RESUMEN
BACKGROUND: Acinic cell carcinoma (AciCC) of the breast is a rare subtype of breast cancer. It was considered a low-grade triple-negative breast cancer (TNBC) with the potential to progress or transform into a high-grade lesion because of the molecular similarities with conventional aggressive TNBC in several genetic studies. Microscopically, the coexistence of classical low-grade and high-grade triple-negative components in breast AciCC is not uncommon. However, there is a scarcity of research on the comparative histopathological and genetic aspects of both components. CASE PRESENTATION: A 34-year-old woman with a nontender mass in the upper outer quadrant of the left breast was initially diagnosed with a malignant small round cell tumor (undifferentiated or poorly differentiated carcinoma) based on a preoperative biopsy, which was later identified as breast AciCC with a high-grade solid component. Left breast-conserving surgery with sentinel lymph node biopsy was performed. Microscopically, the breast AciCC consisted of a classical acinic component and a high-grade component. The latter demonstrated a solid sheet-like pattern characterized by large, round, pleomorphic or vesicular nuclei, prominent nucleoli, and frequent mitotic activities. Classical acinic architectures focally merged together to form solid nests and transited into high-grade areas. Remarkably, in the high-grade lesion, conventional immunochemical markers for breast AciCC, such as α1-antitrypsin (AAT), Lysozyme (LYS), Epithelial membrane antigen (EMA), S100 protein (S100), and cytokeratin (CK) were negative, whereas cell cycle protein D1 (cyclin D1) and vimentin showed diffuse expression. Nextgeneration sequencing (NGS) revealed that 43.5% of variants were identical in both components. Furthermore, PAK5 mutation; copy number (CN) loss of CDH1, CHEK1, and MLH1; and CN gains of CDK6, HGF, and FOXP1 were identified in the high-grade lesion. The patient was treated with eight cycles of adjuvant chemotherapy (epirubicin combined with cyclophosphamide) and radiotherapy after surgery, and she is currently alive for 43 months with no metastases or recurrences. CONCLUSIONS: This case demonstrates a comparative analysis of the histopathological and genetic characteristics of classical low-grade and high-grade components of AciCC within the same breast. This information may serve as a morphological and molecular basis for further investigation into the molecular mechanisms underlying high-grade lesions in breast AciCC.
Asunto(s)
Neoplasias de la Mama , Carcinoma de Células Acinares , Humanos , Femenino , Adulto , Carcinoma de Células Acinares/patología , Carcinoma de Células Acinares/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Clasificación del Tumor , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/terapia , Neoplasias de la Mama Triple Negativas/química , Mastectomía SegmentariaRESUMEN
OBJECTIVE: The purpose of this work was to evaluate c-MYC gene amplification in the substrate of prostate acinar adenocarcinoma at various Gleason scores and various stages of the disease, taking into account the morphological characteristics of the tumor. MATERIAL AND METHODS: The number of cases in the study was 82, including the control group - 12 cases. Morphological assessment included: determination of the total Gleason score, grading group, assessment of lymphovascular/perineural invasion, and architectural characteristics of the tumor. Gene amplification was assessed by FISH using the c-MYC (8q24)/SE8 probe. RESULTS: In all cases of the study group, amplification of the c-MYC gene was detected in the tumor, with a significant difference from the control group (p<0.05). When assessing cases with 4-6 fold copies of the gene, significant differences were established between patients with stages II and III of the disease and stage IV (10.0 and 13.5 versus 30.0) (p<0.05). Cluster amplification of the c-MYC gene was detected with equal frequency in groups of patients with stages III and IV of the disease, while in stage II of the disease, the event almost did not occur (p<0.05). A significant increase in the level of c-MYC gene amplification was found in groups with advanced stages of the disease (p<0.02). Non-cluster amplification significantly distinguishes T4M0 and T4M1 stage patients from the rest with a significant increase in the score (p<0.05). In the metastatic stage of the disease, there was an increase c-MYC gene amplification compared to the non-metastatic stage (p<0.02). The copy number of the c-MYC gene was significantly higher in cases with perineural and lymphovascular invasion, as well as in cases of cribriform tumor organization (p<0.05). CONCLUSION: Amplification of the c-MYC gene in prostate tumor cells is associated with advanced stages of the disease (T4M0 and T4M1) with an increase in the copy number of the gene during the metastatic stage of the process. It was found that increased amplification of the c-MYC gene distinguishes groups of patients whose tumors exhibit perineural and lymphovascular invasion, as well as a cribriform pattern of tumor organization.
