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Wang CW, Liu TC, Lai PJ, Muzakky H, Wang YC, Yu MH, Wu CH, Chao TK. Ensemble transformer-based multiple instance learning to predict pathological subtypes and tumor mutational burden from histopathological whole slide images of endometrial and colorectal cancer. Med Image Anal 2025; 99:103372. [PMID: 39461079 DOI: 10.1016/j.media.2024.103372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 08/30/2024] [Accepted: 10/09/2024] [Indexed: 10/29/2024]
Abstract
In endometrial cancer (EC) and colorectal cancer (CRC), in addition to microsatellite instability, tumor mutational burden (TMB) has gradually gained attention as a genomic biomarker that can be used clinically to determine which patients may benefit from immune checkpoint inhibitors. High TMB is characterized by a large number of mutated genes, which encode aberrant tumor neoantigens, and implies a better response to immunotherapy. Hence, a part of EC and CRC patients associated with high TMB may have higher chances to receive immunotherapy. TMB measurement was mainly evaluated by whole-exome sequencing or next-generation sequencing, which was costly and difficult to be widely applied in all clinical cases. Therefore, an effective, efficient, low-cost and easily accessible tool is urgently needed to distinguish the TMB status of EC and CRC patients. In this study, we present a deep learning framework, namely Ensemble Transformer-based Multiple Instance Learning with Self-Supervised Learning Vision Transformer feature encoder (ETMIL-SSLViT), to predict pathological subtype and TMB status directly from the H&E stained whole slide images (WSIs) in EC and CRC patients, which is helpful for both pathological classification and cancer treatment planning. Our framework was evaluated on two different cancer cohorts, including an EC cohort with 918 histopathology WSIs from 529 patients and a CRC cohort with 1495 WSIs from 594 patients from The Cancer Genome Atlas. The experimental results show that the proposed methods achieved excellent performance and outperforming seven state-of-the-art (SOTA) methods in cancer subtype classification and TMB prediction on both cancer datasets. Fisher's exact test further validated that the associations between the predictions of the proposed models and the actual cancer subtype or TMB status are both extremely strong (p<0.001). These promising findings show the potential of our proposed methods to guide personalized treatment decisions by accurately predicting the EC and CRC subtype and the TMB status for effective immunotherapy planning for EC and CRC patients.
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Affiliation(s)
- Ching-Wei Wang
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, 10607, Taiwan
| | - Tzu-Chien Liu
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, 10607, Taiwan
| | - Po-Jen Lai
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, 10607, Taiwan
| | - Hikam Muzakky
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, 10607, Taiwan
| | - Yu-Chi Wang
- Department of Gynecology and Obstetrics, Tri-Service General Hospital, Taipei, 114202, Taiwan; Department of Gynecology and Obstetrics, National Defense Medical Center, Taipei, 11490, Taiwan
| | - Mu-Hsien Yu
- Department of Gynecology and Obstetrics, Tri-Service General Hospital, Taipei, 114202, Taiwan; Department of Gynecology and Obstetrics, National Defense Medical Center, Taipei, 11490, Taiwan
| | - Chia-Hua Wu
- Department of Pathology, Tri-Service General Hospital, Taipei, 114202, Taiwan
| | - Tai-Kuang Chao
- Department of Pathology, Tri-Service General Hospital, Taipei, 114202, Taiwan; Institute of Pathology and Parasitology, National Defense Medical Center, Taipei, 11490, Taiwan.
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Guo F, Lu R, Kong W, Anwar M, Feng Y. DNA mismatch repair system regulates the expression of PD-L1 through DNMTs in cervical cancer. Cancer Cell Int 2024; 24:25. [PMID: 38200495 PMCID: PMC10782574 DOI: 10.1186/s12935-024-03214-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 01/03/2024] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND Cervical cancer (CC) is a potential clinical application of PD-1/PD-L1 inhibitor. We aimed to study the mechanism of DNA mismatch repair (MMR) system regulating the expression of PD-L1 in CC through DNA methyltransferase (DNMTs). METHODS We collected pathological specimens from 118 cases of CC to analyze the relationship between PD-L1 expression and DNMTs in different MMR states. RNA interference (RNAi) technique was used to simulate the formation of CC cell line with MMR deficiency (dMMR) state, and subcutaneous tumor formation experiment was carried out in nude mice to verify the relationship between PD-L1 expression and DNMTs in MMR state. RESULTS The PD-L1 positive rate in 118 cases of CC was 58.47%, while the microsatellite instability (MSI) status accounted for 5.93%. There was a significant difference in the expression of PD-L1 between patients within the dMMR and MMR proficient (pMMR) groups (χ2 = 21.405, P < 0.001). Subcutaneous inoculation after infection of Siha cells led to successful tumorigenesis in nude mice, accompanied by a significant increase in the level of PD-L1 expression in the mouse tumors, while the expression level of MLH1 and MSH2 protein decreased significantly. We also found that PD-L1 expression was closely related to the expression of DNMTs. CONCLUSION PD-L1 is universal expressed on the surface of CC cells, dMMR status enhances the expression of PD-L1 on the surface of CC cells, dMMR states of CC are related to the demethylation status of the PD-L1 gene promoter region.
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Affiliation(s)
- Fan Guo
- Department of Medical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, No 789 Suzhou Road, Urumqi, China
- Postdoctoral Research Workstation of Tumor Hospital affiliated to Xinjiang Medical University, Urumqi, China
| | - Ruijiao Lu
- Department of Medical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, No 789 Suzhou Road, Urumqi, China
| | - Weina Kong
- Department of Medical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, No 789 Suzhou Road, Urumqi, China
| | - Miyessar Anwar
- Department of Medical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, No 789 Suzhou Road, Urumqi, China
| | - Yangchun Feng
- Department of Medical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, No 789 Suzhou Road, Urumqi, China.
- Postdoctoral Research Workstation of Tumor Hospital affiliated to Xinjiang Medical University, Urumqi, China.
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Sharma K, Sundling KE, Zhang R, Matkowskyj KA. Pathologic Features of Primary Colon, Rectal, and Anal Malignancies. Cancer Treat Res 2024; 192:233-263. [PMID: 39212924 DOI: 10.1007/978-3-031-61238-1_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
In USA, colorectal cancer is the third most commonly diagnosed cancer in men, second in women, as well as the third leading cause of cancer deaths (Siegel et al. in Cancer J Clin 73:1-112, 2023 [109]). Worldwide, colorectal cancer is the second leading cause of death and causes almost 916,000 deaths each year (Ferlay in Global cancer observatory: cancer today. International Agency for Research on Cancer, Lyon, 2020 [28]). Fortunately, due to the colon's surgical and endoscopic accessibility and functional redundancy, colorectal cancer is very treatable. Colonoscopic surveillance has the potential for not only providing tissue for the diagnosis of precancerous polyps and invasive carcinoma, but also preventing development of invasive carcinoma by the removal of precancerous lesions. This chapter discusses the clinical and pathologic features of the spectrum of epithelial, hematolymphoid, and mesenchymal malignant tumors of the colon, rectum, appendix, and anus.
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Affiliation(s)
- Kusum Sharma
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Kaitlin E Sundling
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
- Wisconsin State Laboratory of Hygiene, Madison, WI, USA
| | - Ranran Zhang
- Alberta Precision Laboratories, Grande Prairie Regional Hospital, Grande Prairie, Canada
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Kim S, Huh JW, Lee WY, Yun SH, Kim HC, Cho YB, Park Y, Shin JK. Prognostic Impact of Mucinous Adenocarcinoma in Stage II and III Colon Cancer. Dis Colon Rectum 2023; 66:1473-1480. [PMID: 37260257 DOI: 10.1097/dcr.0000000000002733] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
BACKGROUND Mucinous adenocarcinoma is a rare histologic feature of colorectal cancer and is characterized by oncologic features that are different from those of adenocarcinoma. However, there are conflicting views regarding the prognostic impact of mucinous adenocarcinoma on colon cancer. OBJECTIVE This study aimed to evaluate the prognostic impact of mucinous adenocarcinoma in stage II and III colon cancer. DESIGN This was a retrospective cohort study. SETTINGS This study was conducted between January 2010 and December 2015. Patients were divided into the mucinous adenocarcinoma and nonmucinous adenocarcinoma groups. Disease-free survival and overall survival were assessed using propensity score matching. PATIENTS Overall, 2532 patients who underwent radical surgery for stage II and III colon cancer were included in the study. MAIN OUTCOME MEASURES The main outcome measures were disease-free survival and overall survival. RESULTS The median follow-up duration was 86 months. The disease-free survival and overall survival were significantly lower in the mucinous adenocarcinoma group than in the nonmucinous adenocarcinoma group. In subgroup analysis, there was no significant difference in the disease-free survival and overall survival between patients with and without mucinous adenocarcinoma with stage II colon cancer. In stage III colon cancer, the disease-free survival and overall survival were significantly lower in patients with mucinous adenocarcinoma than in those without mucinous adenocarcinoma. Multivariable analysis showed that mucinous adenocarcinoma was a poor prognostic factor for disease-free survival and overall survival. LIMITATION The study's limitations include those that are inherently associated with retrospective single-center studies. CONCLUSIONS Mucinous adenocarcinoma is a poor prognostic factor in stage III but not in stage II colon cancer. Therefore, mucinous adenocarcinoma might not be regarded as an independent risk factor requiring chemotherapy for favorable oncologic outcomes. However, for stage III colon cancer, patients with mucinous adenocarcinoma require close observation. IMPACTO PRONSTICO DEL ADENOCARCINOMA MUCINOSO EN LAS ETAPAS II Y III DE CNCER DE CLON ANTECEDENTES:El adenocarcinoma mucinoso es una característica histológica rara del cáncer colorrectal, se caracteriza por propiedades oncológicas que son diferentes a las del adenocarcinoma. Sin embargo, existen puntos de vista contradictorios con respecto al impacto pronóstico del adenocarcinoma mucinoso en el cáncer de colon.OBJETIVO:Este estudio tuvo como objetivo evaluar el impacto pronóstico del adenocarcinoma mucinoso en las etapas II y III de cáncer de cólon.DISEÑO Y CONFIGURACIONES:Este estudio de cohorte retrospectivo se realizó entre enero de 2010 y diciembre de 2015. Los pacientes se dividieron entre grupos de adenocarcinoma mucinoso y adenocarcinoma no mucinoso. La supervivencia libre de enfermedad y la supervivencia global se evaluaron utilizando emparejamiento por puntuación de propensión.PACIENTES:En general, 2,532 pacientes que se sometieron a cirugía radical para etapa II y III de cáncer de colon se incluyeron en el estudio.PRINCIPALES MEDIDAS DE RESULTADO:Las principales medidas de resultado fueron la supervivencia libre de enfermedad y la supervivencia general.RESULTADOS:La mediana de duración del seguimiento fue de 86 meses. La supervivencia libre de enfermedad y la supervivencia global fueron significativamente menores en el grupo de adenocarcinoma mucinoso que en el grupo de adenocarcinoma no mucinoso. En el análisis de subgrupos, no hubo diferencias significativas en la supervivencia libre de enfermedad y la supervivencia global entre los pacientes con o sin adenocarcinoma mucinoso con cáncer de cólon etapa II. En el cáncer de colon etapa III, la supervivencia libre de enfermedad y la supervivencia global fueron significativamente más bajas en pacientes con adenocarcinoma mucinoso que en aquellos sin adenocarcinoma mucinoso. El análisis multivariable mostró que el adenocarcinoma mucinoso era un factor de mal pronóstico para la supervivencia libre de enfermedad y la supervivencia global.LIMITACIONES:Las limitaciones del estudio incluyen aquellas que están inherentemente asociadas con estudios retrospectivos de un solo centro.CONCLUSIONES:El adenocarcinoma mucinoso es un factor de mal pronóstico en el cáncer de colon etapa III pero no en etapa II. Por lo tanto, el adenocarcinoma mucinoso podría no considerarse un factor de riesgo independiente que requiera quimioterapia para obtener resultados oncológicos favorables. Sin embargo, para el cáncer de colon etapa III, los pacientes con adenocarcinoma mucinoso requieren observación cercana. (Traducción-Dr. Aurian Garcia Gonzalez ).
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Affiliation(s)
- Seijong Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Dos Santos Cunha AC, Simon AG, Zander T, Buettner R, Bruns CJ, Schroeder W, Gebauer F, Quaas A. Dissecting the inflammatory tumor microenvironment of esophageal adenocarcinoma: mast cells and natural killer cells are favorable prognostic factors and associated with less extensive disease. J Cancer Res Clin Oncol 2023; 149:6917-6929. [PMID: 36826594 PMCID: PMC10374824 DOI: 10.1007/s00432-023-04650-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 02/12/2023] [Indexed: 02/25/2023]
Abstract
PURPOSE Esophageal adenocarcinoma (EAC) remains a challenging and lethal cancer entity. A promising target for new therapeutic approaches, as demonstrated by the success of immune checkpoint inhibitors, are tumor-associated immune cells and the tumor microenvironment (TME). However, the understanding of the TME in esophageal cancer remains limited and requires further investigation. METHODS Over 900 EAC samples were included, including patients treated with primary surgery and neoadjuvant (radio-)chemotherapy. The immune cell infiltrates of mast cells (MC), natural killer cells (NK cells), plasma cells (PC), and eosinophilic cells (EC) were assessed semi-quantitatively and correlated with histopathological parameters and overall survival (OS). RESULTS A high presence of all four immune cell types significantly correlated with a less extensive tumor stage and a lower frequency of lymph node metastasis, and, in case of NK cells, with less distant metastasis. The presence of MC and NK cells was favorably associated with a prolonged OS in the total cohort (MC: p < 0.001; NK cells: p = 0.004) and patients without neoadjuvant treatment (MC: p < 0.001; NK cells: p = 0.01). NK cells were a favorable prognostic factor in the total cohort (p = 0.007) and in the treatment-naïve subgroup (p = 0.04). Additionally, MC were a favorable prognostic factor in patients with lymph node metastasis (p = 0.009). CONCLUSION Our results indicate a complex and important role of mast cells, NK cells, and the other assessed immune cells in the tumor microenvironment of EAC. Therefore, they are one further step to a better understanding of the immune cell environment and the potential therapeutic implications in this cancer entity.
