MYB Translocations in Both Myoepithelial and Ductoglandular Epithelial Cells in Adenoid Cystic Carcinoma: A Histopathologic and Genetic Reappraisal in Six Primary Cutaneous Cases.

ABSTRACT: Adenoid cystic carcinoma (ACC) is an infiltrating carcinoma composed of 2 cell types, myoepithelial and ductoglandular epithelial cells. Although approximately 70% of ACC exhibit translocations of the MYB proto-oncogene or MYB proto-oncogene like 1 (MYBL1), expression of MYB is known to be limited in myoepithelial cells. We investigated the histopathologic and genetic characteristics of ACC in 6 primary cutaneous cases. Histopathologically, 3 cases (50%) exhibited well-demarcated nodules composed of large nests, easily misdiagnosed as polymorphous sweat gland carcinoma. Two cases (33%) harbored large cystic structures resembling spiradenoma, hidradenoma, and digital papillary adenocarcinoma. A papillary pattern was focally observed in 2 cases (33%). A melting phenomenon within the myxoid stroma was seen in one case (17%). Fluorescence in situ hybridization (FISH) revealed MYB break-apart in 3 cases (50%). A combined FISH and immunohistochemical method revealed MYB break-apart signals in both p63-positive myoepithelial and p63-negative ductoglandular epithelial cells, suggesting that both cell types constitute elements of the tumor in ACC. Moreover, we established a well-circumscribed variant of ACC and proposed 3 new patterns of cystic, papillary, and melting in addition to the 3 patterns of cribriform, tubular, and solid growth.

Unusual Presentations of Primary and Metastatic Adenoid Cystic Carcinoma Involving the Skin.

Adenoid cystic carcinoma (ACC) is most commonly seen in the salivary glands but may occur at other sites. Primary or metastatic involvement of the skin is unusual. We report 2 cases of ACC with unusual presentation. In the first case, a 55-year-old woman presented with a cutaneous lesion on the right shin, and final pathology showed ACC. An extracutaneous origin was excluded by clinical and imaging studies. In the second case, a 49-year-old woman presented with a nodule on the breast, and biopsy confirmed high-grade ACC (>30% solid areas). She underwent lumpectomy and subsequent mastectomy after recurrence. Sixteen months after the initial diagnosis of ACC of the breast, distant metastases at multiple sites, including the skin, were identified. This report will increase awareness of these rare presentations of cutaneous ACC and allow correct diagnosis and appropriate management of such cases.

MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB-NFIB fusion gene.

Breast adenoid cystic carcinoma (AdCC), a rare type of triple-negative breast cancer, has been shown to be driven by MYB pathway activation, most often underpinned by the MYB-NFIB fusion gene. Alternative genetic mechanisms, such as MYBL1 rearrangements, have been reported in MYB-NFIB-negative salivary gland AdCCs. Here we report on the molecular characterization by massively parallel sequencing of four breast AdCCs lacking the MYB-NFIB fusion gene. In two cases, we identified MYBL1 rearrangements (MYBL1-ACTN1 and MYBL1-NFIB), which were associated with MYBL1 overexpression. A third AdCC harboured a high-level MYB amplification, which resulted in MYB overexpression at the mRNA and protein levels. RNA-sequencing and whole-genome sequencing revealed no definite alternative driver in the fourth AdCC studied, despite high levels of MYB expression and the activation of pathways similar to those activated in MYB-NFIB-positive AdCCs. In this case, a deletion encompassing the last intron and part of exon 15 of MYB, including the binding site of ERG-1, a transcription factor that may downregulate MYB, and the exon 15 splice site, was detected. In conclusion, we demonstrate that MYBL1 rearrangements and MYB amplification probably constitute alternative genetic drivers of breast AdCCs, functioning through MYBL1 or MYB overexpression. These observations emphasize that breast AdCCs probably constitute a convergent phenotype, whereby activation of MYB and MYBL1 and their downstream targets can be driven by the MYB-NFIB fusion gene, MYBL1 rearrangements, MYB amplification, or other yet to be identified mechanisms. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Genomic landscape of adenoid cystic carcinoma of the breast.