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Amplificación de Genes , Neoplasias de la Próstata , Proteínas Proto-Oncogénicas c-myc , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas c-myc/genética , Persona de Mediana Edad , Anciano , Genes myc/genética , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patologíaRESUMEN
A 73-year-old Japanese man with a history of distal biliary cancer treated by pancreatoduodenectomy developed pancreatic acinar cell carcinoma (PACC) treated by remnant pancreatectomy and adjuvant chemotherapy. Thirteen months after surgery, multiple liver metastases developed and FOLFOX chemotherapy was initiated. Based on the PACC diagnosis and a positive family history for breast and ovarian cancer genetic testing was performed which revealed a pathogenic germline BRCA2 variant (c.8629G > T, p.Glu2877Ter). Olaparib therapy was initiated and the metastases responded well (partial response). PACC is a BRCA2-associated cancer which may respond well to PARP inhibitors.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Proteína BRCA2 , Carcinoma de Células Acinares , Mutación de Línea Germinal , Neoplasias Pancreáticas , Ftalazinas , Piperazinas , Humanos , Piperazinas/uso terapéutico , Anciano , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Masculino , Ftalazinas/uso terapéutico , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/tratamiento farmacológico , Carcinoma de Células Acinares/patología , Proteína BRCA2/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Organoplatinos/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Leucovorina/uso terapéutico , Fluorouracilo/uso terapéutico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundarioRESUMEN
Acinic cell carcinoma of the salivary gland (AciCC) is a low-grade carcinoma characterized by the overexpression of the transcription factor nuclear receptor subfamily 4 group A member 3 (NR4A3). AciCC has been the subject of a few molecular research projects. This study delves into AciCC's molecular landscape to identify additional alterations and explore their clinical implications. RNA sequencing and immunohistochemical staining for markers NR4A3/NR4A2, DOG-1, S100, and mammaglobin were utilized on 41 AciCCs and 11 secretory carcinoma (SC) samples. NR4A3 was evident in 35 AciCCs, while the residual 6 were NR4A3-negative and NR4A2-positive; SC samples were consistently NR4A3-negative. A novel fusion, PON3 exon 1- LCN1 exon 5, was detected in 9/41 (21.9%) AciCCs, exhibiting a classical histologic pattern with serous cell components growing in solid sheets alongside the intercalated duct-like component. Clinical follow-up of 39 patients over a median of 59 months revealed diverse prognostic outcomes: 34 patients exhibited no disease evidence, whereas the remaining 5 experienced poorer prognosis, involving local recurrence, lymph node, and distant metastasis, and disease-associated death, 4 of which harbored the PON3::LCN1 fusion. In addition, the HTN3::MSANTD3 fusion was recurrently identified in 7/41 AciCC cases. SC patients lacked both fusions. Immunohistochemistry uncovered differential expression of DOG-1, S100, and mammaglobin across samples, providing nuanced insights into their roles in AciCC. This study accentuates PON3::LCN1 and HTN3::MSANTD3 fusions as recurrent molecular events in AciCC, offering potential diagnostic and prognostic utility and propelling further research into targeted therapeutic strategies.
Asunto(s)
Biomarcadores de Tumor , Carcinoma de Células Acinares , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares , Neoplasias de las Glándulas Salivales , Humanos , Masculino , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Femenino , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/mortalidad , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/química , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Adulto , Anciano , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/análisis , Receptores de Esteroides/genética , Receptores de Esteroides/metabolismo , Receptores de Hormona Tiroidea/genética , Receptores de Hormona Tiroidea/análisis , Receptores de Hormona Tiroidea/metabolismo , Adulto Joven , Fusión Génica , Anciano de 80 o más Años , Proteínas de Unión al ADN/genética , Proteínas de Fusión Oncogénica/genética , InmunohistoquímicaAsunto(s)
Carcinoma de Células Acinares , Neoplasias de la Parótida , Humanos , Neoplasias de la Parótida/patología , Neoplasias de la Parótida/genética , Carcinoma de Células Acinares/patología , Carcinoma de Células Acinares/genética , Factores de Transcripción/genética , Masculino , Proteínas Activadoras de GTPasa/genética , Femenino , Glándula Parótida/patología , Proteínas de Fusión Oncogénica/genética , Persona de Mediana EdadRESUMEN
Ductal adenocarcinoma of the prostate (DAP) is an uncommon variant of prostate cancer associated with aggressive disease and poor outcome. It presents most frequently as a mixed tumor combined with acinar adenocarcinoma. Although the histopathological features of DAP are well known, its genomic characteristics are still evolving, prompting the suggestion that all DAP would benefit from molecular analysis with the purpose of improving tumor recognition, genetic classification, and, ultimately, personalized therapy. Herein, we report a case of DAP with novel genetic alterations (BCOR P1153S, ERG M219I, KDR A750E, POLE S1896P, and RAD21 T461del).
