Conventional Adenoid Cystic Carcinoma Research Articles

Adenoid Cystic Carcinoma With Striking Tubular Hypereosinophilia: A Unique Pattern Associated With Nonparotid Location and Both Canonical and Novel EWSR1::MYB and FUS::MYB Fusions.

The classification of salivary gland tumors is ever-evolving with new variants of tumors being described every year. Next-generation sequencing panels have helped to prove and disprove prior assumptions about tumors' relationships to one another, and have helped refine this classification. Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and occurs at all major and minor salivary gland and seromucous gland sites. Most AdCC are predominantly myoepithelial and basaloid with variable cribriform, tubular, and solid growth. The luminal tubular elements are often less conspicuous. AdCC has largely been characterized by canonical MYB fusions, with MYB::NFIB and rarer MYBL1::NFIB. Anecdotal cases of AdCC, mostly in nonmajor salivary gland sites, have been noted to have unusual patterns, including squamous differentiation and macrocystic growth. Recently, this has led to the recognition of a subtype termed "metatypical adenoid cystic carcinoma." Another unusual histology that we have seen with a wide range of architecture, is striking tubular hypereosinophilia. The hypereosinophilia and luminal cell prominence is in stark contrast to the vast majority of AdCC that are basaloid and myoepithelial predominant. A total of 16 cases with tubular hypereosinophilia were collected, forming morular, solid, micropapillary, and glomeruloid growth, and occasionally having rhabdoid or Paneth-like cells. They were subjected to molecular profiling demonstrating canonical MYB::NFIB (5 cases) and MYBL1::NFIB (2 cases), as well as noncanonical EWSR1::MYB (2 cases) and FUS::MYB (1 case). The remaining 6 cases had either no fusion (3 cases) or failed sequencing (3 cases). All cases were present in nonmajor salivary gland sites, with seromucous glands being the most common. These include sinonasal tract (7 cases), laryngotracheal (2 cases), external auditory canal (2 cases), nasopharynx (1 case), base of tongue (2 cases), palate (1 case), and floor of mouth (1 case). A tissue microarray of 102 conventional AdCC, including many in major salivary gland sites was examined for EWSR1 and FUS by fluorescence in situ hybridization and showed that these novel fusions were isolated to this histology and nonmajor salivary gland location. In summary, complex and striking tubular hypereosinophilia and diverse architectures are present within the spectrum of AdCC, particularly in seromucous gland sites, and may show variant EWSR1/FUS::MYB fusions.

Distinct clinicopathological and genomic features in solid and basaloid adenoid cystic carcinoma of the breast

Adenoid cystic carcinoma (AdCC) of the breast is a rare indolent carcinoma of salivary gland-type tumors, frequently associated with MYB genetic alteration. Solid and basaloid adenoid cystic carcinoma (SB-AdCC) is considered a sparse variant of AdCC. This study sought to search for clinicopathological and genomic features in SB-AdCC. Registered clinicopathological data on a cohort of 13 AdCC of the breast cases, including six conventional adenoid cystic carcinoma (C-AdCC) cases and seven SB-AdCC cases, were collected. MYB gene rearrangement via fluorescent in situ hybridization was investigated and MYB protein expression was evaluated by immunohistochemistry. Compared with C-AdCC, we found that the distribution of SB-AdCC cases were shifted to older age and were more frequently distant metastasis. Moreover, metastasis cases also showed a high (exceed 30%) Ki-67 index. Both groups showed MYB rearrangements and MYB protein expression, but they were less frequent in SB-AdCC than C-AdCC. To conclude, our results suggest that SB-AdCC is an aggressive variant of mammary AdCC with a higher incidence of distant metastases compared with C-AdCC, though they share common molecular features. A high Ki-67 index may be an adverse prognostic factor for metastasis.

Exploration of High-Grade Transformation and Postoperative Radiotherapy on Prognostic Analysis for Primary Adenoid Cystic Carcinoma of the Head and Neck.