Adenoid cystic carcinoma (AdCC) is a rare type of triple-negative breast cancer (TNBC) characterized by the presence of the MYB-NFIB fusion gene. The molecular underpinning of breast AdCCs other than the MYB-NFIB fusion gene remains largely unexplored. Here we sought to define the repertoire of somatic genetic alterations of breast AdCCs. We performed whole-exome sequencing, followed by orthogonal validation, of 12 breast AdCCs to determine the landscape of somatic mutations and gene copy number alterations. Fluorescence in situ hybridization and reverse-transcription PCR were used to define the presence of MYB gene rearrangements and MYB-NFIB chimeric transcripts. Unlike common forms of TNBC, we found that AdCCs have a low mutation rate (0.27 non-silent mutations/Mb), lack mutations in TP53 and PIK3CA and display a heterogeneous constellation of known cancer genes affected by somatic mutations, including MYB, BRAF, FBXW7, SMARCA5, SF3B1 and FGFR2. MYB and TLN2 were affected by somatic mutations in two cases each. Akin to salivary gland AdCCs, breast AdCCs were found to harbour mutations targeting chromatin remodelling, cell adhesion, RNA biology, ubiquitination and canonical signalling pathway genes. We observed that, although breast AdCCs had rather simple genomes, they likely display intra-tumour genetic heterogeneity at diagnosis. Taken together, these findings demonstrate that the mutational burden and mutational repertoire of breast AdCCs are more similar to those of salivary gland AdCCs than to those of other types of TNBCs, emphasizing the importance of histological subtyping of TNBCs. Furthermore, our data provide direct evidence that AdCCs harbour a distinctive mutational landscape and genomic structure, irrespective of the disease site of origin.

Myoepithelial differentiation in cribriform, tubular and solid pattern of adenoid cystic carcinoma: A potential involvement in histological grading and prognosis.

Adenoid cystic carcinoma (AdCC) is known as a biphasic tumor composed of ductal and myoepithelial cells. The present study aimed to evaluate the amount and distribution of the myoepithelial cells in cribriform, tubular and solid subtypes of AdCC and analyze their relationship with histological grading and prognosis. A panel of myoepithelial markers including CK5/6, p63, p40, D2-40, calponin, α-SMA, S-100, and vimentin, together with a luminal cell marker CK7, and Ki-67 were used for immunohistochemical study in 109 AdCCs that included 38 cribriform, 36 tubular and 35 solid subtypes. The myoepithelial cells were labeled and found lined cystic-like paces, located at the periphery of the cribriform arrangements, and presented at the nonluminal cells of the two-layered tubular structures, while absent or dispersed in the solid pattern. Meantime, the solid subtype presented a higher proliferation rate assessed by mitotic count and Ki-67 labeling index, followed by poorer overall survival and recurrent-free survival. Furthermore, CK7 expression was found higher in solid pattern than in cribriform-tubular subtype, which showed negative correlation with the myoepithelial markers including D2-40, Calponin, α-SMA, p63, p40 and vimentin. The solid pattern of AdCC showed gland differentiation but loss of myoepithelial differentiation with a higher proliferation and more aggressiveness as well as poorer prognosis compared with the cribriform-tubular subtypes, which implies that loss of MEC differentiation might contribute to the poor prognosis of the solid subtype of AdCC. However, further studies are required to clarify its exact role in AdCC progression.

[Salivary gland-type lung tumor: An update]. / Tumeurs de type glandes salivaires du poumon.

"Salivary gland-type" tumors arising from the bronchi and lung are rare but not exceptional entities. They are mostly represented by malignant entities such as cystic adenoid carcinoma, mucoepidermoid carcinoma and epithelial/myoepithelial carcinoma. Benign tumors are rare, mainly encompassing pleomorphic adenomas, which are to differentiate from mucous gland adenomas, another entity arising specifically from the peri-bronchial glands. These tumours develop in the proximal bronchi and are not associated with smoke abuse. Their main treatment is surgery. It is important to differentiate them from other broncho-pulmonary tumours as they do not share the same prognosis and therapeutic. This article will review the WHO 2015 classification of these tumours as well as recent updates from the literature to help define diagnosis criteria for these uncommon entities.

A study on the inhibition of VEGF expression in salivary gland adenoid cystic carcinoma cells via iNOS gene RNAi in vitro.