Asunto(s)
Carcinoma de Células Acinares , Carcinoma Ductal , Neoplasias de la Próstata , Masculino , Humanos , Próstata/patología , Carcinoma Ductal/genética , Carcinoma Ductal/patología , Neoplasias de la Próstata/terapia , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
INTRODUCTION: Pancreatic acinar cell carcinomas are rare malignant neoplasms. High-quality evidence about the best treatment strategy is lacking. We present the case of a 52-year-old male with a BRAFV600E -mutated PACC who experienced a complete remission after chemotherapy with BRAF-/MEK-inhibitors. CASE: The patient presented with upper abdomen pain, night sweat, and weight loss. CT scan showed a pancreatic tumor extending from the pancreas head to body. Histological workup identified an acinar cell carcinoma. As the tumor was inoperable, chemotherapy with FOFIRNIOX was initiated and initially showed a slight regression of disease. The regimen had to be discontinued due to severe side effects. Molecular analysis identified a BRAFV600E mutation, so the patient was started on BRAF- and MEK-inhibitors (dabrafenib/trametinib). After 16 months, CT scans showed a near complete remission with a markedly improved overall health. DISCUSSION: Studies suggest that up to one-fourth of PACCs carry a BRAF mutation and might therefore be susceptible to a BRAF-/MEK-inhibitor therapy. This offers a new therapeutic pathway to treat this rare but malignant neoplasm.
Asunto(s)
Carcinoma de Células Acinares , Neoplasias Pancreáticas , Humanos , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Acinares/tratamiento farmacológico , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/inducido químicamente , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Mutación , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Piridonas/farmacología , Pirimidinonas/farmacologíaRESUMEN
Pancreatic acinar cell carcinoma is a rare form (0.2-4.3%) of pancreatic neoplasm with unique clinical and molecular characteristics, which largely differ from pancreatic ductal adenocarcinoma. Pancreatic acinar cell carcinoma occurs more frequently in males and can occur in children. Serum lipase is elevated in 24-58% of patients with pancreatic acinar cell carcinoma. Pancreatic acinar cell carcinomas tend to be large at diagnosis (median tumour size: ~5 cm) and are frequently located in the pancreas head. Radiologically, pancreatic acinar cell carcinoma generally exhibits a solid appearance; however, necrosis, cystic changes and intratumoral haemorrhage can occur in larger lesions. Immunostaining is essential for the definitive diagnosis of pancreatic acinar cell carcinoma. Compared with pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma has a more favourable prognosis. Although radical surgery is recommended for patients with pancreatic acinar cell carcinoma who do not have distant metastases, the recurrence rate is high. The effectiveness of adjuvant therapy for pancreatic acinar cell carcinoma is unclear. The response to FOLFIRINOX is generally favourable, and some patients achieve a complete response. Pancreatic acinar cell carcinoma has a different genomic profile compared with pancreatic ductal adenocarcinoma. Although genomic analyses have shown that pancreatic acinar cell carcinoma rarely has KRAS, TP53 and CDKN2A mutations, it has a higher prevalence of homologous recombination-related genes, including BRCA1/2 and ATM, than pancreatic ductal adenocarcinoma, suggesting high sensitivity to platinum-containing regimens and PARP inhibitors. Targeted therapies for genomic alternations are beneficial. Therefore, genetic testing is important for patients with pancreatic acinar cell carcinoma to choose the optimal therapeutic strategy.
