcinomas are also positive for epidermal membrane antigen (EMA), carcinoembryonic antigen, and p63; and are negative for calponin, smooth muscle actin (SMA), and S100. (25, 26) Most cases of MEC are characterized by a unique and recurrent chromosome translocation t(11;19)(q21-22;p13), resulting in fusions involving mastermind-like 2 gene (MAML2) and cAMP response element-binding protein regulated transcription coactivator 1 gene (CRTC1), or more rarely, cAMP response element-binding protein regulated transcription coactivator 3 gene. (27, 28) CRTC1 encodes a cAMP response element-binding protein coactivator, and MAML2 encodes a mastermind-like coactivator for Notch receptors. The N-terminal part of the fusion protein is critical for transforming activity, and the fusion protein activates epidermal growth factor receptor signaling in an autocrine manner and activates transcription of cAMP/cAMP response element-binding protein target genes including phosphoenolpyruvate carboxykinase 1; amphiregulin; MMP10; interleukin 6; nuclear receptor subfamily 4, group A, member 2; and nuclear receptor subfamily 4, group A, member 3. (29, 30) Several independent and well-documented studies (31) have indicated CRTC1-MAML2 gene fusion preferentially occurs in low- and intermediate-grade MECs with favorable prognosis. In high-grade MEC, a subset is CRTC1-MAML2 fusion positive, with multiple genomic imbalances including cyclin-dependent kinase inhibitor 2A deletion; another subset is fusion negative, still with multiple genomic imbalance. Prognosis for high-grade MEC is unfavorable. (32) A subset of Warthin tumors (so-called metaplastic variant of Warthin tumor) and clear cell hidradenoma of the skin and breast also harbor the CRTC1-MAML2 gene fusion. (33, 34)

Adenoid Cystic Carcinoma

Adenoid cystic carcinoma (ACC) is the second most common salivary gland carcinoma, although it can also arise in breast, sinonasal tract, tracheobronchial tree, skin, and vulva. (35) Adenoid cystic carcinoma is a basaloid tumor morphologically in tubular, cribriform, and solid patterns (Figure 3). The clinical course of ACC is usually indolent, but most patients with head and neck ACC die of disease in 10 to 15 years. (36) Immunohistochemically, ACCs are usually positive for keratin, carcinoembryonic antigen, EMA, and myoepithelial cell markers (calponin, SMA, p63). Ninety-four percent (62 of 66) of ACCs are strongly positive for cluster of differentiation protein 117 (CD117; c-kit, cytoplasmic), but no mutation in CD117 gene has been identified. (37)

Adenoid cystic carcinoma has a signature chromosomal translocation t(6;9)(q22-23;p23-24) resulting in a fusion involving the v-myb myeloblastosis viral oncogene homolog (MYB) oncogene and the transcription factor gene NFIB. (38, 39)

The MYB activation due to gene fusion, or more rarely, copy number gain or insertion of the 30-part of NF1B in the vicinity of the MYB locus, is identified in 97% (39 of 40) of ACCs. (40) On the other hand, MYB-NF1B fusion or rearrangements of MYB locus have not been detected in any other type of salivary gland carcinoma. (41) The MYB-NF1B fusion oncoprotein activates transcription of MYB targets, involving cell cycle control, DNA repair, and apoptosis. Indeed, several MYB targets, including B-cell CLL/lymphoma 2 (BCL2), v-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (Kit), CD34, baculoviral IAP repeat-containing 3, v-Myc avian myelocytomatosis viral oncogene homolog, and mitotic arrest deficient-like 1, were shown to be upregulated in ACC. (25) For pathologic practice, the MYB-NFlB fusion and/or MYB activation may be identified by reverse transcription-polymerase chain reaction analysis of fusion transcripts, fluorescence in situ hybridization analysis using probes for MYB and NF1B, or by immunohistochemical staining of MYB proteins. (21)

Acinic Cell Carcinoma

Acinic cell carcinoma (AciCC) is a low-grade, slow-growing tumor, which usually recapitulates growth of normal acinar cells, and is generally associated with a good prognosis. A subset of cases may occasionally develop recurrent and/or metastatic disease or undergo high-grade transformation. No specific molecular changes have been identified in AciCC. Karyotypic profiling of 11 AciCCs reveals that the only common change is trisomy 8 in 3 cases. (42) In addition to periodic acid-Schiff-positive cytoplasmic zymogen granules, recent studies (43, 44) show AciCCs are positive for deletion of guanine-rich DNA 1 (DOG-1), SRY-related HMG-box 10 (Sox10), amylase, carbonic anhydrase VI, and salivary proline-rich proteins; and negative for maspin and myoepithelial markers. The tumor may have focal neuroendocrine staining pattern.