In this study, we aimed to explore the effect of inducible nitric oxide synthase (iNOS) on vascular endothelial growth factor (VEGF) expression in salivary gland adenoid cystic carcinoma (SACC). Using RNAi, we transfected chemically synthesised iNOS siRNA into ACC-M cells (a highly metastatic adenoid cystic carcinoma cell line) and detected the change in the gene and protein expression levels of iNOS and VEGF by qRT-PCR and Western blotting. A transwell invasiveness assay was used to examine the changes in invasive ability of ACC-M cells. Cell growth was determined using a CCK-8 assay. Apoptosis and cell-cycle phases were detected by flow cytometry. We found that silencing iNOS down-regulated the expression of VEGF and then inhibited cell growth and invasiveness of SACC cells, while it increased apoptosis. Therefore, we concluded that iNOS can regulate VEGF expression and iNOS may be a therapeutic target.

[Clinicopathologic observation of adenoid cystic carcinoma of esophagus].

OBJECTIVE: To study the clinicopathologic features and differential diagnosis of adenoid cystic carcinoma in the esophagus. METHODS: Ten cases of primary adenoid cystic carcinoma of the esophagus were retrieved from the archival file. The clinicopathologic and immunohistochemical features were studied. The differential diagnosis was analyzed. RESULTS: The male-to-female ratio was 9: 1. The age of patients ranged from 59 to 76 years. There were 4 cases with tumor located in mid esophagus, 4 cases with tumor located in mid to lower esophagus and the remaining 2 cases in lower esophagus. Low-power histologic examination showed mainly expansive growth pattern, with cribriform, solid and focal tubular architectures identified. The tumor cells showed nuclear hyperchromasia. Both ductal and myoepithelial differentiation was demonstrated. The stroma showed myxoid degeneration in areas. Comedo-type necrosis was observed in 8 cases and moderate to severe squamous dysplasia was present in one case. Three cases showed focal areas of squamous cell carcinoma. Immunohistochemical study showed that the tumor cells were positive for p63 (10/10), CD117 (10/10) and S-100 protein (9/10). There was focal staining for calponin (2/10) and smooth muscle actin (2/10). The ductal structures expressed CK7 (10/10). CONCLUSIONS: Adenoid cystic carcinoma of the esophagus demonstrates unique morphologic features with expression of S-100 protein and consistent expression of CD117. The above characteristics help to distinguish this entity from basaloid squamous cell carcinoma, mucoepidermoid carcinoma and small cell carcinoma of the esophagus.

Analysis of MYB oncogene in transformed adenoid cystic carcinomas reveals distinct pathways of tumor progression.

Adenoid cystic carcinomas can occasionally undergo dedifferentiation, a phenomenon also referred to as high-grade transformation. However, cases of adenoid cystic carcinomas have been described showing transformation to adenocarcinomas that are not poorly differentiated, indicating that high-grade transformation may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form, which may encompass a wide spectrum of carcinomas in terms of aggressiveness. The aim of this study was to gain more insight in the biology of this pathological phenomenon by means of genetic profiling of both histological components. Using microarray comparative genomic hybridization, we compared the genome-wide DNA copy-number changes of the conventional and transformed area of eight adenoid cystic carcinomas with high-grade transformation, comprising four with transformation into moderately differentiated adenocarcinomas and four into poorly differentiated carcinomas. In general, the poorly differentiated carcinoma cases showed a higher total number of copy-number changes than the moderately differentiated adenocarcinoma cases, and this correlated with a worse clinical course. Special attention was given to chromosomal translocation and protein expression of MYB, recently being considered to be an early and major oncogenic event in adenoid cystic carcinomas. Our data showed that the process of high-grade transformation is not always accompanied by an accumulation of genetic alterations; both conventional and transformed components harbored unique genetic alterations, which indicate a parallel progression. Our data further demonstrated that the MYB/NFIB translocation is not necessarily an early event or fundamental for the progression to adenoid cystic carcinoma with high-grade transformation.

Evaluation of cell proliferation marker CDC-7 in salivary adenoid cystic carcinoma.

BACKGROUND: Adenoid cystic carcinoma (AdCC) is considered one of the most common destructive types of malignant salivary gland tumor that have high affinity to perineural invasion (PNI). This study was conducted to access different histological features of AdCC, and assessment of the immunohistochemical expression of CDC-7. METHODS: Thirty formalin-fixed paraffin incorporated tissue blocks of AdCC were classified according to the WHO histopathological types. The immune-expression of CDC-7 positive area was evaluated according to percentage area as following: Negative = 0 %, Weak = 1-10 %, Moderate = 11-49 %, and Strong = 50-100. The correlations between expression of the marker and different clinico-pathological variables were investigated using Chi-square (χ2) test. The P-value ≤ 0.05 was considered statistically significant. RESULTS: The expression of CDC-7 revealed statistical significant difference between the different tumor types (p ≤ 0.05). CONCLUSION: The biological behavior of AdCC can be predicated from the expression of CDC-7.