Asunto(s)
Carcinoma de Células Acinares , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Masculino , Niño , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/genética , Carcinoma de Células Acinares/diagnóstico , Carcinoma de Células Acinares/epidemiología , Carcinoma de Células Acinares/genética , Protocolos de Quimioterapia Combinada Antineoplásica , Proteína BRCA1 , Proteína BRCA2 , Carcinoma Ductal Pancreático/patologíaRESUMEN
Objective: To investigate the expression differences of LLGL2 between prostatic ductal adenocarcinoma (PDA) and prostatic acinar adenocarcinoma, and its potential clinical significance. Methods: Eighteen patients diagnosed of PDA or prostatic acinar adenocarcinoma with PDA component by histopathology during January 2015 and December 2019 in the Beijing Hospital, China were retrospectively studied. The transcriptome analysis was conducted using the tissue of PDA and prostatic acinar adenocarcinoma. Differentially expressed genes and the differences in expression profiles were identified. Further, differentially expressed proteins were verified by immunohistochemistry. Results: The tissue from 8 of the 18 patients were used for transcriptome analysis, the results of which were compared with data from public databases. 129 differentially expressed genes were identified. 45 of them were upregulated while 84 were downregulated. The results of gene enrichment analysis and gene oncology (GO) analysis revealed that the differentially expressed genes were mostly enriched in the hypertrophic cardiomyopathy and interleukin-17 related pathways. GPAT2, LLGL2, MAMDC4, PCSK9 and SMIM6 were differentially expressed between PDA and prostatic acinar adenocarcinoma. Moreover, LLGL2 was more likely expressed in the cytoplasm (P=0.04) than the nucleus (P<0.01) in PDA, compared with prostatic acinar adenocarcinoma. Conclusions: The gene expression profiling indicates that PDA are very similar to prostatic acinar adenocarcinoma. Among the differentially expressed proteins screened and verified in this study, the expression of GPAT2, LLGL2, MAMDC4 and PCSK9 is increased in PDA, while that of SMIM6 is reduced in PDA. The expression of LLGL2 shows significantly different patterns between PDA and prostatic acinar carcinoma, and thus may help differentiate PDA from prostatic acinar adenocarcinoma in clinical practice.
Asunto(s)
Carcinoma de Células Acinares , Neoplasias de la Próstata , Masculino , Humanos , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Proproteína Convertasa 9 , Próstata/metabolismo , Próstata/patología , Estudios Retrospectivos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismoRESUMEN
PURPOSE: To determine the genetic predisposition underlying pancreatic acinar cell carcinoma (PACC) and characterize its genomic features. METHODS: Both somatic and germline analyses were performed using an Food and Drug Administration-authorized matched tumor/normal sequencing assay on a clinical cohort of 28,780 patients with cancer, 49 of whom were diagnosed with PACC. For a subset of PACCs, whole-genome sequencing (WGS; n = 12) and RNA sequencing (n = 6) were performed. RESULTS: Eighteen of 49 (36.7%) PACCs harbored germline pathogenic variants in homologous recombination (HR) and DNA damage response (DDR) genes, including BRCA1 (n = 1), BRCA2 (n = 12), PALB2 (n = 2), ATM (n = 2), and CHEK2 (n = 1). Thirty-one PACCs displayed pure, and 18 PACCs harbored mixed acinar cell histology. Fifteen of 31 (48%) pure PACCs harbored a germline pathogenic variant affecting HR-/DDR-related genes. BRCA2 germline pathogenic variants (11 of 31, 35%) were significantly more frequent in pure PACCs than in pancreatic adenocarcinoma (86 of 2,739, 3.1%; P < .001), high-grade serous ovarian carcinoma (67 of 1,318, 5.1%; P < .001), prostate cancer (116 of 3,401, 3.4%; P < .001), and breast cancer (79 of 3,196, 2.5%; P < .001). Genomic features of HR deficiency (HRD) were detected in 7 of 12 PACCs undergoing WGS, including 100% (n = 6) of PACCs with germline HR-related pathogenic mutations and 1 of 6 PACCs lacking known pathogenic alterations in HR-related genes. Exploratory analyses revealed that in PACCs, the repertoire of somatic driver genetic alterations and the load of neoantigens with high binding affinity varied according to the presence of germline pathogenic alterations affecting HR-/DDR-related genes and/or HRD. CONCLUSION: In a large pan-cancer cohort, PACC was identified as the cancer type with the highest prevalence of both BRCA2 germline pathogenic variants and genomic features of HRD, suggesting that PACC should be considered as part of the spectrum of BRCA-related malignancies.
