Signet‐ring cell change in adenoid cystic carcinoma: a clinicopathological and immunohistochemical study of four cases

Altemani, Albina; Costa, Ana Flávia; Montalli, Victor Ângelo Martins; Mosqueda‐Taylor, Adalberto; Almeida, Oslei Paes de; León, Jorge Esquiche; Hermsen, Mario

doi:10.1111/j.1365-2559.2013.04352.x

Cited by 9 publications

(4 citation statements)

References 40 publications

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“…15 PDC cases carried more complex genotypes, and in addition, they showed a more adverse clinical behavior. This finding supports the idea that classical ACC can undergo transformation into adenocarcinomas with variable degrees of differentiation, or even to other histological types, 41 which are not always high-grade, contributing to the controversy related to this phenomenon.…”

Section: Discussionsupporting

confidence: 84%

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

Costa

Altemani

García‐Inclán

et al. 2014

Laboratory Investigation

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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.

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Section: Discussionsupporting

confidence: 84%

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

Costa

Altemani

García‐Inclán

et al. 2014

Laboratory Investigation

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“…As we have found that inflammation appears to be responsible for an increase Myb expression during early events of CRC, for example, ACF and adenoma formation (Pereira et al , in press) prior to detectable mutated Myb regulatory sequences we decided to activate Myb in the initiation phase of CRC. MybER mice were treated with tamoxifen over a period of 8 weeks, six of which also employed weekly colon carcinogen azoxymethane (AOM) injections 26 ( Figure 3d ). Hence, MybER was activated for 2 weeks prior to AOM-treatment to allow the expansion of the ISC pool.…”

Section: Resultsmentioning

confidence: 99%

“…MybER transgenic mice were backcrossed onto a C57/BL6 background and experiments were conducted between generations 2–8 and used to generate compound p27 ± :MybER 53 and Apc min/+ :MybER 54 mice approved by the PMCC Animal Ethic Committee. Mice were fed Tamoxifen-chow (1 g Kg −1 ) for 2 weeks prior to the start of AOM intraperitoeal injections (10 mg Kg −1 body weight) once weekly over 6 consecutive weeks 26 during which mice were provided with tamoxifen.…”

Section: Methodsmentioning

confidence: 99%

Intestinal-specific activatable Myb initiates colon tumorigenesis in mice

et al. 2015

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Transcription factor Myb is overexpressed in most colorectal cancers (CRC). Patients with CRC expressing the highest Myb are more likely to relapse. We previously showed that mono-allelic loss of Myb in an Adenomatous polyposis coli (APC)-driven CRC mouse model (Apc Min/+ ) significantly improves survival. Here we directly investigated the association of Myb with poor prognosis and how Myb co-operates with tumor suppressor genes (TSGs) (Apc) and cell cycle regulator, p27. Here we generated the first intestinalspecific, inducible transgenic model; a MybER transgene encoding a tamoxifen-inducible fusion protein between Myb and the estrogen receptor-α ligand-binding domain driven by the intestinal-specific promoter, Gpa33. This was to mimic human CRC with constitutive Myb activity in a highly tractable mouse model. We confirmed that the transgene was faithfully expressed and inducible in intestinal stem cells (ISCs) before embarking on carcinogenesis studies. Activation of the MybER did not change colon homeostasis unless one p27 allele was lost. We then established that MybER activation during CRC initiation using a pro-carcinogen treatment, azoxymethane (AOM), augmented most measured aspects of ISC gene expression and function and accelerated tumorigenesis in mice. CRC-associated symptoms of patients including intestinal bleeding and anaemia were faithfully mimicked in AOM-treated MybER transgenic mice and implicated hypoxia and vessel leakage identifying an additional pathogenic role for Myb. Collectively, the results suggest that Myb expands the ISC pool within which CRC is initiated while co-operating with TSG loss. Myb further exacerbates CRC pathology partly explaining why high MYB is a predictor of worse patient outcome.Oncogene ( INTRODUCTIONAberrant activation of the WNT pathway (Adenomatous polyposis coli (APC) or β-catenin mutation) is the pre-eminent early event in colorectal cancers (CRC). Nevertheless, parallel activation of other oncogenes including MYB occurs commonly and is reasonably thought to participate in CRC.1 Furthermore, Myb and β-catenin cooperate to regulate the CRC genes MYC and PTGS2 (COX2) 2 along with the intestinal stem cell (ISC) gene, LGR5.3 Elevated MYB transcripts are a common feature of CRC 2,4,5 and high Myb protein is a poor-prognosis indicator. 6 Others have identified MYB and WNT-target gene, AXIN2 as among nine essential and differentially expressed genes in colon cancer. 7 However, although MYB is on occasion amplified in CRC it is rarely (if ever) found to have mutations in coding regions but rather in transcriptional regulatory regions.1 Thus, it remains unclear how MYB specifically participates in colorectal carcinogenesis.The intestine is a rapidly self-renewing tissue maintained by ISCs. The colonic epithelium is composed of the absorptive and the secretory lineages continuously renewed by rapidly cycling intestinal progenitor cells (IPC) generated from ISC.8 ISC are targets for transformation.9 Two kinds of ISCs have been proposed; crypt basal cells (CBC) 10 and ...