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Affiliation(s)
- Alyne Condurú Dos Santos Cunha
- Institute of Pathology, University Hospital Cologne, Medical Faculty, University of Cologne, Kerpener Str. 62, DE-50937, Cologne, Germany
| | - Adrian Georg Simon
- Institute of Pathology, University Hospital Cologne, Medical Faculty, University of Cologne, Kerpener Str. 62, DE-50937, Cologne, Germany.
| | - Thomas Zander
- Department of Internal Medicine I, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, Germany
| | - Reinhard Buettner
- Institute of Pathology, University Hospital Cologne, Medical Faculty, University of Cologne, Kerpener Str. 62, DE-50937, Cologne, Germany
| | - Christiane Josephine Bruns
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, Germany
| | - Wolfgang Schroeder
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, Germany
| | - Florian Gebauer
- Department of General, Visceral and Cancer Surgery, University Hospital Cologne, Medical Faculty, University of Cologne, Cologne, Germany
| | - Alexander Quaas
- Institute of Pathology, University Hospital Cologne, Medical Faculty, University of Cologne, Kerpener Str. 62, DE-50937, Cologne, Germany
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Miranda J, Pinto PVA, Kinochita F, Garcia CM, El Homsi M, Vilela de Oliveira C, Pandini RV, Nahas CSR, Nahas SC, Gollub MJ, Horvat N. Mucinous Degeneration on MRI After Neoadjuvant Therapy in Patients With Rectal Adenocarcinoma: Frequency and Association With Clinical Outcomes. AJR Am J Roentgenol 2023; 221:206-216. [PMID: 36919880 PMCID: PMC10777341 DOI: 10.2214/ajr.23.29002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
BACKGROUND. Patients with nonmucinous rectal adenocarcinoma may develop mucinous changes after neoadjuvant chemoradiotherapy, which are described as mucinous degeneration. The finding's significance in earlier studies has varied. OBJECTIVE. The purpose of this study was to assess the frequency of mucinous degeneration on MRI after neoadjuvant therapy for rectal adenocarcinoma and to compare outcomes among patients with nonmucinous tumor, mucinous tumor, and mucinous degeneration on MRI. METHODS. This retrospective study included 201 patients (83 women, 118 men; mean age, 61.8 ± 2.2 [SD] years) with rectal adenocarcinoma who underwent neoadjuvant chemoradiotherapy followed by total mesorectal excision from October 2011 to November 2015, underwent baseline and restaging rectal MRI examinations, and had at least 2 years of follow-up. Two radiologists independently evaluated MRI examinations for mucin content, which was defined as T2 hyperintensity in the tumor or tumor bed, and resolved differences by consensus. Patients were classified into three groups on the basis of mucin status: those with nonmucinous tumor (≤ 50% mucin content on baseline and restaging examinations), those with mucinous tumor (> 50% mucin content on baseline and restaging examinations), and those with mucinous degeneration (≤ 50% mucin content on baseline examination and > 50% content on restaging examination). The three groups were compared. RESULTS. Interreader agreement for mucin content, expressed as a kappa coefficient, was 0.893 on baseline MRI and 0.890 on restaging MRI. Of the 201 patients, 156 (77.6%) had nonmucinous tumor, 34 (16.9%) had mucinous tumor, and 11 (5.5%) had mucinous degeneration. Mucin status was not significantly associated with complete pathologic response (p = .41) or local or distant recurrence (both p > .05). The death rate during follow-up was not significantly different (p = .21) between patients with nonmucinous tumor (23.1%), those with mucinous tumor (29.4%), and those with mucinous degeneration (9.1%). In adjusted Cox regression analysis, with mucinous degeneration used as reference, the HR for the overall survival rate for the mucinous tumor group was 4.7 (95% CI, 0.6-38.3; p = .14), and that for the nonmucinous tumor group was 8.0 (95% CI, 0.9-59.9; p = .06). On histopathologic assessment, all 11 patients with mucinous degeneration showed acellular mucin, yet 10 of 11 patients showed viable tumor (i.e., in nonmucinous portions of the tumors). CONCLUSION. Mucinous degeneration on MRI is not significantly associated with pathologic complete response, recurrence, or survival. CLINICAL IMPACT. Mucinous degeneration on MRI is uncommon and should not be deemed an indicator of pathologic complete response.
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Affiliation(s)
- Joao Miranda
- Department of Radiology, University of Sao Paulo, Sao Paulo, Brazil
| | | | | | | | - Maria El Homsi
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Box 29, New York, NY 10065
| | - Camila Vilela de Oliveira
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Box 29, New York, NY 10065
| | | | | | - Sergio C Nahas
- Department of Surgery, University of Sao Paulo, Sao Paulo, Brazil
| | - Marc J Gollub
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Box 29, New York, NY 10065
| | - Natally Horvat
- Department of Radiology, University of Sao Paulo, Sao Paulo, Brazil
- Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, Box 29, New York, NY 10065
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Aminder S, Saveena J, Ankita S, Harpreet K, Kunal J, Vikram N, Sumit G, Bhavna G, Ramneek K. Histopathological Predictors of Microsatellite Instability in Colorectal Cancer-a Tertiary Care Center Experience. Indian J Surg Oncol 2023; 14:137-143. [PMID: 36891442 PMCID: PMC9986156 DOI: 10.1007/s13193-022-01633-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 08/23/2022] [Indexed: 10/14/2022] Open
Abstract
Microsatellite instability (MSI) has a therapeutic and prognostic implication in colorectal carcinomas (CRCs). It can be detected either by immunohistochemistry (IHC) or molecular studies. In developing countries, a significant proportion of the patients experience financial constraints limiting the utilization of healthcare facilities. We aimed to identify the possible clinicopathological variables which can be used as predictors of microsatellite instability in such patients. CRC cases received for MSI detection by IHC (for 1 and 1/2 years) were included. A panel of four IHC markers (anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6) was used. Confirmation by the molecular study was recommended in all the IHC-proven MSI cases. Various clinicopathological parameters were evaluated as predictors of MSI. Microsatellite instability was detected in 40.6% (30/74) cases with MLH1 and PMS2 dual loss in 27% cases, MSH2 and MSH6 dual loss in 6.8%, loss of all four MMR proteins in 2.7%, and isolated PMS2 loss in 4.1%. MSI-H expression was shown by 36.5% cases with only 4.1% cases showing MSI-L expression. The age cut-off value to differentiate both the study groups (MSI vs MSS) was 63 years with a sensitivity of 47.7% and specificity of 86.7%. ROC curve showed an area under the curve of 0.65 (95% CI, 0.515-0.776; p-value = 0.03). On univariate analysis, age < 63 years, colon site, and absence of nodal metastasis were significantly higher in the MSI group. However, on multivariate analysis, only the age < 63 years was found to be significantly higher in the MSI group. Confirmation was molecular study could only be obtained in 12 cases and was completely concordant with MSI detection by IHC. MSI detection can be performed either by IHC or by molecular study. In this study, no histological parameter appeared to be the independent predictor of MSI status. The age < 63 years might predict the microsatellite instability, yet larger studies are needed for its validation. Thus, we recommend that IHC testing should be performed in all CRC cases.
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Affiliation(s)
- Singh Aminder
- Department of Pathology, Dayanand Medical College & Hospital, Tagore Nagar, Ludhiana, Punjab 141001 India
| | - Jindal Saveena
- Department of Pathology, Dayanand Medical College & Hospital, Tagore Nagar, Ludhiana, Punjab 141001 India
| | - Soni Ankita
- Department of Pathology, Dayanand Medical College & Hospital, Tagore Nagar, Ludhiana, Punjab 141001 India
| | - Kaur Harpreet
- Department of Pathology, Dayanand Medical College & Hospital, Tagore Nagar, Ludhiana, Punjab 141001 India
| | - Jain Kunal
- Department of Medical Oncology, Dayanand Medical College & Hospital, Ludhiana, Punjab India
| | - Narang Vikram
- Department of Pathology, Dayanand Medical College & Hospital, Tagore Nagar, Ludhiana, Punjab 141001 India
| | - Grover Sumit
- Department of Pathology, Dayanand Medical College & Hospital, Tagore Nagar, Ludhiana, Punjab 141001 India
| | - Garg Bhavna
- Department of Pathology, Dayanand Medical College & Hospital, Tagore Nagar, Ludhiana, Punjab 141001 India
| | - Kaur Ramneek
- Department of Pathology, Dayanand Medical College & Hospital, Tagore Nagar, Ludhiana, Punjab 141001 India
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Emile SH, Horesh N, Garoufalia Z, Gefen R, Zhou P, Wexner SD. The Prognostic Impact of Microsatellite Instability on the Outcome of Appendiceal Adenocarcinoma: a National Cancer Database Analysis. J Gastrointest Surg 2023; 27:354-362. [PMID: 36650414 DOI: 10.1007/s11605-023-05586-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Accepted: 01/03/2023] [Indexed: 01/19/2023]
Abstract
BACKGROUND Microsatellite instability (MSI) is recognized as a favorable outcome predictor in colorectal cancer. However, its impact on overall survival (OS) of appendiceal carcinoma has not been thoroughly studied. This study aimed to assess the impact of MSI on OS of patients with appendiceal adenocarcinoma, stratified by disease stage, tumor histology, and patients' demographics. METHODS This was a retrospective cohort analysis of the colon cancer National Cancer Database (NCDB) between 2005 and 2019. Patients with appendiceal adenocarcinoma with known MSI status were included and subdivided according to MSI status into positive and negative. Primary outcome was OS stratified by MSI status. RESULTS The study included 1681 (50.1% male) patients with a mean age of 58.9 ± 14.2 years; 211 (12.5%) had MSI-positive tumors (69 MSI low, 53 MSI high, and 89 not specified). Mean 5-year OS of patients with MSI-positive and MSI-negative carcinomas was similar (81.9 versus 78.6 months, p = 0.747). Patients with stage IV MSI-positive carcinomas had significantly longer OS than patients with MSI-negative carcinomas of the same stage (41.3 vs 26.5 months, p = 0.02). Differences in OS for patients with stages I-III were not statistically significant. Compared to MSI-negative/low carcinomas, MSI-high tumors had more advanced pathologic TNM stage (stage III: 23.9% vs 17.8%-stage IV: 41.3% vs 35.4%, p = 0.003), received more chemotherapy (56% vs 41%, p = 0.04), yet had similar OS (81.9 vs 78.9 months, p = 0.357). CONCLUSIONS MSI status of appendiceal adenocarcinomas did not significantly impact survival, except for stage IV disease in which a survival benefit of MSI was noted.
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Affiliation(s)
- Sameh Hany Emile
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd, Weston, FL, 33331, USA
- Colorectal Surgery Unit, General Surgery Department, Mansoura University Hospitals, Mansoura, Egypt
| | - Nir Horesh
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd, Weston, FL, 33331, USA
- Department of Surgery and Transplantation, Sheba Medical Center, Ramat Gan, Tel Aviv University, Tel Aviv, Israel
| | - Zoe Garoufalia
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd, Weston, FL, 33331, USA
| | - Rachel Gefen
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd, Weston, FL, 33331, USA
- Department of General Surgery, Faculty of Medicine, Hadassah Medical Organization, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Peige Zhou
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd, Weston, FL, 33331, USA
| | - Steven D Wexner
- Ellen Leifer Shulman and Steven Shulman Digestive Disease Center, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd, Weston, FL, 33331, USA.