BackgroundDespite Adenoid cystic carcinoma (ACC) with cribriform or tubular components being recognized as a potentially indolent malignancy, ACC displaying solid or, more rarely, high-grade transformation (HGT) components is considered a more aggressive variant of the disease. As it is difficult to measure the proportion of the solid component objectively, and the role of HGT in the current grading system remains unclear, the prognostic influence of tumor grading remains controversial. In addition, postoperative radiotherapy (PORT) has been proven to be effective in local control of ACC of the head and neck (ACCHN) with a high rate of nerve invasion and close surgical margin. However it remains to be explored that whether PORT could improve the survival of patients with ACC, particularly those with HGT.MethodsA series of 73 surgically treated primary ACCHN cases were retrospectively accessed. Immunohistochemical staining was performed to observe the biphasic ductal-myoepithelial differentiation and to identify the HGT components of ACC for tumor grading. The correlation between tumor grading and clinicopathological characteristics was analyzed. Univariate and multivariate prognostic analysis were performed for progression-free survival (PFS) and overall survival (OS).ResultsOf the 73 included cases, 47 were grade I-II ACC and 26 were grade III ACC. Among the grade III cases, 14 with loss of biphasic ductal-myoepithelial differentiation identified by immunostaining were classified as HGT, and could be distinguished from conventional grade III cases. These HGT cases were correlated with a high propensity of lymph node metastases and more advanced stage. Univariate analysis demonstrated that tumor grading, perineural invasion, T stage, stage groups, and PORT were predictors for PFS, whereas tumor grading, margin status, and PORT were predictors for OS. However, only tumor grading and PORT were independent predictors for PFS and OS. The patients with HGT had significantly worse prognosis than those with conventional ACC. Moreover, disease progression tended to occur more frequently in younger patients. Among the patients with HGT, those who received PORT had a longer median survival time than those who did not.ConclusionHGT ACC identified by loss of biphasic differentiation should be considered in tumor grading. Tumor grading and PORT were independent predictors for disease progression and OS in surgically treated ACCHN patients.

Metastatic adenoid cystic carcinoma with high-grade transformation ("dedifferentiation") in pleural effusion and neck lymph node: A diagnostic challenge on cytology?

High-grade transformation (HGT) or "dedifferentiation" is an uncommon phenomenon among salivary gland carcinomas including adenoid cystic carcinoma (ACC), which is important to recognize because it is associated with increased tumor aggressiveness, with a high propensity for lymph node and distant metastases. ACC with HGT is histologically characterized by a distinct population of poorly differentiated cells with loss of the typical biphasic ductal and myoepithelial differentiation seen in conventional ACC, associated with pleomorphism, necrosis and increased mitotic activity. We report the cytologic features of a case of metastatic ACC-HGT in cervical lymph node and effusion, which, to the best of our knowledge, have not been described previously. When ACC presents both in atypical locations and with HGT, the danger of misdiagnosis is increased if the clinical history is lacking, incomplete or inaccurate. Since ACC-HGT are rare (and possibly underdiagnosed) and do not have a specific set of cytological and/or immunohistochemical features, it is important for practicing cytopathologists to be aware of the possibility of encountering them, especially in specimens from patients with a history of ACC, in order to render the correct diagnosis.

Solid-type adenoid cystic carcinoma of the breast, a distinct molecular entity enriched in NOTCH and CREBBP mutations.