Asunto(s)
Carcinoma de Células Acinares , Neoplasias Pancreáticas , Masculino , Humanos , Carcinoma de Células Acinares/genética , Neoplasias Pancreáticas/genética , Proteína BRCA2/genética , Proteína BRCA1/genética , Mutación de Línea Germinal , Predisposición Genética a la Enfermedad , Recombinación Homóloga , Genómica , Neoplasias PancreáticasRESUMEN
OBJECTIVES: As a rare tumor in pancreas, pancreatic acinar cell carcinoma (PACC) possesses a distinct molecular feature from pancreatic ductal carcinoma (PDAC). Though the diagnosis of PACC is often established based on cytology specimens, its cytologic diagnosis can be challenging. Furthermore, the correlation between PACC cytomorphology and its unique different molecular alterations have not been fully explored. METHODS: Cytology features were analyzed in 8 histologically proven PACC and cytohistological correlation was performed. Immunocytochemistry for trypsin, chymotrypsin, BCL10, synaptophysin, chromogranin A, INSM1, ß-catenin, and Ki-67 was assessed. Comprehensive molecular profiling and additional targetable treatment biomarker assessment were also performed. RESULTS: The cohort included 4 mixed acinar-neuroendocrine carcinomas, 3 pure PACCs, and 1 mixed acinar-ductal carcinoma. Immunophenotypical features are consistent with diagnoses of PACC or PACC with neuroendocrine features. Identified genetic alterations included somatic mutations of CTNNB1, TP53, MAP2K1, PTEN, RAC1, germline mutations of NBN and BRAC2, and gene fusion of CCDC6-RET. CONCLUSIONS: The current study is the first attempt to explore the correlation between the cytomorphology characteristics and molecular features of PACC and a few intriguing findings were observed. Further validation in larger cohorts is warranted.
Asunto(s)
Carcinoma de Células Acinares , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Páncreas/patología , Carcinoma Ductal Pancreático/patología , Proteínas Represoras , Neoplasias PancreáticasRESUMEN
PURPOSE: Pure pancreatic acinar cell carcinomas (PACC) are rare malignancies with no established treatment. PACC demonstrates significant genetic intertumoral heterogeneity with multiple pathways involved, suggesting using targeted cancer therapeutics to treat this disease. We aggregated one of the largest datasets of pure PACC to examine the genomic variability and explore patient-specific therapeutic targets. EXPERIMENTAL DESIGN: PACC specimens (n = 51) underwent next-generation sequencing of DNA (n = 29) or whole exome (n = 22) and RNA (whole transcriptome, n = 29) at a commercial laboratory. We performed comparative analyses of a genomic cohort of pancreatic ductal adenocarcinomas (PDAC; n = 4,205). In parallel, we conducted a retrospective review of patients with PACC treated at Huntsman Cancer Institute (HCI). RESULTS: The real-world dataset included samples from 51 patients with PACC. We found key molecular differences between pure PACC and PDAC, highlighting the unique characteristics of pure PACC. Major differences in PACC include lower MAPK signaling and less stromal cell abundance compared with PDAC. Pure PACC showed genomic loss-of-heterozygosity to largely coincide with mutations in BRCA1, BRCA2, and PALB2. Of the 7 patients treated at HCI, one had a tumor that harbored a BRAF-V600E mutation. Leveraging precision oncology, this patient is being treated with encorafenib plus binimetinib, achieving an exceptionally durable and ongoing complete response of more than 3 years. CONCLUSIONS: There are major differences between PACC and PDAC, including downregulation of the MAPK signaling pathway, and less stromal cell abundance. In addition, genomic characterization of pure PACC revealed frequent targetable alterations, which can guide patient treatment.
Asunto(s)
Carcinoma de Células Acinares , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Medicina de Precisión , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Mutación , GenómicaRESUMEN
Acinic cell carcinoma (AciCC) is a tumor that is recognized in both the breast and salivary glands. Recently, the recurrent genomic rearrangement, t(4;9)(q13;q31) was identified in salivary AciCC that results in constitutive upregulation of the nuclear transcription factor NR4A3, which can be detected by immunohistochemistry. In this study, we sought to evaluate NR4A3 expression in breast AciCC using immunohistochemistry. Strong and diffuse nuclear staining was considered a positive result. Sixteen AciCCs were studied, including 8 pure AciCCs and 8 AciCCs admixed with other types (invasive carcinoma of no special type in 5 cases and metaplastic carcinoma in 3 cases). All 16 AciCCs showed negative results for NR4A3 expression. Four cases with available material were evaluated for rearrangements of the NR4A3 gene by fluorescence in situ hybridization and no rearrangements were observed. Whole-genome sequencing of 1 AciCC revealed a TP53 splice-site mutation, high levels of genomic instability, and genomic features of homologous recombination DNA repair defects; a structural variant analysis of this case did not reveal the presence of a t(4;9) rearrangement. We conclude that breast AciCCs consistently lack NR4A3 rearrangement or overexpression, unlike most of the salivary AciCCs, and that consistent with previous results, breast AciCCs are associated with genomic alterations more similar to those seen in triple-negative breast carcinomas than salivary gland AciCCs. These results suggest that unlike other salivary gland-like tumors that occur in the breast, the molecular underpinnings of the salivary gland and breast AciCCs are different and that the salivary gland and breast AciCCs likely represent distinct entities.