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van Zwam PH, Vink-Börger EM, Bronkhorst CM, de Bruine AP, van der Wurff AA, Rutten HJT, Lemmens VEPP, Nagtegaal ID, Hugen N. Prognosis of mucinous colon cancer is determined by histological biomarkers rather than microsatellite instability. Histopathology 2023; 82:314-323. [PMID: 36217248 PMCID: PMC10100398 DOI: 10.1111/his.14818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 09/14/2022] [Accepted: 09/27/2022] [Indexed: 12/24/2022]
Abstract
The prognostic value of microsatellite instability (MSI), as well as other histological characteristics such as lymphovascular invasion (LI), perineural invasion (PNI) and extramural vascular invasion (EMVI), is unclear in colorectal mucinous carcinoma (MC). This study aims to determine the relevance of these factors in MC patients and analyses the role of MSI in stage III MC patients treated with adjuvant chemotherapy. A cohort of 650 patients diagnosed with stages I-IV colonic MC from 2000 to 2010 was selected from PALGA, the nationwide Dutch pathology databank. Histopathology was revised and mismatch repair (MMR) status determined. Univariate and multivariate survival analyses were performed. Deficient MMR (dMMR) was found in 33% of MCs and correlated with female gender and right-sidedness, but also with lower tumour stage (stages I/II: 73.2 versus 47%; P < 0.0001) and the absence of EMVI (9.7 versus 23.7%; P < 0.0001) and PNI (5.6 versus 12.7%; P = 0.005). On univariate analysis OS was better for dMMR MC than for proficient MMR (pMMR) MC (median OS of 9.7 versus 5.0 years; P = 0.009), but MMR status was no longer a relevant prognostic factor on multivariate analysis [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.70-1.18]. Stage III MC patients benefited from adjuvant chemotherapy, and dMMR status was associated with better OS in this group (HR = 0.35, 95% CI = 0.13-0.94). EMVI, LI and PNI, but not MMR, status are independent prognostic factors for survival in MC patients. Stage III MC patients benefit from adjuvant chemotherapy and dMMR status is associated with improved survival when adjuvant chemotherapy is given.
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Affiliation(s)
| | | | | | | | | | | | | | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Center, Nijmegen
| | - Niek Hugen
- Department of Surgery, Radboud University Medical Center, Nijmegen.,Department of Surgery, Antoni van Leeuwenhoek Hospital, The Netherlands Cancer Institute, Amsterdam, the Netherlands
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10
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Wu CWK, Reid M, Leedham S, Lui RN. The emerging era of personalized medicine in advanced colorectal cancer. J Gastroenterol Hepatol 2022; 37:1411-1425. [PMID: 35815339 PMCID: PMC7617119 DOI: 10.1111/jgh.15937] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 12/09/2022]
Abstract
Colorectal cancer (CRC) is a genetically heterogeneous disease with its pathogenesis often driven by varying genetic or epigenetic alterations. This has led to a substantial number of patients developing chemoresistance and treatment failure, resulting in a high mortality rate for advanced disease. Deep molecular analysis has allowed for the discovery of key intestinal signaling pathways which impacts colonic epithelial cell fate, and the integral role of the tumor microenvironment on cancer growth and dissemination. Through transitioning pre-clinical knowledge in research into clinical practice, many potential druggable targets within these pathways have been discovered in the hopes of overcoming the roadblocks encountered by conventional therapies. A personalized approach tailoring treatment according to the histopathological and molecular features of individual tumors can hopefully translate to better patient outcomes, and reduce the rate of recurrence in patients with advanced CRC. Herein, the latest understanding on the molecular science behind CRC tumorigenesis, and the potential treatment targets currently at the forefront of research are summarized.
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Affiliation(s)
- Claudia WK Wu
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
| | - Madeleine Reid
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Simon Leedham
- Translational Gastroenterology Unit, John Radcliffe hospital, University of Oxford, Oxford, United Kingdom
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Rashid N Lui
- Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China
- Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, China
- Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China
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11
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Surgical and functional outcomes of robot-assisted laparoscopic partial nephrectomy for renal cell carcinoma in adolescents and young adults: a propensity score matching study. Int J Clin Oncol 2022; 27:1624-1631. [PMID: 35877053 DOI: 10.1007/s10147-022-02222-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 07/14/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND Cancer development in adolescents and young adults (AYAs) has elicited recent interest. We investigated the surgical and functional outcomes of robot-assisted laparoscopic partial nephrectomy (RAPN) for renal cell carcinoma (RCC) in AYAs. METHODS We retrospectively reviewed the medical records of 1023 patients with clinical stage I RCC who underwent RAPN before January 2021. Patients were divided into two groups: AYAs (aged 18-39 years) and non-AYAs (aged 40-89 years). The trifecta criteria, defined as a negative surgical margin, no perioperative complications (Clavien-Dindo grade > 2), and preserved postoperative renal function (1-year postoperative estimated glomerular filtration rate > 90% of baseline), were used to compare outcomes. We performed 1:1 propensity-score matching on the patient cohort. RESULTS There were initially 125 and 898 patients in the AYAs and non-AYAs groups, respectively, and 108 patients were included in each group after propensity score matching. There were no significant differences in surgical factors (operation time, clamping ischemia time, estimated blood loss, length of hospital stay, surgical complication rate) or renal function in the early postoperative period. The mean postoperative renal function was better (p = 0.0200) and the decrease in estimated glomerular filtration rate was lower (p = 0.0026) in AYAs than in non-AYAs 12 months postoperatively. The trifecta achievement rates in the AYAs and non-AYAs groups were significantly different (67.6% and 53.7%, respectively, p = 0.0220). CONCLUSION Although there was no difference in surgical burden between the groups, the estimated glomerular filtration rate was better preserved in AYAs than in non-AYAs at 6 and 12 months post-RAPN.
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12
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Lee JE, Choi YY, An JY, Kim KT, Shin SJ, Cheong JH. Clinicopathologic and genomic characteristics of mucinous gastric adenocarcinoma. Gastric Cancer 2022; 25:697-711. [PMID: 35534656 DOI: 10.1007/s10120-022-01295-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 03/18/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND Mucinous gastric adenocarcinoma (MGC) is a rare but distinctive histologic subtype of gastric cancer (GC). The clinico-pathologic and genomic characteristics of MGC have not been well evaluated. METHODS We collected individual data from five cohorts targeting the microsatellite instability (MSI) of GC (n = 5089) to evaluate the clinico-pathologic characteristics of MGC. In addition, public genomic databases were used for genomic analysis. The characteristics of MGC were compared with those of non-mucinous GC (NMGC). RESULTS MGC (n = 158, 3.1%) showed distinctive characteristics in terms of age, sex, and TNM stage compared to NMGC (n = 4931). MGC was frequently associated with MSI-high (OR: 2.24, 95% confidence interval [CI] 1.44-3.40, p < 0.001), while mutually exclusive to the Epstein-Barr virus type. The prognosis of MGC was better than that of NMGC (adj.HR: 0.731, 95% CI 0.556-0.962, p = 0.025). There was no clear benefit from postoperative chemotherapy in MGC. TP53 was the main driver mutation in the MGC without recurrent variants. MGC was related to high expression of GPR120 and B3GNT6 and moderate regulation of epithelial-mesenchymal transition (EMT)-up signature with a high EMT-down signature, and those characteristics was related to favorable prognosis of GC (log-rank p = 0.044, p < 0.001, p < 0.001, respectively). MSI-H of MGC was associated with low cancer-associate fibroblasts but high CD274 (PD-L1) expression compared to microsatellite stable MGC, suggesting that immune checkpoint inhibitors may be useful for the MSI-H of MGC. CONCLUSION MGC could be a surrogate for performing MSI but not the EBV test in GC. Further, its genetic characteristics lead to a favorable prognosis for MGC.
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Affiliation(s)
- Jae Eun Lee
- Graduate School of Integrated Medicine, CHA Ilsan Medical Center, CHA University School of Medicine, Pocheon, Korea
| | - Yoon Young Choi
- Department of Surgery, CHA Ilsan Medical Center, CHA University School of Medicine, Pocheon, Korea.,Department of Surgery, Soonchunhyang Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Ji Yeong An
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ki Tae Kim
- Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Korea
| | - Su-Jin Shin
- Department of Pathology, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea.
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13
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Rosty C, Webster F, Nagtegaal ID. Pathology Reporting of Colorectal Local Excision Specimens: Recommendations from the International Collaboration on Cancer Reporting (ICCR). Gastroenterology 2021; 161:382-387. [PMID: 33961885 DOI: 10.1053/j.gastro.2021.04.066] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/13/2021] [Accepted: 04/13/2021] [Indexed: 12/02/2022]
Affiliation(s)
- Christophe Rosty
- Envoi Pathology, Brisbane, Queensland, Australia; Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia; Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Fleur Webster
- International Collaboration on Cancer Reporting, Sydney, New South Wales, Australia
| | - Iris D Nagtegaal
- Department of Pathology, Radboud University Medical Centre, Nijmegen, the Netherlands
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14
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Toh JWT, Phan K, Reza F, Chapuis P, Spring KJ. Rate of dissemination and prognosis in early and advanced stage colorectal cancer based on microsatellite instability status: systematic review and meta-analysis. Int J Colorectal Dis 2021; 36:1573-1596. [PMID: 33604737 DOI: 10.1007/s00384-021-03874-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/27/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION For the past two decades, microsatellite instability (MSI) has been reported as a robust clinical biomarker associated with survival advantage attributed to its immunogenicity. However, MSI is also associated with high-risk adverse pathological features (poorly differentiated, mucinous, signet cell, higher grade) and exhibits a double-edged sword phenomenon. We performed a systematic review and meta-analysis to evaluate the rate of dissemination and the prognosis of early and advanced stage colorectal cancer based on MSI status. METHODS A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, Clinical Trials databases from inception of database to June 2019. Colorectal cancer, microsatellite instability, genomic instability and DNA mismatch repair were used as key words or MeSH terms. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were pooled using a random-effects model with odds ratio (OR) as the effect size. Statistical analysis was performed using RevMan ver 5.3 Cochrane Collaboration. RESULTS From 5288 studies, 136 met the inclusion criteria (n = 92,035; MSI-H 11,746 (13%)). Overall, MSI-H was associated with improved OS (OR, 0.81; 95% CI 0.73-0.90), DFS (OR, 0.73; 95% CI 0.66-0.81) and DSS (OR, 0.69; 95% CI 0.52-0.90). Importantly, MSI-H had a protective effect against dissemination with a significantly lower rate of lymph node and distant metastases. By stage, the protective effect of MSI-H in terms of OS and DFS was observed clearly in stage II and stage III. Survival in stage I CRC was excellent irrespective of MSI status. In stage IV CRC, without immunotherapy, MSI-H was not associated with any survival benefit. CONCLUSIONS MSI-H CRC was associated with an overall survival benefit with a lower rate of dissemination. Survival benefit was clearly evident in both stage II and III CRC, but MSI-H was neither a robust prognostic marker in stage I nor stage IV CRC without immunotherapy.
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Affiliation(s)
- James W T Toh
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia. .,Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. .,Discipline of Surgery, The University of New South Wales, Sydney, NSW, Australia. .,Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia.
| | - Kevin Phan
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Faizur Reza
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Pierre Chapuis
- Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Kevin J Spring
- Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia
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15
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Reynolds IS, O'Connell E, Fichtner M, Blümel A, Mason SE, Kinross J, McNamara DA, Kay EW, O'Connor DP, Das S, Burke JP, Prehn JHM. An Insight Into the Driver Mutations and Molecular Mechanisms Underlying Mucinous Adenocarcinoma of the Rectum. Dis Colon Rectum 2021; 64:677-688. [PMID: 33955407 DOI: 10.1097/dcr.0000000000001825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Mucinous adenocarcinoma of the rectum accounts for 10% of all rectal cancers and has an impaired response to neoadjuvant chemoradiotherapy and worse overall survival. To date, insufficient genomic research has been performed on this histological subtype. OBJECTIVE This study aims to define the mismatch repair deficiency rate and the driver mutations underpinning mucinous adenocarcinoma of the rectum and to compare it with rectal adenocarcinoma not otherwise specified. DESIGN Immunohistochemistry and sequencing were performed on tumor samples from our tumor biobank. SETTINGS This study was conducted across 2 tertiary referral centers. PATIENTS Patients with mucinous adenocarcinoma and rectal adenocarcinoma not otherwise specified who underwent rectal resection between 2008 and 2018 were included. MAIN OUTCOME MEASURES Mismatch repair status was performed by immunohistochemical staining. Mutations in the panel of oncogenes and tumor suppressor genes were determined by sequencing on the MiSeq V3 platform. RESULTS The study included 33 patients with mucinous adenocarcinoma of the rectum and 100 patients with rectal adenocarcinoma not otherwise specified. Those with mucinous adenocarcinoma had a mismatch repair deficiency rate of 12.1% compared to 2.0% in the adenocarcinoma not otherwise specified cohort (p = 0.04). Mucinous adenocarcinoma and adenocarcinoma not otherwise specified rectal tumors had similar mutation frequencies in most oncogenes and tumor suppressor genes. No difference was found in the KRAS mutation rate (50.0% vs 37.1%, p = 0.29) or BRAF mutation rate (6.7% vs 3.1%, p = 0.34) between the cohorts. No difference was found between the cohorts regarding recurrence-free (p = 0.29) or overall survival (p = 0.14). LIMITATIONS The major limitations of this study were the use of formalin-fixed, paraffin-embedded tissue over fresh-frozen tissue and the small number of patients included, in particular, in the mucinous rectal cohort. CONCLUSIONS Most mucinous rectal tumors develop and progress along the chromosomal instability pathway. Further research in the form of transcriptomics, proteomics, and analysis of the effects of the mucin barrier may yield valuable insights into the mechanisms of resistance to chemoradiotherapy in this cohort. See Video Abstract at http://links.lww.com/DCR/B464. UNA PERCEPCIN SOBRE MUTACIONES IMPULSORAS Y MECANISMOS MOLECULARES SUBYACENTES AL ADENOCARCINOMA MUCINOSO DEL RECTO ANTECEDENTES:El adenocarcinoma mucinoso del recto, representa el 10% de todos los cánceres rectales y tiene una respuesta deficiente a la quimioradioterapia neoadyuvante y una peor supervivencia en general. A la fecha, se han realizado muy pocas investigaciones genómicas sobre este subtipo histológico.OBJETIVO:Definir la tasa de deficiencia en la reparación de desajustes y mutaciones impulsoras, que sustentan el adenocarcinoma mucinoso del recto y compararlo con el adenocarcinoma rectal no especificado de otra manera.DISEÑO:Se realizaron inmunohistoquímica y secuenciación en muestras tumorales de nuestro biobanco de tumores.AJUSTE:El estudio se realizó en dos centros de referencia terciarios.PACIENTES:Se incluyeron pacientes con adenocarcinoma mucinoso y adenocarcinoma no especificado de otra manera, sometidos a resección rectal entre 2008 y 2018.PRINCIPALES MEDIDAS DE RESULTADO:El estado de reparación de desajustes se realizó mediante tinción inmunohistoquímica. Las mutaciones en el panel de oncogenes y genes supresores de tumores, se determinaron mediante secuenciación en la plataforma MiSeq V3.RESULTADOS:El estudio incluyó a 33 pacientes con adenocarcinoma mucinoso del recto y 100 pacientes con adenocarcinoma del recto no especificado de otra manera. Aquellos con adenocarcinoma mucinoso, tenían una tasa de deficiencia de reparación de desajustes del 12,1% en comparación con el 2,0% en la cohorte de adenocarcinoma no especificado de otra manera (p = 0,04). El adenocarcinoma mucinoso y el adenocarcinoma no especificado de otra manera, tuvieron frecuencias de mutación similares en la mayoría de los oncogenes y genes supresores de tumores. No se encontraron diferencias en la tasa de mutación de KRAS (50,0% frente a 37,1%, p = 0,29) o la tasa de mutación de BRAF (6,7% frente a 3,1%, p = 0,34) entre las cohortes. No se encontraron diferencias entre las cohortes con respecto a la supervivencia libre de recurrencia (p = 0,29) o la supervivencia global (p = 0,14).LIMITACIONES:Las mayores limitaciones de este estudio, fueron el uso de tejido embebido en parafina y fijado con formalina, sobre el tejido fresco congelado y el pequeño número de pacientes incluidos, particularmente en la cohorte mucinoso rectal.CONCLUSIONES:La mayoría de los tumores rectales mucinosos se desarrollan y progresan a lo largo de la vía de inestabilidad cromosómica. La investigación adicional en forma transcriptómica, proteómica y análisis de los efectos de la barrera de la mucina, puede proporcionar información valiosa sobre los mecanismos de resistencia a la quimioradioterapia, en esta cohorte. Consulte Video Resumen en http://links.lww.com/DCR/B464.