Adenoid cystic carcinoma (ACC) of the breast with a predominant solid pattern is difficult to diagnose with certainty and differentiate from more common triple-negative breast cancers (TNBCs) of basal-phenotype. To better characterize solid ACC, we performed a clinical, morphological, immunohistochemical, and molecular comparative analysis of 33 ACCs of the breast comprising 17 solid variant ACCs and 16 conventional ACCs. Solid ACCs displayed basaloid morphology with an exclusive or predominant epithelial cell population associated with decreased myoepithelial differentiation, while demonstrating MYB protein overexpression similar to the more common type of ACC. Strong and diffuse MYB expression by immunochemistry was observed in 14/17 (82%) of solid ACCs while MYB rearrangements were detected by break apart fluorescence in situ hybridization (FISH) in only 3/16 (19%) of solid ACCs. Conversely, weak MYB immunohistochemical expression was observed in only 7/204 (3%) of TNBC. Solid ACCs displayed a transcriptomic profile distinct from conventional ACCs with 549 genes showing a highly significant differential expression between conventional and solid ACC [false discovery rate (FDR) < 0.01; log2FC > |1|]. EnrichR and Kegg Pathway analyses identified PI3K-Akt and focal adhesion signaling pathways as significantly overexpressed in conventional ACCs compared with solid ACCs which significantly overexpressed the nitrogen metabolism pathway. CREBBP mutations and NOTCH activating gene mutations were only present in solid ACCs, concerning 5/16 (31%) of cases for each gene. Tumors with NOTCH activating mutations displayed a strong diffuse nuclear NICD1 staining, an established marker of Notch pathway activation. Solid ACCs also differed from basal-type TNBC, with fewer TP53 mutations and a more stable genomic profile on array comparative genomic hybridization (CGH). In summary, solid-type ACC of the breast is a distinct molecular entity within the ACC family and is different from common basal-type TNBC. MYB is a diagnostically useful biomarker of solid ACC and NOTCH could be a novel potential therapeutic target in 30% of cases.

Predictors of Outcome in Mammary Adenoid Cystic Carcinoma: A Multi-Institutional Study.

Mammary adenoid cystic carcinoma (ACC) is a rare subtype of breast cancer with a favorable prognosis. Here we report on predictors of outcome based on a detailed morphologic review and analysis of 108 mammary ACC. Sixty-four tumors (59.2%) were pure conventional ACC, 23 (21.3%) were pure basaloid ACC. Follow-up was available for 87 patients (median: 51 mo). Eighteen patients (20.7%) developed recurrence: 7 (8%) had local recurrence and 14 (16%) had distant metastasis. Two patients died of disease, 1 died of an unrelated cause, 14 were alive with disease (including 8 in palliative care), and 70 (80.5%) were alive with no evidence of disease. Of 90 patients with known lymph node (LN) status 9 (10%) had nodal involvement (all with basaloid ACC). Distant metastases in patients with predominantly basaloid ACC compared with pure conventional ACC were more common (40% vs. 7.7%) and occurred earlier (22 vs. 84 mo). The following factors were found to be predictive of recurrence-free survival: positive margin, Nottingham grade, neovascularization, basaloid component, perineural invasion, lymphovascular invasion, >30% solid growth, necrosis and LN involvement; the first 3 remained statistically significant on multivariate analysis. Factors predictive of distant disease-free survival were neovascularization, Nottingham grade, lymphovascular invasion, solid component >50%, LN involvement, basaloid component >50%, tumor necrosis, perineural invasion, and final margin. Only neovascularization remained statistically significant on multivariate analysis. Basaloid ACC is an aggressive variant of mammary ACC with more frequent nodal involvement and higher incidence of distant spread. LN staging should be performed for all mammary basaloid ACC.

Cytological features of dedifferentiated adenoid cystic carcinoma of the trachea

Adenoid cystic carcinoma (AdCC) is a distinct type of carcinoma, and cytological examination has been recognized as a useful tool in its diagnosis. Dedifferentiation is defined as the abrupt transformation of a low-grade tumor into a tumor with high-grade components. Albeit extremely rare, dedifferentiated AdCC has been reported: however, the cytological features of this tumor have not been documented. We observed a case in which a 66-year-old Japanese male had stenosis and thickness of the lower tracheal and bronchial walls. Cytological smears of a bronchial brush specimen revealed features typical for low-grade AdCC. However, a few cohesive epithelial cell clusters composed of large, atypical polygonal cells with large nuclei and conspicuous nucleoli also were present. This component was considered to represent dedifferentiated carcinoma. Histopathological study of the resected bronchial tumor revealed dedifferentiated AdCC. The cytological diagnosis of conventional low-grade AdCC is straightforward in most cases, although extremely rare, dedifferentiated carcinoma can occur within the conventional AdCC, and detection of a dedifferentiated component is possible in a cytological specimen because of obvious nuclear atypia. Therefore, careful observation is needed because cytologic diagnosis of dedifferentiated AdCC can help expedite treatment of this highly aggressive tumor.