Asunto(s)
Carcinoma de Células Acinares , Carcinoma , Receptores de Esteroides , Neoplasias de las Glándulas Salivales , Humanos , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Hibridación Fluorescente in Situ , Neoplasias de las Glándulas Salivales/patología , Carcinoma/genética , Reordenamiento Génico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Proteínas de Unión al ADN/genética , Receptores de Esteroides/genética , Receptores de Hormona Tiroidea/genéticaRESUMEN
Acinic cell carcinoma (AciCC) is a rare salivary gland cancer with excellent prognosis in most cases. However, a subset of patients will develop distant metastasis and die of disease. Recently, a 2-tiered grading scheme in AciCC was proposed to recognize patients at risk of poor outcome. We performed a genetic analysis of AciCC to explore the underlying molecular correlates of the tumor grade and examined programmed death ligand 1 (PD-L1) expression to identify potential candidates for immunotherapy. A retrospective cohort of 55 patients included 34 high-grade (HG) and 21 low-grade AciCCs. Forty-three cases were subjected to targeted exome sequencing by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets. PD-L1 immunohistochemistry was performed in 33 cases. Tumor mutation burden was low with a median of 1 and 2 mutations in low-grade and HG AciCCs, respectively. CDKN2A/B was the most frequently altered gene, and loss-of-function mutations were found only in HG but not in low-grade AciCCs (18/31 [58.1%] vs 0/12 [0%], P < .001). CDKN2A/B alterations were significantly associated with distant metastasis, which occurred in 16/18 (88.9%) CDKN2A/B mutants versus 11/25 (44%) wild-type cases (P = .004, Fisher exact test). Sequential profiling of multiple temporally distant samples from the same patient demonstrated intratumor heterogeneity, including the detection of CDKN2A/B deletion in the second, in HG metastasis only. ATM and PTEN mutations were detected in 6/31 (19.4%) and 5/31 (16.1%); ARID2, BIRC3, and FBXW7 mutations each in 4/31 (12.9%); and TP53, MTAP, and FAT1 each in 3/31 (9.7%) HG AciCC. PD-L1-positive labeling was more common in HG AciCC (9/17, 52.9% vs 3/16, 18.9%, P = .071). CDKN2A/B mutations in AciCC represent a molecular marker of HG histology and disease progression, providing a rationale for further studies to determine their prognostic and therapeutic significance in this salivary gland cancer. AciCC with ATM mutations may be amenable to targeted therapy. Immunotherapy can be considered to be a treatment option for a subset of patients with AciCC.
Asunto(s)
Carcinoma de Células Acinares , Neoplasias de las Glándulas Salivales , Humanos , Antígeno B7-H1 , Biomarcadores de Tumor/análisis , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/diagnóstico , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Estudios Retrospectivos , Neoplasias de las Glándulas Salivales/patologíaRESUMEN
Acinar cell carcinoma (ACC) of the pancreas is a malignant tumor of the exocrine cell lineage with a poor prognosis. Due to its rare incidence and technical difficulties, few authentic human cell lines are currently available, hampering detailed investigations of ACC. Therefore, we applied the organoid culture technique to various types of specimens, such as bile, biopsy, and resected tumor, obtained from a single ACC patient. Despite the initial propagation, none of these organoids achieved long-term proliferation or tolerated cryopreservation, confirming the challenging nature of establishing ACC cell lines. Nevertheless, the biopsy-derived early passage organoid developed subcutaneous tumors in immunodeficient mice. The xenograft tumor histologically resembled the original tumor and gave rise to infinitely propagating organoids with solid features and high levels of trypsin secretion. Moreover, the organoid stained positive for carboxylic ester hydrolase, a specific ACC marker, but negative for the duct cell marker CD133 and the endocrine lineage marker synaptophysin. Hence, we concluded the derivation of a novel ACC cell line of the pure exocrine lineage, designated HS-1. Genomic analysis revealed extensive copy number alterations and mutations in EP400 in the original tumor, which were enriched in primary organoids. HS-1 displayed homozygous deletion of CDKN2A, which might underlie xenograft formation from organoids. Although resistant to standard cytotoxic agents, the cell line was highly sensitive to the proteasome inhibitor bortezomib, as revealed by an in vitro drug screen and in vivo validation. In summary, we document a novel ACC cell line, which could be useful for ACC studies in the future.