Detection of claudin-4 in salivary gland neoplasms (a study utilizing RT-PCR and immunohistochemistry).

BACKGROUND: Claudins are transmembrane proteins of tight junctions emerging as targets for diagnosis, prediction of prognosis, disease recurrence, and metastasis. Our goal was to evaluate expression of claudin-4 in the most common benign and malignant salivary gland neoplasms. METHODS: Claudin-4 gene levels and protein expression were determined by real-time polymerase chain reaction (PCR), and immunohistochemistry in a total of 30 specimens containing normal salivary tissue, pleomorphic adenoma, Warthin's tumor, mucoepidermoid carcinoma, and adenoid cystic carcinoma. RESULTS: We identified down-regulation of claudin-4 gene levels and protein expression from normal control to benign salivary gland neoplasms and reached their lowest values in the malignant salivary gland neoplasms. CONCLUSIONS: Low claudin-4 expression could be considered as a sign of increasing cellular disorientation and invasion of salivary gland tumors.

Claudin expression in pulmonary adenoid cystic carcinoma and mucoepidermoid carcinoma.

Background: Although the expression of tight junction protein claudins (CLDNs) is well known in common histological subtypes of lung cancer, it has not been investigated in rare lung cancers. The aim of our study was to examine the expression of different CLDNs in pulmonary salivary gland tumors. Methods: 35 rare lung cancers including pathologically confirmed 12 adenoid cystic carcinomas (ACCs) and 23 mucoepidermoid carcinomas (MECs) were collected retrospectively. Immunohistochemical (IHC) staining was performed on formalin fixed paraffin embedded (FFPE) tumor tissues, and CLDN1, -2, -3, -4, -5, -7, and -18 protein expressions were analyzed. The levels of immunopositivity were determined with H-score. Certain pathological characteristics of ACC and MEC samples (tumor grade, presence of necrosis, presence of blood vessel infiltration, and degree of lymphoid infiltration) were also analyzed. Results: CLDN overexpression was observed in both tumor types, especially in CLDN2, -7, and -18 IHC. Markedly different patterns of CLDN expression were found for ACC and MEC tumors, especially for CLDN1, -2, -4, and -7, although none of these trends remained significant after correction for multiple testing. Positive correlations between expressions of CLDN2 and -5, CLDN3 and -4, and CLDN5 and -18 were also demonstrated. Tumors of never-smokers presented lower levels of CLDN18 than tumors of current smokers (p-value: 0.003). Conclusion: This is the first study to comprehensively describe the expression of different CLDNs in lung ACC and MEC. Overexpression of certain CLDNs may pave the way for targeted anti-claudin therapy in these rare histological subtypes of lung cancer.

Detection of human papilloma virus and p16 expression in high-grade adenoid cystic carcinoma of the head and neck.

Squamous cell carcinoma of the head and neck, particularly basaloid squamous cell carcinoma, may be difficult to distinguish from high-grade adenoid cystic carcinoma. Evidence of human papilloma virus (HPV) infection, particularly HPV 16, is frequently found in non-keratinizing oropharyngeal squamous cell carcinoma. Immunoreactivity for p16, a surrogate marker for HPV infection, often parallels the HPV infection status in oropharyngeal squamous cell carcinoma. However, the incidence and correlation between p16 expression and HPV infection in high-grade adenoid cystic carcinoma is unknown. Sixteen cases of high-grade adenoid cystic carcinoma, three cases of dedifferentiated adenoid cystic carcinoma and eight cases of low-/intermediate-grade adenoid cystic carcinoma were identified for inclusion in the study. All cases were tested by immunohistochemistry for p16 expression and in situ hybridization for high- and low-risk HPV. Eight cases (100%) of low-to-intermediate-grade adenoid cystic carcinoma were focally positive for p16, all of which were negative for HPV. In all, 14 of 16 cases (88%) of high-grade adenoid cystic carcinoma and three cases (100%) of dedifferentiated adenoid cystic carcinoma were positive for p16; strong and diffuse staining was noted in three cases (3 of 19, 16%). Two cases (11%) of high-grade adenoid cystic carcinoma, which were also diffusely positive for p16, showed the presence of high-risk HPV. These findings suggest that the presence of HPV infection in high-grade adenoid cystic carcinoma is infrequent, even in the presence of p16 immunostaining. Nevertheless, HPV positivity should not be used to exclude the possibility of high-grade adenoid cystic carcinoma when the differential diagnosis includes squamous cell carcinoma. Moreover, although p16 overexpression is often used as a surrogate marker for HPV in squamous cell carcinoma, it cannot be used in this manner in high-grade adenoid cystic carcinoma.