Mammary Analogue Secretory Carcinoma of Salivary Gland

Mammary analogue secretory carcinoma (MASC) is a recently identified entity, so named for its almost identical histomorphologic, immunohistochemical, and molecular features to those of secretory carcinoma of the breast. (45) MASC is usually circumscribed but not encapsulated, consisting of lobules composed of tubular, solid, and cribriform structures with microcystic, glandular spaces and rare larger cysts. The tumor cells have low-grade vesicular nuclei with finely granular chromatin and centrally located small nucleoli; the cytoplasm is vacuolated or is pale pink, granular. (46) MASC is lipid-rich, with occasional intracytoplasmic mucin. Cellular atypia is mild, and mitotic figures are rare. (47)

Immunohistochemically, MASC shows strong and diffuse staining with cytokeratins, EMA, and mammaglobin. DOG1, usually displaying strongly positive staining in AciCC, is largely negative in MASC. Basal/myoepithelial cell markers including p63, calponin, cytokeratin (CK) 5/6, and SMA usually stain negatively. (48)

Mammary analogue secretory carcinoma and secretory carcinoma of breast also share a balanced chromosomal translocation, t(12;15)(p13;q25), resulting in an identical E26 transformation-specific variant gene 6 (ETV6)-neurotrophic tyrosine kinase receptor type 3 (NTRK3) gene fusion. (46, 49) This translocation is present in 93% (13 of 14) of MASCs but is not found in normal tissue or any other salivary gland neoplasms. (21, 45) The ETV6-NTRK3 fusion gene encodes a chimeric tyrosine kinase; the latter activates both Rasmitogen-activated protein kinase pathway and phosphatidylinositol-3-kinase-ATK pathway. (50) It has been suggested that salivary MASC is clinically more aggressive than its breast counterpart, and high-grade transformation of MASC has been reported, with ETV6-NTRK3 translocation. (11) Other than MASC and secretory carcinoma of breast, ETV6NTRK3 fusions have been found in congenital mesoblastic nephroma, congenital fibrosarcoma, and acute myeloid leukemia. (51)

Hyalinizing Clear Cell Carcinoma (Clear Cell Carcinoma, Not Otherwise Specified)

Monomorphic or hyalinizing clear cell carcinoma (HCCC) is composed of a single population of tumor cells having an optically clear cytoplasm on hematoxylin-eosin staining and most cytologic preparations. It used to be a diagnosis of exclusion, but recent developments in molecular pathology make an accurate diagnosis of HCCC a reality. (52) The hyaline stroma of HCCC is collagen type I and fibronectin; the tumor cells are positive for 34PE12 keratin, CK 7, p63, EMA; and negative for CK 20, SMA, calponin, and S100. (53, 54) A recurrent translocation t(12,22)(q13;q12) resulting in Ewing sarcoma breakpoint region 1 (EWSRl)-activating transcription factor 1 (ATF1) fusion gene, originally found in soft tissue clear cell sarcoma, has been recently identified in HCCC. (55) Actually, up to 82% (18 of 22) of HCCCs show EWSR1 rearrangement. (10, 56) In salivary gland, this molecular change is specific for HCCC, but clear cell odontogenic carcinoma also harbors this gene fusion. (57)

CONCLUSIONS

The role of molecular markers for salivary gland neoplasms will continue to increase. There is currently a lack of standardization in reporting/terminology for salivary neoplasms. We propose a novel classification system for salivary gland fine-needle aspirates, which we feel provides a more succinct, standardized interpretation of results that will ultimately assist in communication between clinicians, clinical decision making, and preoperative patient counseling.

Please Note: Illustration(s) are not available due to copyright restrictions.

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He Wang, MD, PhD; Christopher Fundakowski, MD; Jasvir S. Khurana, MD; Nirag Jhala, MD

Accepted for publication August 12, 2015.

From the Departments of Pathology (Drs Wang, Khurana, and Jhala) and Otolargyngology (Dr Fundakowski), Temple University Hospital, Temple University School of Medicine, Philadelphia, Pennsylvania.

The authors have no relevant financial interest in the products or companies described in this article.