Asunto(s)
Carcinoma de Células Acinares , Neoplasias Pancreáticas , Humanos , Ratones , Animales , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/metabolismo , Carcinoma de Células Acinares/patología , Homocigoto , Eliminación de Secuencia , Neoplasias Pancreáticas/patología , Organoides/metabolismo , Línea Celular , Neoplasias PancreáticasRESUMEN
Acinic cell carcinoma (AciCC) is a common salivary gland malignancy, typically composed of neoplastic acinic cells with zymogen granules. The vast majority of cases are driven by a t(4;9)(q13;q31) leading to enhancer hijacking and upregulation of the NR4A3 gene. However, a minority of cases do not display NR4A3 overexpression on immunohistochemical examination and are negative for the rearrangement involving the NR4A3 gene when tested by FISH. Such cases overexpress NR4A2, and the protein product is detectable by immunohistochemistry. In this study, we aimed to assess the utility of NR4A2 and NR4A3 immunohistochemistry in the differential diagnosis of salivary gland tumors. Eighty-five cases of classic low-grade ACiCC, as well as 36 cases with high-grade transformation (HGT) and 7 high-grade AciCC cases were included in the analysis. NR4A3 was at least focally positive in 105/128 (82%) cases. Out of the 23 cases that were immunohistochemically negative for NR4A3, 6 displayed nuclear immunopositivity with the NR4A2 antibody. The NR4A3 rearrangement was confirmed by FISH in 38/52 (73%) cases. In addition, this is the first report of an NR4A2 rearrangement being detected by FISH in 2 AciCC cases that were negative for the NR4A3 rearrangement. Our analysis confirms that the majority of AciCC, including high-grade cases and cases with HGT, are immunopositive for NR4A3, and suggests that NR4A3 immunohistochemistry is a powerful tool in the differential diagnosis of salivary gland tumors. However, its utility is limited in sub-optimally fixed samples which often display weaker and focal positivity. Our study also indicates that in a minority of cases, AciCC might be negative for NR4A3 immunostaining, because the pathogenic genetic event in these cases is instead a rearrangement involving the NR4A2 gene.
Asunto(s)
Carcinoma de Células Acinares , Receptores de Esteroides , Neoplasias de las Glándulas Salivales , Humanos , Carcinoma de Células Acinares/diagnóstico , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/metabolismo , Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/diagnóstico , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Núcleo Celular/patología , Inmunohistoquímica , Biomarcadores de Tumor/análisis , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Proteínas de Unión al ADN/metabolismo , Receptores de Esteroides/genética , Receptores de Hormona Tiroidea/metabolismoRESUMEN
Acinic cell carcinoma of the breast is an extremely rare tumor. To the best of our knowledge, only one case is reported to have bilateral tumors and had both BRCA1 and TP53 mutation. Herein, we report another case of acinic cell carcinoma of the breast in a 29-years-old female carrying germline BRCA1 and TP53 mutation, and the tumor showed a complex combination of histological features which had not only the reported common features such as diffuse infiltrative small acinar or glandular structures mixed with solid nests, but also the uncommon widespread clear cells, high grade tumor cells. The immunohistochemical profile of the tumor cells was strongly positive for lysozyme and triple negative for ER, PR, HER2. Although she had bilateral high grade breast cancers, this patient refused postoperative adjuvant therapy this time and has been doing well in the past 12 months. As a rare form of triple-negative breast cancer with a relatively not so bad prognosis, more reports are needed to understand its biological characteristics.