Expression of ERBB3 binding protein 1 (EBP1) in salivary adenoid cystic carcinoma and its clinicopathological relevance.

BACKGROUND: ERBB3 binding protein 1 (EBP1) gene transfer into human salivary adenoid cystic carcinoma cells has been shown to significantly inhibit cell proliferation and reduce tumor metastasis in mouse models. In the current study, to evaluate if EBP1 is a novel biomarker capable of identifying patients at higher risk of disease progression and recurrence, we examined the EBP1 expression profile in adenoid cystic carcinoma (ACC) patients and analyzed its clinicopathological relevance. To understand the underlying anti-metastatic mechanism, we investigated if EBP1 regulates invasion-related molecules. METHODS: We performed immunohistochemical analysis on 132 primary adenoid cystic carcinoma and adjacent non-cancerous tissues using commercial EBP1, MMP9, E-cadherin and ICAM-1 antibodies. Results were correlated to clinicopathological parameters, long-term survival and invasion-related molecules by statistical analysis. Cell motility and invasiveness of vector or wild-type EBP1-transfected ACC-M cell lines were evaluated using wound healing and Boyden chamber assays. MMP9, E-cadherin and ICAM-1 proteins in these cell lines were detected using western blot assay. RESULTS: The expression of EBP1 was significantly higher in non-cancerous adjacent tissues compared with corresponding cancer tissues. The intensity and percentage of cells that reacted with EBP1 antibodies were significantly higher in cases with tubular pattern than those with solid pattern (P<0.0001). We also found adenoid cystic carcinoma with local lymphatic metastasis had significantly lower EBP1 expression than ACC with no local lymphatic node metastasis (P<0.0001). Similar findings were observed in ACC with lung metastasis compared with cases with no lung metastasis (P<0.0001), in particular, in cases with perineural invasion compared with cases with no perineural invasion (P<0.0001). Furthermore, a decrease in EBP1 expression was positively associated with a reduction in overall survival of ACC patients. Of note, EBP1 inhibits migration and invasiveness of ACC cells by upregulating E-cadherin but downregulating MMP9. In clinical adenoid cystic carcinoma patients, higher EBP1 expression was positively correlated with E-cadherin levels (P<0.001) but negatively correlated with MMP9 expression (P=0.0002). CONCLUSIONS: EBP1 expression is reduced in adenoid cystic carcinoma, indicating unfavorable prognosis of ACC patients. Its regulation of MMP9 and E-cadherin protein levels suggests a critical therapeutic potential.

Spiradenoma of the breast: a rare diagnostic pitfall in the evaluation of solid-basaloid breast lesions with a dual cell population.

Breast spiradenoma is extremely rare, with only 4 cases reported previously. We describe an instructive case of breast spiradenoma resembling adenoid cystic carcinoma (AdCC). A 71-year-old woman underwent excisional biopsy of a breast mass after a conclusive diagnosis was unable to be obtained from core needle biopsy showing an AdCC-like pattern. Histopathologically, the lesion demonstrated solid and cribriform foci comprising basaloid cells, luminal cells, and eosinophilic hyaline material, reminiscent of solid-basaloid AdCC, alongside convoluted lumens, stromal edema, lymphocytic infiltration, and c-kit negativity. On molecular analysis, neither MYB fusion genes nor CYLD gene abnormalities were identified. These results were supportive of spiradenoma. Salivary gland- and skin adnexal-type tumors are challenging to diagnose due to morphological overlaps. This case, highlighting histopathological and molecular features, shows that breast spiradenoma can be a diagnostic pitfall among the differential diagnoses of AdCC.