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Affiliation(s)
- Ian S Reynolds
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Emer O'Connell
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Michael Fichtner
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Anna Blümel
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Sam E Mason
- Department of Surgery & Cancer, Imperial College London, London, United Kingdom
| | - James Kinross
- Department of Surgery & Cancer, Imperial College London, London, United Kingdom
| | - Deborah A McNamara
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland
- Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Elaine W Kay
- Department of Pathology, Beaumont Hospital, Dublin, Ireland
| | - Darran P O'Connor
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Sudipto Das
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - John P Burke
- Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland
| | - Jochen H M Prehn
- Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
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16
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Lan YT, Chang SC, Lin PC, Lin CC, Lin HH, Huang SC, Lin CH, Liang WY, Chen WS, Jiang JK, Lin JK, Yang SH. Clinicopathological and Molecular Features of Colorectal Cancer Patients With Mucinous and Non-Mucinous Adenocarcinoma. Front Oncol 2021; 11:620146. [PMID: 33738258 PMCID: PMC7962409 DOI: 10.3389/fonc.2021.620146] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 01/18/2021] [Indexed: 01/10/2023] Open
Abstract
Background The prognosis of mucinous adenocarcinoma (MAC) and non-mucinous adenocarcinoma (NMAC) in colorectal cancer (CRC) is controversial, and the molecular differences between them are unclear. Methods Between 2000 and 2010, a total of 1,483 CRC patients were included. Among them, 73 patients (4.9%) were diagnosed with MAC. The clinicopathological features and genetic alterations were compared between MAC and NMAC. Results After propensity score matching to balance age and sex between MAC and NMAC patients, 292 CRC patients (73 MAC and 219 NMAC) were enrolled in the analysis at a 1:3 ratio. In right-sided colon cancer, patients with MAC were more likely to have Borrmann types 3 and 4 tumors, poor differentiation, and advanced T category and tumor, node, metastasis (TNM) stage, chemotherapy, and a similar 5-year overall survival (OS) rate compared with patients with NMAC. In left-sided colon cancer and rectal cancer, patients with MAC were more likely to have Borrmann types 3 and 4 tumors, poor differentiation, lymphovascular invasion, advanced T and N categories and TNM stages, chemotherapy, and a worse 5-year OS rate than patients with NMAC. Regarding genetic alterations, for NMAC, right-sided colon cancer had more BRAF mutations than left-sided colon cancer and rectal cancer. For MAC, right-sided colon cancer was associated with more microsatellite instability-high tumors and more AKT1 mutations than left-sided colon cancer and rectal cancer. Conclusion The genetic alterations are distinct between MAC and NMAC in CRC. Tumor location may have an impact on genetic alterations and patient prognosis in MAC and NMAC.
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Affiliation(s)
- Yuan-Tzu Lan
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shih-Ching Chang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Pei-Ching Lin
- Department of Clinical Pathology, Taipei City Hospital, Taipei, Taiwan.,Department of Health and Welfare, University of Taipei, Taipei, Taiwan
| | - Chun-Chi Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hung-Hsin Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shen-Chieh Huang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chien-Hsing Lin
- Division of Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan
| | - Wen-Yi Liang
- Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Wei-Shone Chen
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jeng-Kai Jiang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Jen-Kou Lin
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shung-Haur Yang
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Department of Surgery, National Yang Ming Chiao Tung University Hospital, Yilan, Taiwan
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17
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Choi YW, Kim YH, Oh SY, Suh KW, Kim Y, Lee G, Yoon JE, Park SS, Lee Y, Park YJ, Kim HS, Park SH, Kim J, Park TJ. Senescent Tumor Cells Build a Cytokine Shield in Colorectal Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2002497. [PMID: 33643790 PMCID: PMC7887594 DOI: 10.1002/advs.202002497] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 10/09/2020] [Indexed: 05/25/2023]
Abstract
Cellular senescence can either support or inhibit cancer progression. Here, it is shown that intratumoral infiltration of CD8+ T cells is negatively associated with the proportion of senescent tumor cells in colorectal cancer (CRC). Gene expression analysis reveals increased expression of C-X-C motif chemokine ligand 12 (CXCL12) and colony stimulating factor 1 (CSF1) in senescent tumor cells. Senescent tumor cells inhibit CD8+ T cell infiltration by secreting a high concentration of CXCL12, which induces a loss of CXCR4 in T cells that result in impaired directional migration. CSF1 from senescent tumor cells enhance monocyte differentiation into M2 macrophages, which inhibit CD8+ T cell activation. Neutralization of CXCL12/CSF1 increases the effect of anti-PD1 antibody in allograft tumors. Furthermore, inhibition of CXCL12 from senescent tumor cells enhances T cell infiltration and results in reducing the number and size of tumors in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC. These findings suggest senescent tumor cells generate a cytokine barrier protecting nonsenescent tumor cells from immune attack and provide a new target for overcoming the immunotherapy resistance of CRC.
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Affiliation(s)
- Yong Won Choi
- Department of Biochemistry and Molecular BiologyAjou University School of MedicineSuwon16499Korea
- Department of Hematology–OncologyAjou University School of MedicineSuwon16499Korea
- Inflamm‐Aging Translational Research CenterAjou University Medical CenterSuwon16499Korea
| | - Young Hwa Kim
- Department of Biochemistry and Molecular BiologyAjou University School of MedicineSuwon16499Korea
- Department of Biomedical SciencesAjou University Graduate School of MedicineSuwon16499Korea
| | - Seung Yeop Oh
- Department of SurgeryAjou University School of MedicineSuwon16499Korea
| | - Kwang Wook Suh
- Department of SurgeryAjou University School of MedicineSuwon16499Korea
| | - Young‐Sam Kim
- Department of Biochemistry and Molecular BiologyAjou University School of MedicineSuwon16499Korea
- Department of Biomedical SciencesAjou University Graduate School of MedicineSuwon16499Korea
| | - Ga‐Yeon Lee
- Department of Biochemistry and Molecular BiologyAjou University School of MedicineSuwon16499Korea
- Department of Biomedical SciencesAjou University Graduate School of MedicineSuwon16499Korea
| | - Jung Eun Yoon
- Department of Biochemistry and Molecular BiologyAjou University School of MedicineSuwon16499Korea
- Department of Biomedical SciencesAjou University Graduate School of MedicineSuwon16499Korea
| | - Soon Sang Park
- Department of Biochemistry and Molecular BiologyAjou University School of MedicineSuwon16499Korea
- Department of Biomedical SciencesAjou University Graduate School of MedicineSuwon16499Korea
| | - Young‐Kyoung Lee
- Department of Biochemistry and Molecular BiologyAjou University School of MedicineSuwon16499Korea
- Inflamm‐Aging Translational Research CenterAjou University Medical CenterSuwon16499Korea
- Department of Biomedical SciencesAjou University Graduate School of MedicineSuwon16499Korea
| | - Yoo Jung Park
- Department of Hematology–OncologyAjou University School of MedicineSuwon16499Korea
| | - Hong Seok Kim
- Department of Molecular MedicineInha University School of MedicineIncheon22212Korea
| | - So Hyun Park
- Department of PathologyAjou University School of MedicineSuwon16499Korea
| | - Jang‐Hee Kim
- Inflamm‐Aging Translational Research CenterAjou University Medical CenterSuwon16499Korea
- Department of PathologyAjou University School of MedicineSuwon16499Korea
| | - Tae Jun Park
- Department of Biochemistry and Molecular BiologyAjou University School of MedicineSuwon16499Korea
- Inflamm‐Aging Translational Research CenterAjou University Medical CenterSuwon16499Korea
- Department of Biomedical SciencesAjou University Graduate School of MedicineSuwon16499Korea
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18
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Sayhan S, Kahraman DS. Pathologic Features of Colorectal Carcinomas. COLON POLYPS AND COLORECTAL CANCER 2021:455-480. [DOI: 10.1007/978-3-030-57273-0_23] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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19
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Kim Y, Bae JM, Kim JH, Cho NY, Kang GH. A comparative prognostic performance of definitions of Crohn-like lymphoid reaction in colorectal carcinoma. J Pathol Transl Med 2020; 55:53-59. [PMID: 33238662 PMCID: PMC7829571 DOI: 10.4132/jptm.2020.10.06] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 10/06/2020] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND The prognostic potential of Crohn-like lymphoid reaction (CLR) in colorectal carcinoma (CRC) has been investigated through the assessment of different criteria. METHODS The prognostic impact of CLR was investigated in 636 CRC patients to compare methods from previously published articles. These methods included CLR measured by number of lymphoid aggregates (LAs) (CLR count), LA size greater than or equal to 1 mm (CLR size), CLR density with a cutoff value of 0.38, and subjective criteria as defined by intense CLR. RESULTS In univariate survival analysis, CLR-positive CRC as defined by the four aforementioned methods was associated with better overall survival (OS) (hazard ratio [HR], 0.463; 95% confidence interval [CI], 0.305 to 0.702; p <.001; HR, 0.656; 95% CI, 0.411 to 1.046; p=.077; HR, 0.363; 95% CI, 0.197 to 0.669; p=.001; and HR, 0.433; 95% CI, 0.271 to 0.690; p<.001, respectively) and disease-free survival (DFS) (HR, 0.411; 95% CI, 0.304 to 0.639; p<.001; HR, 0.528; 95% CI, 0.340 to 0.821; p=.004; HR, 0.382; 95% CI, 0.226 to 0.645, p=.004; and HR, 0.501; 95% CI, 0.339 to 0.741; p<.001, respectively) than CLR-negative CRC, regardless of criteria with the exception of OS for CLR density. In multivariate analysis, two objective criteria (CLR count and CLR density) and one subjective criterion (intense CLR) for defining CLR were considered independent prognostic factors of OS and DFS in CRC patients. CONCLUSIONS CLR has similar traits regardless of criteria, but CLR-positivity should be defined by objective criteria for better reproducibility and prognostic value.