Presented in part at the First Princeton Integrated Pathology Symposium: Head and Neck Pathology; February 9, 2014; Princeton, New Jersey.

Reprints: He Wang, MD, PhD, Department of Pathology, Temple University School of Medicine, 3401 N Broad St, PA 19104 (e-mail: he.wang@tuhs.temple.edu).

Caption: Figure 1. Nonnecrotizing granuloma in parotid gland, Diff-Quik smear (original magnification X400).

Caption: Figure 2. Warthin tumor, Diff-Quik smear (original magnification X400).

Caption: Figure 3. Adenoid cystic carcinoma, Diff-Quik smear (original magnification X400).

Caption: Figure 4. Diffuse large B-cell lymphoma involving parotid gland, Diff-Quik smear (original magnification X400).
Table 1. Proposed Classification of Salivary Gland Fine-Needle
Aspiration Samples

6-Tier                   Explanation for Each
Classification              Classification

Unsatisfactory   Less than the following standard:
                 [greater than or equal to] 4
                 clusters of epithelial and/or
                 mesenchymal cells, each cluster
                 [greater than or equal to] 10
                 cells; [greater than or equal to]
                 200 cells if only hematopoietic
                 cells;
                 In conjunction with clinical and/
                 or radiologic changes if aspirate
                 contains only fluid, keratin
                 debris, or other extracellular
                 deposits. See text.

Negative for     No neoplastic cells noted.
neoplasm         Efforts to subcategorize should
                 be made. This entity includes
                 acute and chronic inflammation,
                 sialadenitis, benign cysts,
                 granuloma (Figure 1), and
                 amyloidosis.

Lesion of        This entity refers to lesions
unknown          with clear cellular atypia
significance     present; however, reactive versus
                 neoplastic processes cannot be
                 clearly identified. Examples of
                 this entity include a few
                 atypical pleomorphic cells in an
                 inflammatory background or a few
                 atypical clear cells. Every
                 effort should be made to reduce
                 the frequency of this category.

                 Every effort should be made to
                 reduce the frequency of this
                 category including the
                 application of ancillary tests
                 (molecular and
                 immunohistochemistry). See Tables
                 2 and 3 for details.

Positive         Combined cytologic features of
for neoplasm     epithelial cells, myoepithelial
                 cells, mesenchymal cells, stroma,
                 and smear background clearly
                 indicate neoplastic process.
                 These features include but are
                 not limited to high cellularity,
                 cellular crowding in the same
                 cluster, nuclear pleomorphism,
                 hyperchromasia, nuclear contour
                 irregularities.
                   1. Pleomorphic adenoma
                   2. Warthin tumor (Figure 2)
                   3. Oncocytoma
                   4. Benign mesenchymal tumor
                   (vascular leiomyoma, infant
                   hemangioma)
                   5. Basal cell adenoma
                   6. Myoepithelioma

Suggestive of    Certain features of malignancy
malignancy       are present in the specimen, but
                 the findings are not sufficient
                 to make a conclusive diagnosis.

                 Every effort should be made to
                 reduce the frequency of this
                 category, including the
                 application of ancillary tests
                 (molecular and
                 immunohistochemistry). See Tables
                 2 and 3 for details.

Positive for     Combined cytologic features in
malignancy       epithelial cells, myoepithelial
                 cells, and/or mesenchymal cells
                 clearly indicate malignant
                 neoplasm. The features include
                 crowding and disorientation of
                 cells in the same cluster,
                 significantly increased nuclear
                 to cytoplasmic ratio, uneven
                 distribution of nuclear
                 chromatin, irregular nuclear
                 contour, nuclear pleomorphism,
                 and prominent nucleoli. Certain
                 features in the smear background,
                 such as necrosis, may also help
                 to establish malignant diagnosis.
                   1. Mucoepidermoid carcinoma
                   2. Acinic cell carcinoma
                   3. Adenoid cystic carcinoma
                     (Figure 3)
                   4. Malignant mixed tumor
                   5. Salivary duct carcinoma
                   6. Polymorphous low-grade
                      adenocarcinoma
                   7. Basal cell adenocarcinoma
                   8. Epithelial-myoepithelial
                      carcinoma
                   9. Small cell carcinoma
                  10. Lymphoepithelial carcinoma
                  11. Adenocarcinoma, not otherwise
                       specified
                  12. Squamous cell carcinoma
                  13. Hyalinizing clear cell
                       carcinoma
                  14. Lymphoma involving the
                       salivary gland (Figure 4)
                  15. Secondary malignancy
                       involving salivary gland