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“…Subsequent to the description of SRCA, other primary salivary tumor types such as salivary duct carcinoma [3] and adenoid cystic carcinoma [4] have been described with signet ring cell components. Additionally, the recently described mammary analog secretory carcinoma (MASC) may show a mucin rich vacuolated appearance resembling SRCA [5].…”

Section: Introductionmentioning

confidence: 99%

Secretory Myoepithelial Carcinoma: A Histologic and Molecular Survey and a Proposed Nomenclature for Mucin Producing Signet Ring Tumors

Bastaki

Purgina

Đačić

et al. 2014

Head and Neck Pathol

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Signet ring cell (mucin producing) adenocarcinoma is a rare low grade salivary gland malignancy. While currently designated as an adenocarcinoma, myoepithelial differentiation has been implied in previously reported cases. We herein perform a survey of our cases of signet ring cell adenocarcinoma and review the literature in order to refine categorization of this rare tumor. Five cases were retrieved. One was reclassified as a mammary analogue secretory carcinoma, leaving four that fulfilled the criteria for signet ring cell adenocarcinoma: the presence of prominent signet ring or vacuolated cells arranged in islands, interconnecting strands, cords or sheets in a myxoid or hyaline stroma, or pools of mucin. An extensive panel of histochemical and immunohistochemical stains and fluorescence in situ hybridization (FISH) (modeled after common phenotypes and molecular alterations seen in signet ring and myoepithelial tumors at other sites) was performed. The male-to-female ratio was 3:1. The mean age was 56 years (range 18-81). Sites involved included buccal mucosa (2), soft palate (1) and deep parotid (1). Perineural and angiolymphatic invasion were present in three and two cases respectively. One patient was lost to follow up and the remainder were alive and without disease at time of last follow up (mean 38 months). All cases showed mucicarmine positive vacuolated/signet ring cells embedded in a myxoid stroma. Three cases showed at least focal p63 staining and two cases showed positivity for calponin. Membranous E-cadherin was retained in all cases. FISH was negative for ETV6, EWSR1, and ALK1 rearrangements in all four cases. Based on the current series and the previously reported cases, it is evident that signet ring adenocarcinomas have a dual secretory and myoepithelial phenotype and thus as a whole more appropriately designated as 'secretory myoepithelial carcinoma.' They behave in a fairly indolent fashion and do not share the major molecular alterations seen in other signet ring and myoepithelial tumor types.

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Signet‐ring cell change in adenoid cystic carcinoma: a clinicopathological and immunohistochemical study of four cases

Cited by 9 publications

References 40 publications

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

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

Intestinal-specific activatable Myb initiates colon tumorigenesis in mice

Secretory Myoepithelial Carcinoma: A Histologic and Molecular Survey and a Proposed Nomenclature for Mucin Producing Signet Ring Tumors

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