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Affiliation(s)
- Younghoon Kim
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Jeong Mo Bae
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Jung Ho Kim
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Nam-Yun Cho
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
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20
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Yu F, Huang L, Shen F, Wu S, Chen J. Prognostic implications of mucinous histology in stage III colon cancer with the receipt of adjuvant chemotherapy. J Gastrointest Oncol 2020; 11:858-869. [PMID: 33209482 DOI: 10.21037/jgo-20-160] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background There is still a debate about the survival benefit of chemotherapy in stage III mucinous colon cancer, we then conduct a comprehensive assessment of the efficacy of adjuvant chemotherapy in this population. Methods The data used in the current study were extracted from the Surveillance, Epidemiology and End Results (SEER) database. Chi-squared (χ2) test was used to compared patient characteristics according to the histology. The outcome of the survival analysis used in the current study was cancer-specific survival (CSS). Univariable and multivariable analyses were carried out using the Cox proportional hazards regression models to evaluate the prognostic characteristics associated with CSS of colon cancer. And the risks of mortality were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Results A total of 68,976 patients diagnosed with stage III colon cancer were included in our analyses, including mucinous adenocarcinoma (MAC, N=6,592) and non-mucinous adenocarcinoma (NMA, N=62,384). In NMA, the receipt of chemotherapy had 46.0% independently decreased risk of colon cancer-specific mortality compared to non-chemotherapy group (HR =0.540, 95% CI: 0.523-0.558, P<0.001). In MAC, the receipt of chemotherapy had 37.7% independently decreased risk of colon cancer-specific mortality compared to non-chemotherapy group (HR =0.623, 95% CI: 0.566-0.685, P<0.001). Conclusions MAC was associated with worse prognosis and was less responsive to chemotherapy compared with NMA in stage III colon cancer. However, stage III mucinous colon cancer still need to be treated with chemotherapy because of the significant survival benefit and specialized treatment plans for MAC were quite necessary in the future.
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Affiliation(s)
- Feng Yu
- Department of Colorectal Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Luqiao Huang
- Department of Colorectal Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Feng Shen
- Department of Colorectal Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Shuang Wu
- Department of Colorectal Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, China
| | - Jian Chen
- Department of Gastrointestinal Surgery, Tongde Hospital of Zhejiang Province, Hangzhou, China
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21
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Triki M, Kallel R, Feki J, Mellouli M, Charfi S, Ayadi L, Boudawara T. Prognostic significance of E-cadherin and Cox 2 expression in Tunisian patients with colorectal mucinous adenocarcinoma. Ann Diagn Pathol 2020; 49:151624. [PMID: 32919337 DOI: 10.1016/j.anndiagpath.2020.151624] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/16/2020] [Accepted: 09/02/2020] [Indexed: 01/18/2023]
Abstract
INTRODUCTION Mucinous colorectal carcinoma (MC) is a rare subtype of colorectal adenocarcinoma known to be associated with bad prognosis. Lately, research has turned to identify new prognostic markers allowing the use of targeted therapy. The aim of our study is to evaluate the prognostic impact of E-cadherin and Cox-2expression in MC. MATERIALS AND METHOD A total of 40 formalin-fixed, paraffin-embedded MC specimens were collected within a period of 13 years and were studied for the expression of the two proteins. We used SPSS 22 software to study associations with clinicopathological parameters and overall survival (OS). RESULTS A reduced or absent E-cadherin expression was noted in 52.5% of cases. It was associated with distant metastases (p = 0.049) and venous invasion (p = 0.049). Cox-2 was overexpressed in 17.5% of cases. It was associated with negative lymph node status (p = 0.020) and with early stage tumor (p = 0.020). A significant association between the two proteins was also noted (p = 0.04). No significant association with OS was found; However, there was an improvement in the survival of patients overexpressing Cox-2 (p = 0.16). CONCLUSION Our findings link the loss of E-cadherin expression with spread and aggressiveness in MC and Cox-2 overexpression with better prognosis and survival. Because MC has a distinct genetic pathway we encourage the analysis of MSI and Cox-2 expression in all MC. Cox-2 inhibitors may not be effective chemopreventative agents in the setting of defective DNA mismatch repair. More molecular studies are needed to better understand the role of these markers and their prognostic significance in MC.
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Affiliation(s)
- Meriam Triki
- Department of Pathology, Habib Bourguiba University Hospital, Sfax, Tunisia.
| | - Rim Kallel
- Department of Pathology, Habib Bourguiba University Hospital, Sfax, Tunisia
| | - Jihene Feki
- Department of Oncology, Habib Bourguiba University Hospital, Sfax, Tunisia
| | - Manel Mellouli
- Department of Pathology, Habib Bourguiba University Hospital, Sfax, Tunisia
| | - Slim Charfi
- Department of Pathology, Habib Bourguiba University Hospital, Sfax, Tunisia
| | - Lobna Ayadi
- Department of Pathology, Habib Bourguiba University Hospital, Sfax, Tunisia
| | - Tahya Boudawara
- Department of Pathology, Habib Bourguiba University Hospital, Sfax, Tunisia
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22
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Tricoli JV. Genomic and molecular alterations associated with early-onset and adolescent and young adult colorectal cancer. COLORECTAL CANCER 2020. [DOI: 10.2217/crc-2020-0009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
While the incidence of colorectal cancer (CRC) in the US has declined at a pace of 3% annually between 2003 and 2012, there has been an increase in the incidence of early-onset colorectal cancer (EOCRC). The reasons for this increase are unclear. Diet, the environment, the microbiome and alcohol consumption have all been proposed as contributing factors. There is the possibility that EOCRC has a unique biology. Overlapping with the EOCRC age range is CRC in adolescent and young adults (AYA) that share many molecular characteristics with EOCRC. The purpose of this review is to cover current progress in our understanding of the biology of CRC in the context of adolescent and young adult CRC and EOCRC and discuss future directions.
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Affiliation(s)
- James V Tricoli
- Cancer Diagnosis Program, Division of Cancer Treatment & Diagnosis, National Cancer Institute, 6909 Medical Center Drive, Rockville, MD 20892, USA
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23
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Williams DS, Mouradov D, Newman MR, Amini E, Nickless DK, Fang CG, Palmieri M, Sakthianandeswaren A, Li S, Ward RL, Hawkins NJ, Skinner I, Jones I, Gibbs P, Sieber OM. Tumour infiltrating lymphocyte status is superior to histological grade, DNA mismatch repair and BRAF mutation for prognosis of colorectal adenocarcinomas with mucinous differentiation. Mod Pathol 2020; 33:1420-1432. [PMID: 32047231 DOI: 10.1038/s41379-020-0496-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 01/12/2020] [Accepted: 01/13/2020] [Indexed: 12/12/2022]
Abstract
Mucinous colorectal adenocarcinoma (CRC) is conventionally defined by extracellular mucin comprising >50% of the tumour area, while tumours with ≤50% mucin are designated as having a mucinous component. However, these definitions are largely arbitrary and comparisons of clinico-molecular features and outcomes by proportion of mucinous component are limited. A cohort of 1643 patients with stage II/III cancer was examined for tumour mucinous component, DNA mismatch repair (MMR) status, BRAF mutation and tumour infiltrating lymphocytes (TILs). Tumours with ≤50% mucinous component exhibited similar characteristics as mucinous tumours, including association with female gender, proximal location, high grade, TIL-high, defective MMR (dMMR) and BRAF mutation. Proportion of mucinous component did not stratify disease-free survival (DFS). In univariate analysis dMMR status, but not histological grade, stratified survival for mucinous and mucinous component tumours; however, in multivariate analysis dMMR status was not an independent predictor. BRAF mutation prognostic value depended on mucinous differentiation and MMR status, with poor prognosis limited to non-mucinous pMMR tumours (HR 2.61, 95% CI 1.69-4.03; p < 0.001). TIL status was a strong independent predictor of DFS in mucinous/mucinous component tumours (HR 0.40, 95% CI 0.23-0.67; p < 0.001), and a superior predictor of prognosis compared with histological grade, MMR and BRAF mutation. Mucinous component and mucinous stage II/III CRCs exhibit clinico-molecular resemblances, with histological grade and BRAF mutation lacking prognostic value. Prognosis for these tumours was instead strongly associated with TIL status, with the most favourable outcomes in TIL-high dMMR tumours, whilst TIL-low tumours had poor outcomes irrespective of MMR status.
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Affiliation(s)
- David S Williams
- Department of Pathology, Austin Health, Heidelberg, VIC, Australia.,Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.,Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, Australia
| | - Dmitri Mouradov
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, VIC, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Marsali R Newman
- Department of Pathology, Austin Health, Heidelberg, VIC, Australia
| | - Elham Amini
- Clinipath Pathology, Sonic Healthcare, Perth, WA, Australia
| | | | - Catherine G Fang
- Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
| | - Michelle Palmieri
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, VIC, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Anuratha Sakthianandeswaren
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, VIC, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
| | - Shan Li
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, VIC, Australia
| | - Robyn L Ward
- Prince of Wales Clinical School and Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.,Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Nicholas J Hawkins
- School of Medical Sciences, UNSW Sydney, Sydney, NSW, Australia.,Faculty of Medicine, The University of Queensland, Herston, QLD, Australia
| | - Iain Skinner
- Department of Surgery, Western Health, Footscray, VIC, Australia
| | - Ian Jones
- Department of Surgery, Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Peter Gibbs
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, VIC, Australia.,Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.,Department of Medical Oncology, Parkville, VIC, Australia.,Department of Medical Oncology, Western Health, Footscray, VIC, Australia
| | - Oliver M Sieber
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, VIC, Australia. .,Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. .,Department of Surgery, The University of Melbourne, Parkville, VIC, Australia. .,School of Biomedical Sciences, Monash University, Clayton, VIC, Australia.
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24
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Lee HS, Hwang DY, Han HS. Histology and its prognostic effect on KRAS-mutated colorectal carcinomas in Korea. Oncol Lett 2020; 20:655-666. [PMID: 32565990 PMCID: PMC7285809 DOI: 10.3892/ol.2020.11606] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 04/15/2020] [Indexed: 12/13/2022] Open
Abstract
KRAS mutation is frequently identified in advanced colorectal carcinoma (CRC); however, its prognostic significance and the associated histological features have remained to be clarified. In the present study, the precise histological results and prognostic value of KRAS-mutated CRCs were investigated in patients from South Korea. A retrospective review of the results from KRAS mutation testing, as well as evaluation of the histology of 310 cases of CRC at various stages, were performed. Cross-tabulation and survival analysis were performed according to the KRAS status. Patients with KRAS mutation more frequently exhibited serrated and papillary architectures (P=0.009 and P=0.014, respectively). KRAS mutation was an independent unfavorable prognostic factor for overall survival (OS) according to multivariate analysis (P=0.001), whereas no association was observed with disease-free survival (DFS) (P=0.611). Of note, in the subgroup of KRAS-mutated carcinomas, the presence of a solid component on histology was associated with less favorable OS (P=0.032). Furthermore, among the wild type cases, patients with a micropapillary component had a worse OS than those who did not (P=0.018). However, no subgroup or specific histological features were associated with DFS. In summary, KRAS-mutated CRCs had a moderate association with particular histological features, and according to the KRAS mutational status, there was a certain degree of association between histology and prognosis.
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Affiliation(s)
- Hye Seung Lee
- Department of Pathology, Korea Clinical Laboratory, Seoul 05396, Republic of Korea
| | - Dae Yong Hwang
- Department of Surgery, Konkuk University School of Medicine, Seoul 05030, Republic of Korea
| | - Hye Seung Han
- Department of Pathology, Konkuk University School of Medicine, Seoul 05030, Republic of Korea
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25
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Li X, Sun K, Liao X, Gao H, Zhu H, Xu R. Colorectal carcinomas with mucinous differentiation are associated with high frequent mutation of KRAS or BRAF mutations, irrespective of quantity of mucinous component. BMC Cancer 2020; 20:400. [PMID: 32384877 PMCID: PMC7206795 DOI: 10.1186/s12885-020-06913-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/29/2020] [Indexed: 02/08/2023] Open
Abstract
Background Mucinous adenocarcinoma (MAC) is a distinct type of colorectal cancer (CRC) associated with poor response to treatment and poorer prognosis. MAC is diagnosed by WHO definition when the extracellular mucin is more than 50% of the lesion. We aimed at assessing the gene expression profiles of the CRCs with any mucinous features (> 5%) in a retrospective study. Methods The data of a 50-gene next generation sequencing (NGS) panel of 166 CRCs was analyzed and the gene mutational profile with morphologic features was correlated. Results We identified the different genetic mutation profiles between CRCs with and without mucinous component, but noticed a similar genetic profile between MACs and CRCs with mucinous component, irrespective of the percentage (if mucinous component more than 5%). The different genetic mutation profile related to MSI status was also identified between two groups of tumors. The most frequent mutations in CRCs with mucinous component are KRAS (28/49, 57.1%) and BRAF (19/49, 38.7%), PIK3CA (16/49, 32.6%), followed by APC (12/49, 24.5%) and TP53 (11/49, 22.5%). The combined mutation frequency of the two key factors in the EGFR signaling pathway, KRAS and BRAF, in the CRCs with and without mucinous component is 95.9 and 52.1%, respectively. Conclusions The dysregulation of EGFR pathway plays a critical role in the development of CRCs with mucinous component, irrespective of the percentage. The result suggested that the current cut off of 50% mucin component to define mucinous adenocarcinoma might be challengeable.
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Affiliation(s)
- Xiaodong Li
- Department of Pathology, NYU Langone Medical Center, New York, NY, USA.,Present address: Department of Pathology, University of California Irvine, Orange, CA, USA
| | - Katherine Sun
- Department of Pathology, NYU Langone Medical Center, New York, NY, USA
| | - Xiaoyan Liao
- Department of Pathology, University of Rochester Medical Center, Rochester, NY, USA.,Department of Pathology, Mount Sinai Medical Center, New York, NY, USA
| | - Haijuan Gao
- Present address: Department of Pathology, University of California Irvine, Orange, CA, USA
| | - Hongfa Zhu
- Department of Pathology, Mount Sinai Medical Center, New York, NY, USA
| | - Ruliang Xu
- Department of Pathology, NYU Langone Medical Center, New York, NY, USA. .,Department of Pathology, White Plains Hospital, Montefiore Health System, White Plains, NY, USA.