Progressive Genetic Alterations of Adenoid Cystic Carcinoma With High-Grade Transformation

Although genome-wide imbalances have been characterized in conventional adenoid cystic carcinoma, other than p53 mutational status, the molecular profile of adenoid cystic carcinoma with high-grade transformation has not been explored. To evaluate progressive genetic alterations in adenoid cystic carcinoma with high-grade transformation using array comparative genomic hybridization. Five adenoid cystic carcinomas with high-grade transformation (4 primary tumors and 1 paired metastasis) were selected and characterized at the DNA level by array comparative genomic hybridization on formalin-fixed paraffin-embedded tissue. Select alterations were validated by fluorescence in situ hybridization. Chromosomal gains were mostly confined to the areas of high-grade transformation while losses were seen only in the conventional areas. Chromosomal regions with significant gains included 8q24, 17q11.2-q12, 17q23, and 15q11-13. Regions that showed the significant losses included 9q34, 4p16, 1p36.1, and 11q22. Fluorescence in situ hybridization analysis demonstrated increases in C-MYC (8q24.12-q24.13) and a low level increases in ERBB2 ( formerly HER2/neu ) (17q11.2-q12) in cases showing gains by array comparative genomic hybridization in these regions. However, no tumor showed HER2/ neu immunopositivity. High-grade transformation in adenoid cystic carcinoma is a complex process that is reflected by several chromosomal alterations. Our findings implicate C-MYC amplification in this progression, although the role of HER2/neu is still unclear. Other candidate oncogenes, particularly on chromosome 17q23, warrant investigation in this rare tumor.

Progressive Genetic Alterations of Adenoid Cystic Carcinoma With High-Grade Transformation

Abstract Context—Although genome-wide imbalances have been characterized in conventional adenoid cystic carcinoma, other than p53 mutational status, the molecular profile of adenoid cystic carcinoma with high-grade transformation has not been explored. Objective—To evaluate progressive genetic alterations in adenoid cystic carcinoma with high-grade transformation using array comparative genomic hybridization. Design—Five adenoid cystic carcinomas with high-grade transformation (4 primary tumors and 1 paired metastasis) were selected and characterized at the DNA level by array comparative genomic hybridization on formalin-fixed paraffin-embedded tissue. Select alterations were validated by fluorescence in situ hybridization. Results—Chromosomal gains were mostly confined to the areas of high-grade transformation while losses were seen only in the conventional areas. Chromosomal regions with significant gains included 8q24, 17q11.2-q12, 17q23, and 15q11-13. Regions that showed the significant losses include...

High Grade Transformation in Adenoid Cystic Carcinoma of the Parotid: Report of a Case with Cytologic, Histologic and Immunohistochemical Study

Adenoid cystic carcinoma (ACC) constitutes about 4% of salivary epithelial tumors and is the second common malignant epithelial salivary gland tumor involving both the major and minor salivary glands. High grade transformation in ACC is a recently recognized entity with only a few cases reported in literature. We report the first case of ACC with high grade transformation involving the parotid. A 54-year-old man with a history of right parotid painful swelling from 1.5 years presented with recent increase in size of the swelling and facial paresis of 2 months duration. The locally invasive salivary neoplasm was composed predominantly of an undifferentiated carcinoma with foci of conventional ACC occupying less than 10% of tumor area. Immunohistochemical study of the undifferentiated component as compared to conventional ACC showed greater over-expression of p53 and Ki-67. Her-2/Neu was negative in both components. Recognition of occasional clusters of basaloid cells and hyaline globules in association with larger poorly differentiated malignant cell population in aspiration smears can help in cytological diagnosis. The acquisition of high proliferation index and over-expression of p53 may be the probable factors involved in the pathogenesis of high grade transformation in a conventional ACC.