Table 2. Molecular Biomarkers for Salivary Gland Tumors

Tumor         Translocation       Genes Involved

PA        t(3;8)                  PLAG1 fusions
                                  HMG2 fusions
CA-                               PLAG1 fusions
  ex-PA                           HMG2 fusions
                                  HER2/neu
                                  amplification
                                  TP53 mutation
MEC       t(11;19)(q21;p13)       CRTC1-MAML2
          t(11;15)(q21;q26)       CRTC3-MAML2
ACC       t(6;9)(q22-23;p23-24)   MYB-NF1B
MASC      t(12;15)(p13;q25)       ETV6-NTRK3
HCCC      t(12;22)(q13;q12)       EWSR1-ATF1

Tumor                Prevalence

PA        >25% (56/220)17
          ~10% (29/220)17
CA-
  ex-PA

MEC       ~30%-80% ([38/111]-[18/22]) (58)
          ~5% (6/111) (58)
ACC       >80% (34/40) (40)
MASC      Translocation > 80% (13/14) (45)
HCCC      ~80% (18/22) (56)

Abbreviations: ACC, adenoid cystic carcinoma; ATF1, activating
transcription factor 1; CA/ex/PA, carcinoma ex pleomorphic adenoma;
CRTC1, cAMP response element/binding protein regulated
transcription coactivator 1; CRTC3, cAMP response element/binding
protein regulated transcription coactivator 3; ETV6, ETS variant
gene 6;EWSR1, Ewing sarcoma breakpoint region 1; HCCC, hyalinizing
clear cell carcinoma; HER2/neu, human epidermal growth factor
receptor 2; HMG2, high/mobility group AT/hook 2; MAML2,
mastermind/like 2; MASC, mammary analogue secretory carcinoma; MEC,
mucoepidermoid carcinoma; MYB, v/myb avian myeloblastosis viral
oncogene homolog; NF1B, nuclear factor 1/B; NTRK3, neurotrophic
tyrosine kinase receptor type 3; PA, pleomorphic adenoma; PLAG1,
pleomorphic adenoma gene 1; TP53, tumor protein p53.

Table 3. Immunohistochemical Markers for Salivary
Gland Tumors

Tumor                     Markers

PA         PLAG1 (94%, 34/36) (59)
           GFAP (100%,10/10) (60)
           Sox-10 (100%, 14/14) (44)
CA-ex-PA   PLAG1 (77%, 17/22) (61)
MEC        CK 7 (89%, 71/80), CK 8 (83%, 66/80),
           and CK 19 (59%, 47/80) (62)
           p63 (100%, 24/24) (61)
           Calponin (10%, 1/10) (63)
           SMA (0%, 0/10) (63)
           Sox-10 (0%, 0/6) (44)
AciCC      DOG-1 (100%, 28/28) (61)
           Sox-10 (100%, 8/8) (44)
           a-1-Antichymotrypsin (97.4%, 37/38) (64)
           S100 (2.5%, 1/38) (64)
ACC        CD117 (94%, 62/66) (37)
           MYB (65%, 24/37) (41)
           Sox-10 (96%, 22/23) (44)
MASC       S100 (100%, 15/15) (45)
           Mammaglobin (100%, 15/15) (45)
           GCDFP-15 (73%, 8/11) (45)
           p63 (0%, 0/9) (45)
           Estrogen receptor (0%, 0/9) (45)
           Progesterone receptor (0%, 0/9) (45)
           Human epidermal growth factor
           receptor 2 (0%, 0/9) (45)

Abbreviations: ACC, adenoid cystic carcinoma; AciCC, acinic cell
carcinoma; CA-ex-PA, carcinoma ex pleomorphic adenoma; CD117, cluster
of differentiation protein 117; CK, cytokeratin;DOG-1, deletion of
guanine-rich DNA 1; GCDFP-15, gross cystic disease fluid protein;
GFAP, glial fibrillary acidic protein; MASC, mammary analogue
secretory carcinoma; MEC, mucoepidermoid carcinoma; MYB, v-myb avian
myeloblastosis viral oncogene homolog; PA, pleomorphic adenoma; PLAG1,
pleomorphic adenoma gene 1; SMA, smooth muscle actin; Sox-10,
SRY-related HMG-box 10.
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Date:Dec 1, 2015
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