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26
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Gorringe KL, Cheasley D, Wakefield MJ, Ryland GL, Allan PE, Alsop K, Amarasinghe KC, Ananda S, Bowtell DDL, Christie M, Chiew YE, Churchman M, DeFazio A, Fereday S, Gilks CB, Gourley C, Hadley AM, Hendley J, Hunter SM, Kaufmann SH, Kennedy CJ, Köbel M, Le Page C, Li J, Lupat R, McNally OM, McAlpine JN, Pyman J, Rowley SM, Salazar C, Saunders H, Semple T, Stephens AN, Thio N, Torres MC, Traficante N, Zethoven M, Antill YC, Campbell IG, Scott CL. Therapeutic options for mucinous ovarian carcinoma. Gynecol Oncol 2020; 156:552-560. [PMID: 31902686 PMCID: PMC7056511 DOI: 10.1016/j.ygyno.2019.12.015] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 11/18/2019] [Accepted: 12/15/2019] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.
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Affiliation(s)
- Kylie L Gorringe
- Peter MacCallum Cancer Centre, Melbourne, Australia; The University of Melbourne, Melbourne, Australia.
| | - Dane Cheasley
- Peter MacCallum Cancer Centre, Melbourne, Australia; The University of Melbourne, Melbourne, Australia
| | - Matthew J Wakefield
- The University of Melbourne, Melbourne, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
| | | | - Prue E Allan
- Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Kathryn Alsop
- Peter MacCallum Cancer Centre, Melbourne, Australia; The University of Melbourne, Melbourne, Australia
| | | | - Sumitra Ananda
- Peter MacCallum Cancer Centre, Melbourne, Australia; Western Health, St. Albans, Australia
| | - David D L Bowtell
- Peter MacCallum Cancer Centre, Melbourne, Australia; The University of Melbourne, Melbourne, Australia
| | - Michael Christie
- The University of Melbourne, Melbourne, Australia; Royal Melbourne Hospital, Parkville, Australia
| | - Yoke-Eng Chiew
- Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia; The Westmead Institute for Medical Research, Sydney, Australia
| | - Michael Churchman
- Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, University of Edinburgh, UK
| | - Anna DeFazio
- Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia; The Westmead Institute for Medical Research, Sydney, Australia; The University of Sydney, Sydney, Australia
| | - Sian Fereday
- Peter MacCallum Cancer Centre, Melbourne, Australia; The University of Melbourne, Melbourne, Australia
| | | | - Charlie Gourley
- Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, University of Edinburgh, UK
| | | | - Joy Hendley
- Peter MacCallum Cancer Centre, Melbourne, Australia
| | | | | | | | | | | | - Jason Li
- Peter MacCallum Cancer Centre, Melbourne, Australia
| | | | - Orla M McNally
- Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Royal Womens Hospital, Parkville, Australia
| | | | - Jan Pyman
- Royal Womens Hospital, Parkville, Australia; Royal Children's Hospital, Flemington, Australia
| | | | | | | | | | | | - Niko Thio
- Peter MacCallum Cancer Centre, Melbourne, Australia
| | | | - Nadia Traficante
- Peter MacCallum Cancer Centre, Melbourne, Australia; The University of Melbourne, Melbourne, Australia
| | | | - Yoland C Antill
- Cabrini Health, Malvern, Australia; Frankston Hospital, Frankston, Australia
| | - Ian G Campbell
- Peter MacCallum Cancer Centre, Melbourne, Australia; The University of Melbourne, Melbourne, Australia
| | - Clare L Scott
- Peter MacCallum Cancer Centre, Melbourne, Australia; The University of Melbourne, Melbourne, Australia; Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Royal Melbourne Hospital, Parkville, Australia; Royal Womens Hospital, Parkville, Australia
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27
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Rosati G, Galli F, Cantore M, Bergamo F, Banzi M, Zampino MG, Mattioli R, Cardellino GG, Ronzoni M, Di Bartolomeo M, Tamberi S, Marchetti P, Rimassa L, Corsi D, Bochicchio AM, Artioli F, Labianca R, Galli F, Rulli E, Bilancia D, Bregni G. Predictive Impact of Mucinous Tumors on the Clinical Outcome in Patients with Poorly Differentiated, Stage II Colon Cancer: A TOSCA Subgroup Analysis. Oncologist 2020; 25:e928-e935. [PMID: 31943506 DOI: 10.1634/theoncologist.2019-0736] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 12/19/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Although American Society of Clinical Oncology and European Society for Medical Oncology guidelines have identified the negative prognostic factors that clinicians have to consider when treating their patients with stage II colon cancer (CC), the role of histological subtype is controversial. SUBJECTS, MATERIALS, AND METHODS The randomized, multicenter, phase III TOSCA trial compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy in 3,759 patients with high-risk stage II or stage III CC. The objective of this substudy was to evaluate the influence of histological subtypes on the impact of the treatment duration of adjuvant chemotherapy in terms of relapse-free survival (RFS) and overall survival (OS) in 85 mucinous adenocarcinoma (MUC) and 389 nonmucinous adenocarcinoma (NMUC) patients with high-risk stage II, grade 3 CC. RESULTS A significant interaction between treatment duration and histology was observed in both RFS (p = .027) and OS (p = .017). In the subgroup of patients with MUC, worse RFS (adjusted hazard ratio [HR], 3.95; 95% confidence interval [CI], 1.03-15.17; p = .045) and OS (HR, 9.56; 95% CI, 1.14-79.98; p = .037) were detected for patients treated in the 3-month arm. No statistically significant differences were found in the subgroup of patients with NMUC. CONCLUSION Patients with MUC, grade 3, stage II CC require special attention and may need 6 months of oxaliplatin-based chemotherapy. Larger studies are required to assess the combined use of histology and other prognostic/predictive factors to define the administration of chemotherapy in patients with stage II CC and to improve their prognosis. IMPLICATIONS FOR PRACTICE Although ASCO and ESMO guidelines define the prognostic factors for patients with stage II colon cancer to establish the use of adjuvant chemotherapy, the influence of histological subtypes is controversial in this population. This study underscores that patients with grade 3 mucinous adenocarcinomas may need adjuvant chemotherapy with oxaliplatin and fluoropyrimidines for a duration of 6 months rather than 3 months.
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Affiliation(s)
- Gerardo Rosati
- U.O. Oncologia Medica, Ospedale S. Carlo, Potenza, Italy
| | - Fabio Galli
- Methodology for Clinical Research Laboratory, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Maurizio Cantore
- U.O. Oncologia Medica, Azienda USL 1 di Massa e Carrara, Carrara, Italy
| | - Francesca Bergamo
- U.O. Oncologia Medica 1, IRCCS Istituto Oncologico Veneto, Padova, Italy
| | - Maria Banzi
- U.O. Oncologia Medica, Azienda USL-IRCCS, Reggio Emilia, Italy
| | - Maria Giulia Zampino
- Gastrointestinal Medical Oncology Unit and Neuroendocrine Tumors, IRCCS Istituto Europeo di Oncologia, Milan, Italy
| | - Rodolfo Mattioli
- U.O. Oncologia Medica, Azienda Ospedaliera Marche Nord, Pesaro/Fano, Italy
| | | | - Monica Ronzoni
- U.O. Oncologia Medica, Ospedale San Raffaele, Milan, Italy
| | | | - Stefano Tamberi
- U.O. Oncologia Medica, Ospedale degli Infermi, Faenza, Italy
| | - Paolo Marchetti
- U.O. Oncologia Medica, Ospedale Sant'Andrea, Università Sapienza, Roma e IRCCS Istituto Dermopatico dell'Immacolata, Rome, Italy
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center IRCCS, Rozzano, Italy
| | - Domenico Corsi
- U.O. Oncologia Medica, Ospedale S. Giovanni Calibita Fatebenefratelli, Rome, Italy
| | - Anna Maria Bochicchio
- U.O. Oncologia Medica, Ospedale Oncologico Regionale CROB, Rionero in Vulture, Italy
| | | | | | - Francesca Galli
- Methodology for Clinical Research Laboratory, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Eliana Rulli
- Methodology for Clinical Research Laboratory, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | | | - Giacomo Bregni
- U.O. Oncologia Medica, IRCCS San Martino-IST, Genova, Italy
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Mathews NS, Masih D, Mittal R, Perakath B, Sakthi D, Rebekah G, Pai R, Pulimood AB. Microsatellite instability in young patients with mucinous colorectal cancers - characterization using molecular testing, immunohistochemistry, and histological features. Indian J Cancer 2019; 56:309-314. [PMID: 31607698 DOI: 10.4103/ijc.ijc_224_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
CONTEXT The incidence of colorectal cancers (CRCs) in young Indian patients is higher than the international average. CRCs in young patients are commonly of mucinous type and show microsatellite instability (MSI). AIMS To ascertain the MSI status of mucinous CRCs in patients ≤40 years of age by molecular testing and to correlate this with immunohistochemical (IHC) analysis and tumor histology. SUBJECTS AND METHODS Archived formalin-fixed paraffin embedded tissue blocks of 30 young mucinous CRC patients were retrieved. MSI testing was done using two mononucleotide markers - BAT26 and NR24. IHC analysis was done using MLH1, MSH2, and MSH6. Histological features of all cases were studied. Data were analyzed using the SPSS software and the Pearson's chi-square test and Fisher's exact test. RESULTS Eight out of 30 cases (26.7%) showed MSI by molecular testing. IHC identified seven of these cases. Histological features showing a statistically significant association with MSI were the presence of a well-differentiated adenocarcinoma component (P = 0.003), peritumoral lymphocytes (P = 0.002) and tumor budding (P = 0.021). CONCLUSION The detection of defective mismatch repair (MMR) proteins using IHC for MLH1, MSH2, and MSH6 and molecular testing using BAT26 and NR24 appears to be a good protocol to detect CRCs with MSI. Histology could be useful in identifying cases that require screening for presence of MMR protein defects.
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Affiliation(s)
- Nitty Skariah Mathews
- Department of General Pathology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Dipti Masih
- Department of General Pathology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Rohin Mittal
- Department of Colorectal Surgery, Christian Medical College, Vellore, Tamil Nadu, India
| | - Benjamin Perakath
- Department of Colorectal Surgery, Christian Medical College, Vellore, Tamil Nadu, India
| | - Dhananjayan Sakthi
- Department of General Pathology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Grace Rebekah
- Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India
| | - Rekha Pai
- Department of General Pathology, Christian Medical College, Vellore, Tamil Nadu, India
| | - Anna B Pulimood
- Department of General Pathology, Christian Medical College, Vellore, Tamil Nadu, India
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Fields AC, Lu P, Goldberg J, Irani J, Bleday R, Melnitchouk N. The role of adjuvant chemotherapy in stage II and III mucinous colon cancer. J Surg Oncol 2019; 120:1190-1200. [PMID: 31536150 DOI: 10.1002/jso.25705] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 09/07/2019] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Mucinous adenocarcinoma is a subtype of colonic adenocarcinoma associated with worse survival compared to nonmucinous adenocarcinoma. Prior studies on the effect of chemotherapy on survival in mucinous adenocarcinoma have shown mixed results. The aim of this study is to evaluate the effect of chemotherapy on the survival of patients with stage II and III mucinous adenocarcinoma. METHODS The National Cancer Database was used to identify patients diagnosed with stage II or III nonmucinous adenocarcinoma or mucinous adenocarcinoma between 2004 and 2016. The primary outcome was overall survival. RESULTS Fourteen thousand and three hundred patients with stage II mucinous colon adenocarcinoma and 16 741 patients with stage III mucinous colon adenocarcinoma were identified. There was no significant difference in survival between nonmucinous adenocarcinoma and mucinous adenocarcinoma patients in adjusted analysis for stage II disease (HR:1.00, 95%CI:0.98-1.02, P = .99), but there was a significant difference for stage III disease (HR:1.05, 95%CI:1.03-1.07, P < .001). In propensity-matched cohorts of patients with mucinous adenocarcinoma, chemotherapy was significantly associated with survival in stage II (HR:0.79, 95%CI:0.69-0.90, P < .001) and stage III disease (HR:0.56, 95%CI:0.52-0.60, P < .001). CONCLUSIONS Patients with stage II or stage III mucinous adenocarcinoma of the colon who are given adjuvant chemotherapy have significantly improved survival compared to patients not given chemotherapy.
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Affiliation(s)
- Adam C Fields
- Department of Surgery, Division of Colorectal Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Pamela Lu
- Department of Surgery, Division of Colorectal Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.,Center for Surgery and Public Health, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Joel Goldberg
- Department of Surgery, Division of Colorectal Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Jennifer Irani
- Department of Surgery, Division of Colorectal Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Ronald Bleday
- Department of Surgery, Division of Colorectal Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Nelya Melnitchouk
- Department of Surgery, Division of Colorectal Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.,Center for Surgery and Public Health, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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Abstract
Adolescent and young adult (AYA) patients with cancer have not attained the same improvements in overall survival as either younger children or older adults. One possible reason for this disparity may be that the AYA cancers exhibit unique biologic characteristics, resulting in differences in clinical and treatment resistance behaviors. Our current understanding of the unique biological/genomic characteristics of AYA cancers is limited. However, there has been some progress that has provided clues about the biology of AYA cancers. We here review the latest findings in the area of AYA cancer biology and discuss what is required to advance the field for the more effective treatment of this patient population.