Primary adenoid cystic carcinoma of the eyelid.

Adenoid cystic carcinoma is a rare epithelial malignancy, which tends to grow slowly. It is an intractable neoplasm due to its ability to invade perineural spaces. A 59-year-old female presented with a gradually increasing mass in the right lower eyelid. An excisional biopsy with wide margins revealed a diagnosis of primary adenoid cystic carcinoma of eyelid skin with perineural invasion. Although a rare neoplasm, primary adenoid cystic carcinoma of eyelid skin should be included in the differential diagnosis of eyelid tumors.

Identification of c-kit gene mutations in primary adenoid cystic carcinoma of the salivary gland.

The CD117 (KIT) protein is overexpressed in many human neoplasms including adenoid cystic carcinoma of salivary glands. To evaluate the function of c-kit-activating mutations in adenoid cystic carcinoma of the salivary gland, we studied 14 cases (13 primary, 1 cervical lymph node metastasis) from our institution. KIT protein expression was evaluated by immunohistochemistry using formalin-fixed paraffin-embedded tissue. Mutational analyses of c-kit extracellular (exon 9), juxtamembrane (exon 11) and tyrosine kinase domains (exons 13 and 17) were performed by polymerase chain reaction, clonal selection and DNA sequencing. All 14 cases demonstrated strong KIT expression by immunohistochemistry. Molecular analysis was successful in 8 of 14 cases, and c-kit missense point mutations were detected in seven of eight cases (88%) including seven in exon 11, two in exon 9, two in exon 13 and two in exon 17. Eight silent point mutations were detected in five cases. Two cases contained missense mutations in more than one exon. Different mutations were found in the primary tumor and the cervical lymph node metastasis of one patient. Point mutations in domains similar to those described in gastrointestinal stromal tumors were detected, including Pro551Leu and Lys558Glu (5' end of exon 11), Leu576Phe (3' end of exon 11), Val643Ala (exon 13) and Asn822Ser (exon 17). Additional novel point mutations in exons 9, 11, 13 and 17 were also identified. This study is the first to report c-kit gene mutations in primary adenoid cystic carcinoma of the salivary gland. Identification of such potential gain-of-function mutations in exon 11, and less frequently in exons 9, 13 and 17, suggests that KIT may be involved in the pathogenesis of adenoid cystic carcinoma of salivary glands. Our study raises a prospect of correlation of c-kit mutation and a potential treatment of adenoid cystic carcinoma with tyrosine kinase inhibitor (imatinib).

Differential expression of galectin-3, beta-catenin, and cyclin D1 in adenoid cystic carcinoma and polymorphous low-grade adenocarcinoma of salivary glands.

BACKGROUND: Galectin-3 has been implicated in tumor progression of some malignancies as thyroid, prostate, and salivary gland tumors. Recently, it has been suggested that this protein may be an important mediator of the beta-catenin/Wnt pathway. Moreover, nuclear galectin-3 expression has been implicated in cell proliferation, promoting cyclin D1 activation. Thus, the present study aimed to correlate galectin-3 expression with beta-catenin and cyclin D1 expressions in adenoid cystic carcinoma (ACC) and in polymorphous low-grade adenocarcinoma (PLGA). METHODS: Fifteen formalin-fixed paraffin-embedded cases of each tumor were retrieved from the files of the Surgical Oral Pathology Service at the University of São Paulo and the proteins were analyzed by immunohistochemistry. RESULTS: Adenoid cystic carcinoma showed galectin-3 immunostaining mainly in the nuclei, while PLGA revealed a positive mostly cytoplasmic reaction to galectin-3 in the largest part of tumor cells. Both tumors showed intense cytoplasmic/nuclear staining for beta-catenin in majority of cases. Cyclin D1 immunoreactivity was not detected in 14/15 PLGA and showed specific nuclear staining in 10/15 cases of ACC in more than 5% of the neoplastic cells. Cyclin D1 expression was correlated with cytoplasmic and nuclear galectin-3 expression in ACC (P < 0.05). CONCLUSIONS: These results suggest that in ACC galectin-3 may play a role in cellular proliferation through cyclin D1 activation. In addition, nuclear expression of galectin-3 in ACC may be related to a more aggressive behavior of this lesion. Although beta-catenin seems to play a role in carcinogenesis in both lesions, it seems that it does not bind to galectin-3 for cyclin D1 stimulation.