Asunto(s)
Neoplasias de la Mama , Carcinoma de Células Acinares , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Adulto , Carcinoma de Células Acinares/diagnóstico , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Mama/patología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama Triple Negativas/diagnóstico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Mutación , Citoplasma , Proteína BRCA1/genéticaRESUMEN
BACKGROUND: Secretory carcinoma (SC) is a well-established salivary gland malignancy that has earned its popularity for its unique clinicopathological behavior. Although it is an indolent malignancy, few of them have been reported with high grade transformation making it mandatory to differentiate it from its prime histological mimicker, acinic cell carcinoma (AciCC). Recently, many studies have been directed toward validating the sensitivity and specificity of pan-TRK IHC for confirming ETV6::NTRK3 gene fusion in SCs involving salivary gland. AIM: The aim of the present systematic review was to establish the diagnostic utility of pan-TRK immunostaining in histological differentiation of SC from AciCC. MATERIAL AND METHODS: An electronic search was carried out using MEDLINE by PubMed, Scopus, Google scholar, Trip, Cochrane library and EMBASE databases. Articles in which SC assessed with pan-TRK immunohistochemical expressions were included for systematic review and their staining pattern (cytoplasmic, nuclear and/or combined), sensitivity, specificity, positive as well as negative predictive were gathered. Risk of bias was analyzed for each study using QUADAS-2 tool. RESULTS: Thirteen eligible articles were included for the quantitative analysis, which revealed positive immunostaining of pan-TRK by nearly all the ETV6::NTRK3 fusion prevalent SCs alongside negative expression in almost all the cases of AciCC with 100% of sensitivity as well as specificity. CONCLUSION: The evidence from the included studies supports that pan-TRK immunostaining could be used as a reliable preliminary screening tool for discerning SC from AciCC. PROSPERO No: CRD42022308913.
Asunto(s)
Neoplasias de la Mama , Carcinoma de Células Acinares , Carcinoma , Neoplasias de las Glándulas Salivales , Humanos , Femenino , Inmunohistoquímica , Carcinoma de Células Acinares/diagnóstico , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/metabolismo , Biomarcadores de Tumor/metabolismo , Glándulas Salivales/metabolismo , Neoplasias de la Mama/patología , Neoplasias de las Glándulas Salivales/patología , Carcinoma/genéticaRESUMEN
BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a rare tumor. Up to 45% of PACCs have alterations in the DNA damage repair pathway and 23% harbor rearrangements in the BRAF or RAF1 genes. We present a PACC case with a germline BRCA2 likely pathogenic variant (LPV) to highlight the impact of genomic testing on treatment decisions and patient outcomes. In our larger case series, we provide clinic-based information on additional 10 PACC patients treated in our center. CASE SUMMARY: A 70-year-old male was diagnosed with advanced PACC. At presentation, he was cachectic with severe arthralgia despite prednisolone and a skin rash that was later confirmed to be panniculitis. He was treated with modified FOLFIRINOX (mFFX) with the knowledge of the germline BRCA2 LPV. Following 11 cycles of mFFX, a computed tomography (CT) scan demonstrated significant tumor response in the pancreatic primary and hepatic metastases, totaling 70% from baseline as per Response Evaluation Criteria in Solid Tumors. Resolution of the skin panniculitis was also noted. We identified two additional PACCs with druggable targets in our case series. Our data contribute to practical evidence for the value of germline and somatic profiling in the management of rare diseases like PACC. CONCLUSION: This patient and others in our larger case series highlight the importance of genomic testing in PACC with potential utility in personalized treatment.
Asunto(s)
Carcinoma de Células Acinares , Neoplasias Pancreáticas , Paniculitis , Masculino , Humanos , Anciano , Carcinoma de Células Acinares/tratamiento farmacológico , Carcinoma de Células Acinares/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Paniculitis/etiología , Células Germinativas/patología , Proteína BRCA2/genética , Neoplasias PancreáticasRESUMEN
Acinar cell carcinoma (ACC) is a rare pancreatic malignancy with distinctive clinical, molecular, and morphological features. The long-term survival of ACC patients is substantially superior to that of pancreatic adenocarcinoma patients. As there are no significant patient series about ACCs, our understanding of this illness is mainly based on case reports and limited patient series. Surgical resection is the treatment of choice for patients with the disease restricted to one organ; however, with recent breakthroughs in precision medicine, medicines targeting the one-of-a-kind molecular profile of ACC are on the horizon. There are no standard treatment protocols available for people in which a total surgical resection to cure the condition is not possible. As a result of shared genetic alterations, ACCs are chemosensitive to agents with activity against pancreatic adenocarcinomas and colorectal carcinomas. The role of neoadjuvant or adjuvant chemoradiotherapy has not been established. This article aims to do a comprehensive literature study and present the most recent information on acinar cell cancer.