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Song IH, Hong SM, Yu E, Yoon YS, Park IJ, Lim SB, Kim JC, Yu CS, Kim J. Signet ring cell component predicts aggressive behaviour in colorectal mucinous adenocarcinoma. Pathology 2019; 51:384-391. [PMID: 31029443 DOI: 10.1016/j.pathol.2019.03.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 01/15/2019] [Accepted: 03/01/2019] [Indexed: 12/25/2022]
Abstract
Mucinous adenocarcinoma (MAC) is defined by the presence of extracellular mucin covering more than 50% of the tumour area; however, MAC is histologically heterogeneous and some cases exhibit signet ring cell components. The aim of this study was to determine the prognostic impact of such variable morphology. A total of 299 consecutive MAC patients who underwent curative surgery were included. MACs were classified into four categories according to the predominant pattern of floating tumour cells: strips (27.1%), clusters (51.8%), signet ring cells (6.7%), and mixed clusters and signet ring cells (14.4%). In addition, we categorised MACs according to the relative amount of mucin. MACs with signet ring cell component were clearly associated with poor overall and recurrence-free survivals. Moreover, MACs with more than 50% signet ring cell component showed particularly poor clinical outcome just like non-mucinous signet ring cell carcinoma. MACs with a greater amount of extracellular mucin were associated with poor recurrence-free survival, independent of the pathological stage. In addition, lymphovascular and perineural invasion, advanced pathological stage, and old age at diagnosis were also prognostic factors for poor overall survival. MACs with more than 50% signet ring cell component should be classified as signet ring cell carcinoma and the presence of signet ring cells should be included in the pathology report of MACs with 10-50% signet ring cell component.
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Affiliation(s)
- In Hye Song
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Seung-Mo Hong
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Eunsil Yu
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Yong Sik Yoon
- Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - In Ja Park
- Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Seok-Byung Lim
- Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Jin Cheon Kim
- Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Chang Sik Yu
- Division of Colon and Rectal Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
| | - Jihun Kim
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
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Barresi V, Cinnirella G, Valenti G, Spampinato G, Musso N, Castorina S, Condorelli DF. Gene expression profiles in genome instability-based classes of colorectal cancer. BMC Cancer 2018; 18:1265. [PMID: 30563495 PMCID: PMC6299572 DOI: 10.1186/s12885-018-5174-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 12/03/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Broad copy number aberrations (BCNAs) represent a common form of genome instability in colorectal cancer (CRC). CRCs show large variations in their level of aneuploidy: microsatellite-instable (MSI) tumors are known to have a near-diploid karyotype while microsatellite-stable (MSS) tumors show high level of chromosomal instability. However, MSS tumors have great heterogeneity in the number of BCNAs, with a minor percentage of samples showing an almost normal karyotype. In the present work we subdivided MSS CRCs according to a "BCNA score" and characterized their transcriptome profiles, considered as a proxy to their phenotypic features. METHODS Microsatellite testing, genome-wide DNA copy number and whole-transcript expression analysis (HTA) were performed on 33 tumor samples and 25 normal colonic tissue samples from 32 CRC patients. 15.1% of the samples were MSI tumors (n = 5), whereas 84.9% were MSS tumors (n = 28). Gene expression data of 34 additional MSI tumors was retrieved from a public functional genomics data repository. RESULTS Using as a threshold the first quartile of the BCNA score distribution, MSS samples were classified as low-BCNA (LB, n = 7) or high-BCNA (HB, n = 21). LB tumors were enriched for mucinous CRCs and their gene-expression profile resembled that of MSI samples for what concerns a subset of genes involved in secretory processes, mucosal protection, and extracellular matrix remodeling. HB tumors were predominantly non-mucinous adenocarcinomas and showed overexpression of a subset of genes typical of surface colonocytes and EGF signaling. A large percentage of unclassified samples according to the consensus molecular subtypes (CMS) classifier was found in the LB group (43%), whereas 76% HB tumors belonged to CMS2. CONCLUSIONS A classification of colorectal tumors based on the number of BCNAs identifies two groups of MSS tumors which differ for histopathology and gene expression profile. Such information can be exploited for its translational relevance in different aspects of CRC clinical management.
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Affiliation(s)
- Vincenza Barresi
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123 Catania, Italy
- Laboratory of Complex Systems, Scuola Superiore di Catania, University of Catania, Catania, Italy
| | - Giacomo Cinnirella
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123 Catania, Italy
| | - Giovanna Valenti
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123 Catania, Italy
| | - Giorgia Spampinato
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123 Catania, Italy
| | - Nicolò Musso
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123 Catania, Italy
| | - Sergio Castorina
- Department of Surgical Medical Sciences and Advanced Technologies “G. F. Ingrassia”, University of Catania, Catania, Italy
- Fondazione Mediterranea G.B. Morgagni, Catania, Italy
| | - Daniele F. Condorelli
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123 Catania, Italy
- Laboratory of Complex Systems, Scuola Superiore di Catania, University of Catania, Catania, Italy
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Gonzalez RS, Cates JMM, Washington K. Associations among histological characteristics and patient outcomes in colorectal carcinoma with a mucinous component. Histopathology 2018; 74:406-414. [PMID: 30160323 DOI: 10.1111/his.13748] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 08/25/2018] [Indexed: 12/25/2022]
Abstract
AIMS Colorectal carcinoma (CRC) often has a mucinous component, with more than 50% mucin by volume defining the mucinous subtype of CRC. The prognostic impact of the mucinous phenotype remains unclear. METHODS AND RESULTS We evaluated 224 CRC with at least 5% mucinous component (herein 'mCRC') for patient sex, age, race and outcome; tumour size, location, stage and microsatellite instability (MSI) status; percentage of glands producing mucin; percentage of tumour volume composed of mucin; whether tumoral epithelium floated in mucin pools; tumour budding; signet ring cells (SRCs); and peritumoural inflammation (PI). We related these features to disease-specific survival and compared outcomes to 499 stage-matched, conventional colorectal adenocarcinomas. Factors predicting worse prognosis in mCRC on univariable analysis included non-MSI-high status (P = 0.0008), SRC (P = 0.0017) and lack of PI (P = 0.0034). No parameters were independently associated with outcome after adjusting for tumour stage in multivariate analysis. The percentage of glands producing mucin and percentage tumour volume composed of mucin did not affect prognosis, including at the recommended 50% cut-off for subtyping mCRC. Disease-specific survival for mCRC and adenocarcinomas were similar after accounting for stage. CONCLUSIONS Stage-matched mCRCs and adenocarcinomas have similar outcomes, with no prognostic significance to morphological subtyping. Histological characteristics of mCRC, including percentage of tumour volume comprised of mucin, were not predictive of outcome.
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Affiliation(s)
- Raul S Gonzalez
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Justin M M Cates
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
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Ackermann CJ, Guller U, Jochum W, Schmied BM, Warschkow R. The prognostic value of signet ring cell histology in stage I/II colon cancer-a population-based, propensity score-matched analysis. Int J Colorectal Dis 2018; 33:1183-1193. [PMID: 29881972 DOI: 10.1007/s00384-018-3096-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/22/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Previous research associated signet ring cell histology in colon cancer patients with poor survival outcomes. The aim of this study was to analyze the prognostic significance of signet ring cell histology on overall and cancer-specific survival in patients with localized colon cancer. METHODS Stage I and II colon cancer patients treated with surgical resection between 2004 and 2015 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were assessed using risk-adjusted Cox proportional hazards regression models and propensity score methods. RESULTS Eighty-eight thousand nine hundred fifty-eight stage I-II colon cancer patients were identified. Overall, 446 (0.5%) showed signet ring cell histology. In unadjusted analyses, the 5-year OS and CSS rates of patients with signet ring cell histology were 65.8 and 83.1%, respectively, compared with 74.3 and 88.7% in patients with non-signet ring cell adenocarcinoma (p values: OS, p < 0.001; CSS, p < 0.001). Neither in risk-adjusted Cox proportional hazard regression analysis (OS: hazard ratio (HR), 0.96 (95% CI, 0.82-1.12%) p = 0.616; CSS: HR, 1.01 (95% CI, 0.79-1.28%) p = 0.946) nor with propensity score matching (OS: HR, 0.96 (95% CI, 0.82-1.14%) p = 0.669 and CSS: HR: 1.09 (95% CI: 0.84-1.40%) p = 0.529), a survival disadvantage was found for signet ring cell histology. CONCLUSION This is the first propensity score-adjusted population-based investigation on exclusively stage I and II colon cancer patients providing compelling evidence that signet ring cell histology does not negatively impact survival in stage I and II colon cancer after risk-adjusting for known prognostic factors. Therefore, standard treatment strategies can be applied in these patients.
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Affiliation(s)
- Christoph Jakob Ackermann
- Division of Medical Oncology and Hematology, Kantonsspital St. Gallen, 9007, St. Gallen, Switzerland
| | - Ulrich Guller
- Division of Medical Oncology and Hematology, Kantonsspital St. Gallen, 9007, St. Gallen, Switzerland.,University Clinics for Visceral Surgery and Medicine, University Hospital Berne, 3010, Berne, Switzerland
| | - Wolfram Jochum
- Institute of Pathology, Kantonsspital St. Gallen, 9007, St. Gallen, Switzerland
| | - Bruno M Schmied
- Department of Surgery, Kantonsspital St. Gallen, 9007, St. Gallen, Switzerland
| | - Rene Warschkow
- Department of Surgery, Kantonsspital St. Gallen, 9007, St. Gallen, Switzerland. .,Institute of Medical Biometry and Informatics, University of Heidelberg, 69120, Heidelberg, Germany.
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Abstract
GOALS The aim of this study was to assess the histopathologic characteristics of colorectal carcinomas (CRC) in patients with Crohn's disease (CD). BACKGROUND A higher frequency of microsatellite instability (MSI) is seen in mucinous compared with nonmucinous CRC which suggests that its pathogenesis involves distinct molecular pathways. Several publications reported a higher percentage of mucinous adenocarcinoma in CD patients with CRC. So far, there has been no investigation of MSI in CD patients with mucinous CRC. STUDY The medical records of patients who underwent surgery for CRC were reviewed and those with a history of CD identified. The data of histologic classification and MSI status of the tumor were investigated. RESULTS Fourteen patients with CD-associated CRC were identified (5 female, 9 male) resulting in 20 CRC in total. Histologic investigation revealed 7 adenocarcinomas without a mucinous or signet ring cell component. All other CRCs harbored a mucinous (n=11) and/or signet ring cell (n=6) component. All tumors assessed for MSI were found to be microsatellite stable. CONCLUSIONS Our data indicate that CRCs with signet ring cell and mucinous components were much more common in patients with CD than in patients with sporadic CRC. This observation suggests that CRC in CD represent an own entity with distinct histopathologic and molecular features. This may implicate potential consequences for diagnosis and therapy of CRC in CD in the future as well as new factors to identify patients with an increased risk for developing CRC in CD.
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Gil-Raga M, Jantus-Lewintre E, Gallach S, Giner-Bosch V, Frangi-Caregnato A, Safont-Aguilera MJ, Garde-Noguera J, Zorraquino-Pina E, García-Martínez M, Camps-Herrero C. Molecular subtypes in early colorectal cancer associated with clinical features and patient prognosis. Clin Transl Oncol 2018; 20:1422-1429. [DOI: 10.1007/s12094-018-1874-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 04/01/2018] [Indexed: 12/13/2022]
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Patra T, Mandal S, Alam N, Murmu N. Clinicopathological trends of colorectal carcinoma patients in a tertiary cancer centre in Eastern India. CLINICAL EPIDEMIOLOGY AND GLOBAL HEALTH 2018. [DOI: 10.1016/j.cegh.2017.04.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Sarioglu S, Akturk G, Sokmen S, Ellidokuz H, Canda AE, Unlu M, Sirin AH, Sagol O, Terzi C, Fuzun M. The Prognostic Implications of FIX and FLO Patterns in Mucinous Colon Carcinomas. J Gastrointest Cancer 2018; 50:254-259. [PMID: 29376207 DOI: 10.1007/s12029-018-0059-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE Colon mucinous carcinomas (MUCs) have two morphological patterns: (i) glands lined by mucinous epithelium with direct contact to the stroma (FIX) and (ii) carcinoma cells floating in mucin (FLO). In this study, we evaluated the prognostic value of these patterns. METHODS Digital images were captured from the 38 MUC's tissue sections. A grid with 140 points was laid over the computer screen. Totally, 100 points, falling on tumor cells floating in mucin (FLO patterned cells) or on cells contacting stroma (FIX patterned cells), were counted. Tumors were grouped according to the median value of the FIX patterned cells. Cases with more than this value were grouped as FIX and less were grouped as FLO cases. The prognostic value of FIX and FLO pattern was evaluated. RESULTS The median for FIX patterned cells was 66%, and the cases with lower values than this were grouped as FLO (N = 18; 47.37%), while the rest were grouped as FIX cases. There was no significant difference between FIX and FLO cases for overall survival cases (p = 0.167). For FIX cases, 62.7 and 51.3% of the patients were alive at second and third years, while this was 78.9 and 72.4% for the FLO group, respectively. CONCLUSIONS This is the first study using a quantitative methodology depending on count pointing to evaluate FIX/FLO feature of MUCs to the best of our knowledge, although we could not observed any prognostic and clinicopathologic relationship statistically. This distinctive feature should be studied in larger cohorts with prognostic information, with a quantitative method, like the one that was applied in this study, in order to achieve strict conclusions.