Adenoid Cystic Carcinoma With High-grade Transformation

High-grade transformation of adenoid cystic carcinoma (ACC) (previously referred to as dedifferentiation) is a rare phenomenon that does not fit into the traditional ACC grading schemes. The importance and minimal criteria for distinction from solid (grade III) ACC are not well established. We report 11 new cases and review the literature to further define the profile of this tumor. The median age was 61 years (range: 32 to 72 y) with a male predominance (male to female ratio of 1.75:1). The most commonly involved sites were sinonasal (4/11) and submandibular (4/11). Lymph nodes were pathologically positive in 4/7 (57.1%) cases. Distant metastases to the lung (n=2) and soft tissue of the shoulder (n=1) were observed. Five of 9 patients (55.6%) died, all within 5 years with a median overall survival of 12 months. Histologically, ACC with high-grade transformation was distinguished from conventional ACC by nuclear enlargement and irregularity, higher mitotic counts, and the loss of the biphasic ductal-myoepithelial differentiation. Useful supportive criteria were prominent comedonecrosis and fibrocellular desmoplasia. The most common morphologies for the high-grade component were poorly differentiated cribriform adenocarcinoma and solid undifferentiated carcinoma. Micropapillary and squamoid patterns were occasionally present. Ki-67 and p53 labeling indices were elevated in the high-grade components, though c-kit and cyclin-D1 were not. ACC-high-grade transformation is a highly aggressive salivary gland tumor with a variety of histologic patterns. The high propensity for lymph node metastases suggests a role for neck dissection in patients with this rare tumor.

Solid Variant of Mammary Adenoid Cystic Carcinoma With Basaloid Features

Adenoid cystic carcinoma of the breast is a rare neoplasm that represents <1% of breast carcinomas. The tumors are histologically indistinguishable from examples in other sites, and they have a generally favorable prognosis. Several studies have investigated the possible correlation between histologic grade in adenoid cystic carcinoma (largely determined by cytology and growth pattern) and prognosis. Some earlier reports concluded that a solid variant of mammary adenoid cystic carcinoma had a more aggressive clinical course, but others did not confirm this impression. This report describes nine patients with a solid variant of mammary adenoid cystic carcinoma that has a striking basaloid appearance. All were women ranging in age from 37 to 83 years. A solitary mass was evident in all patients. Tumor size was 1.1-15 cm (mean 3.7 cm). The tumors exhibited a predominantly solid architecture comprised of basaloid appearing cells with moderate to marked nuclear atypia. Five tumors had >5 mitotic figures per 10 high power microscopic fields. Intercalated ducts were found in all tumors, being well formed in six and poorly formed in three. Immunohistochemical stains for cytokeratins, basement membranes, and vimentin were consistently positive. Surgery was performed in all cases consisting of excision in seven and mastectomy in two. Axillary lymph node metastases were found in two of six axillary dissections and four had negative lymph nodes. The lymph nodes were not examined in three patients. Follow-up information was available for seven patients. Six women had no evidence of disease after follow-up of 2-88 months (mean 32 months), one patient died of unknown causes, and one patient was lost to follow-up. It is concluded that the solid variant of mammary carcinoma with basaloid features is a histologically distinct tumor that is capable of axillary metastases. Long-term follow-up of a larger series of cases will be needed to determine whether the prognosis of these patients differs significantly from that of women with conventional adenoid cystic carcinoma. Presently, these patients are candidates for axillary staging by sentinel lymph node mapping or low axillary dissection if there is no clinical evidence of axillary metastases. Systemic adjuvant treatment would be prudent when axillary nodal metastases are present. Breast-conserving surgery with radiation is an option if negative margins can be achieved because this appears to be a unicentric form of carcinoma.