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Affiliation(s)
- Sulen Sarioglu
- Faculty of Medicine, Department of Pathology, Dokuz Eylul University, Inciralti, Izmir, Turkey.
| | - Guray Akturk
- Faculty of Medicine, Department of Pathology, Dokuz Eylul University, Inciralti, Izmir, Turkey.,Memorial Sloan Kettering Cancer Center, Department of Pathology, Precision Pathology Biobanking Center, New York, USA
| | - Selman Sokmen
- Faculty of Medicine, Department of General Surgery, Dokuz Eylul University, Izmir, Turkey
| | - Hulya Ellidokuz
- Faculty of Medicine, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey
| | - Aras Emre Canda
- Faculty of Medicine, Department of General Surgery, Dokuz Eylul University, Izmir, Turkey
| | - Mehtat Unlu
- Faculty of Medicine, Department of Pathology, Dokuz Eylul University, Inciralti, Izmir, Turkey
| | - Abdullah Haluk Sirin
- Faculty of Medicine, Department of General Surgery, Dokuz Eylul University, Izmir, Turkey
| | - Ozgul Sagol
- Faculty of Medicine, Department of Pathology, Dokuz Eylul University, Inciralti, Izmir, Turkey
| | - Cem Terzi
- Faculty of Medicine, Department of General Surgery, Dokuz Eylul University, Izmir, Turkey
| | - Mehmet Fuzun
- Faculty of Medicine, Department of General Surgery, Dokuz Eylul University, Izmir, Turkey
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Yun SO, Cho YB, Lee WY, Kim HC, Yun SH, Park YA, Huh JW. Clinical Significance of Signet-Ring-Cell Colorectal Cancer as a Prognostic Factor. Ann Coloproctol 2017; 33:232-238. [PMID: 29354606 PMCID: PMC5768478 DOI: 10.3393/ac.2017.33.6.232] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 09/29/2017] [Indexed: 12/22/2022] Open
Abstract
Purpose The aim of this study is to evaluate the prognosis for patients with a signet-ring-cell carcinoma (SRCC) who undergo curative surgery by comparing them to patients with an adenocarcinoma (ADC), excluding a mucinous ADC. Methods Between September 1994 and December 2013, 14,110 patients with colorectal cancer underwent surgery and among them, 12,631 patients were enrolled in this study. 71 patients with a SRCC and 12,570 patients with a ADC were identified. We analyzed the disease-free survival and the overall survival rates before and after a 1:2 propensity score matching and evaluated those rates after stage stratification. Results The median follow-up durations were 48.5 months for the SRC group and 48.6 months for the ADC group. The disease-free survival rates and the overall survival rates were significantly lower in the SRC group before and after propensity score matching (P < 0.001). After stratification by stage, no differences were observed between the SRC and the ADC groups for the disease-free survival (DFS) and the overall survival (OS) rates for patients with cancer in its early stages (P = 0.913 and P = 0.380 for the DFS and the OS, respectively, in stages 0 and I, and P = 0.223 and P = 0.991 for the DFS and the OS, respectively, in stage II), but those rates were significantly lower in the SRC group for cancer in its later stages (P < 0.001, respectively in stages III and IV). Conclusion For cancer in advanced stages, patients with a resectable colorectal SRCC had a poorer prognosis after propensity score matching than those with an ADC did. Therefore, more intensive surveillance and closer observation should be offered to such patients.
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Affiliation(s)
- Sang-Oh Yun
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong Beom Cho
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Woo Yong Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Cheol Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seong Hyeon Yun
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yoon Ah Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jung Wook Huh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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A Comprehensive Evaluation of Special AT-rich Sequence-binding Protein 2 (SATB2) Immunohistochemical Staining in Mucinous Tumors From Gastrointestinal and Nongastrointestinal Sites. Appl Immunohistochem Mol Morphol 2017; 27:378-385. [PMID: 29271791 DOI: 10.1097/pai.0000000000000627] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Special AT-rich sequence-binding protein 2 (SATB2) is an accurate marker for conventional colorectal carcinoma (CRC), although its sensitivity and specificity in mucinous tumors from the colon and other sites remains unknown. The objective of this study is to evaluate the accuracy of SATB2 expression detected by immunohistochemical assay, as a marker of primary CRC in mucinous adenocarcinomas. SATB2 immunohistochemical stains were performed on whole sections from 63 conventional CRCs (controls), 47 mucinous CRCs (mCRC), and 182 noncolorectal mucinous tumors. SATB2 intensity was scored as 1 to 3 based on the estrogen receptor/progesterone receptor grading system, and the percent positive cells was scored in broad categories as follows: 0 (negative)≤5%, 1=5% to 49%, 2≥50%. An optimal sensitivity/specificity pairing (83% and 95%, respectively) was achieved in the mCRCs when the additive intensity and percent score was ≥3 (ie, intensity score+percent score=total score). Defining this total score (histologic score/"H score") as a "positive" result, the sensitivity of SATB2 for conventional CRC was 98% (62/63) versus 83% (39/47) for mCRCs (P=0.02); whereas 5% (9/182) of all noncolorectal mucinous tumors were considered positive. SATB2 especially demonstrated reduced specificity when applied to mucinous gastroesophageal and breast carcinomas, which showed significant expression in 27% and 9% of cases, respectively. In summary, SATB2 is a less sensitive marker of colorectal origin in mCRC compared with conventional CRC and shows significantly reduced specificity in mucinous gastroesophageal and breast primaries.
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Tricoli JV, Boardman LA, Patidar R, Sindiri S, Jang JS, Walsh WD, McGregor PM, Camalier CE, Mehaffey MG, Furman WL, Bahrami A, Williams PM, Lih CJ, Conley BA, Khan J. A mutational comparison of adult and adolescent and young adult (AYA) colon cancer. Cancer 2017; 124:1070-1082. [PMID: 29194591 DOI: 10.1002/cncr.31136] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 09/25/2017] [Accepted: 10/17/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND It is possible that the relative lack of progress in treatment outcomes among adolescent and young adult (AYA) patients with cancer is caused by a difference in disease biology compared with the corresponding diseases in younger and older individuals. There is evidence that colon cancer is more aggressive and has a poorer prognosis in AYA patients than in older adult patients. METHODS To further understand the molecular basis for this difference, whole-exome sequencing was conducted on a cohort of 30 adult, 30 AYA, and 2 pediatric colon cancers. RESULTS A statistically significant difference in mutational frequency was observed between AYA and adult samples in 43 genes, including ROBO1, MYC binding protein 2 (MYCBP2), breast cancer 2 (early onset) (BRCA2), MAP3K3, MCPH1, RASGRP3, PTCH1, RAD9B, CTNND1, ATM, NF1; KIT, PTEN, and FBXW7. Many of these mutations were nonsynonymous, missense, stop-gain, or frameshift mutations that were damaging. Next, RNA sequencing was performed on a subset of the samples to confirm the mutations identified by exome sequencing. This confirmation study verified the presence of a significantly greater frequency of damaging mutations in AYA compared with adult colon cancers for 5 of the 43 genes (MYCBP2, BRCA2, PHLPP1, TOPORS, and ATR). CONCLUSIONS The current results provide the rationale for a more comprehensive study with a larger sample set and experimental validation of the functional impact of the identified variants along with their contribution to the biologic and clinical characteristics of AYA colon cancer. Cancer 2018;124:1070-82. © 2017 American Cancer Society.
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Affiliation(s)
- James V Tricoli
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland
| | - Lisa A Boardman
- Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota
| | - Rajesh Patidar
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Sivasish Sindiri
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Jin S Jang
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - William D Walsh
- Molecular Characterization and Assay Development Laboratory, Leidos, Frederick, Maryland
| | - Paul M McGregor
- Molecular Characterization and Assay Development Laboratory, Leidos, Frederick, Maryland
| | - Corinne E Camalier
- Molecular Characterization and Assay Development Laboratory, Leidos, Frederick, Maryland
| | - Michele G Mehaffey
- Molecular Characterization and Assay Development Laboratory, Leidos, Frederick, Maryland
| | - Wayne L Furman
- Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Armita Bahrami
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - P Mickey Williams
- Molecular Characterization and Assay Development Laboratory, Leidos, Frederick, Maryland
| | - Chih-Jian Lih
- Molecular Characterization and Assay Development Laboratory, Leidos, Frederick, Maryland
| | - Barbara A Conley
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland
| | - Javed Khan
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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Hashmi AA, Ali R, Hussain ZF, Faridi N, Khan EY, Bakar SMA, Edhi MM, Khan M. Mismatch repair deficiency screening in colorectal carcinoma by a four-antibody immunohistochemical panel in Pakistani population and its correlation with histopathological parameters. World J Surg Oncol 2017. [PMID: 28651545 PMCID: PMC5485685 DOI: 10.1186/s12957-017-1158-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background Microsatellite instability (MSI) operates as the second major pathway in the colorectal carcinogenesis. Although genetic testing remains the gold standard for the detection of MSI, the College of American Pathologists (CAP) recommends an initial immunohistochemical workup with a four-antibody panel (MLH1, PMS2, MSH2, and MSH6) to screen for a defective mismatch repair system. An increased trend towards young age colorectal carcinoma (CRC) has been noticed in our population over recent years; however, neither screening for MSI by immunohistochemistry (IHC)/genetic testing was done nor were its morphological features studied. We aimed to determine the frequency of mismatch repair deficiency (dMMR) by loss of IHC expression of the aforementioned enzymes in CRC patients and its correlatation with clinicopathologic parameters. Methods This was a retrospective study conducted at Liaquat National Hospital, Karachi, between 2012 and 2015. A total of 100 cases of CRC were included in the study that underwent surgical resection. IHC stains using antibodies MLH1, PMS2, MSH2, and MSH6 were performed by DAKO EnVision method on representative tissue blocks. The results were interpreted by senior histopathologists and correlated with clinico-pathological parameters. Results A total of 100 cases of CRC were studied that included 51 males and 49 females. Thirty-four percent (n = 34) of the patients showed loss of IHC staining for MMR markers. Combined loss of expression for MLH1/PMS2 were observed in 16% (n = 16) of the cases. Loss of MSH2/MSH6 were seen in 6% (n = 6) of the cases. Loss of expression for all markers were noted in 7% (n = 7) of the cases. There were 5% (n = 5) of the cases that showed isolated loss of MLH1 only. The tumors with dMMR status were significantly associated with right-sided location (p = 0.013), exhibited intra-tumoral lymphocytosis (p = 0.007), and lymphovascular invasion (p = 0.043). No significant association was seen with gender, age, tumor stage, grade, or other morphological features. Conclusion The frequency of mismatch repair deficiency in CRC patients was found to be 34% in Pakistani population which warrants further genetic testing to exclude Lynch syndrome. Moreover, right-sided location and intra-tumoral lymphocyte count may be used to identify patients who may need further workup.
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Affiliation(s)
- Atif Ali Hashmi
- Histopathology department, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Rabia Ali
- Histopathology department, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Zubaida Fida Hussain
- Histopathology department, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Naveen Faridi
- Histopathology department, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Erum Yousuf Khan
- Histopathology department, Liaquat National Hospital and Medical College, Karachi, Pakistan
| | | | - Muhammad Muzzammil Edhi
- Surgery department, Rhode Island Hospital and Brown University, Providence, Rhode Island, USA
| | - Mehmood Khan
- Medicine department, Dhaka University, Dhaka, Bangladesh.
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El-Nakeep S, Rashad N, Oweira H, Schmidt J, Helbling D, Giryes A, Petrausch U, Mehrabi A, Decker M, Abdel-Rahman O. Intraperitoneal chemotherapy and cytoreductive surgery for peritoneal metastases coupled with curative treatment of colorectal liver metastases: an updated systematic review. Expert Rev Gastroenterol Hepatol 2017; 11:249-258. [PMID: 28099818 DOI: 10.1080/17474124.2017.1284586] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We aimed to assess the efficacy and safety of delivering intraperitoneal chemotherapy and cytoreductive surgery for peritoneal metastases coupled with curative treatment of colorectal liver metastases. Areas covered: A comprehensive literature search using PubMed was conducted to screen for eligible records. Studies evaluating colorectal surgery and intraperitoneal chemotherapy combined with curative treatment of liver metastases were included. We excluded duplicate publications. Sixty-seven full-text papers were assessed and six papers were finally included. The overall survival in the included studies ranged from 6-49 months. Five-year survival ranged from 18%-28%, three-year survival ranged from 22%-42% and two-year survival ranged from 34%-78%. Survival was lower in patients with liver metastases and peritoneal carcinomatosis (PC) than those with PC alone in the majority of studies. Expert commentary: This review poses questions rather than presenting answers. The heterogeneity of survival data suggests the possible benefit of this aggressive treatment approach in selected patients. Standardization of the technique used for intraperitoneal chemotherapy instillation, agent used as well as the systemic chemotherapy and targeted therapy type and duration through prospective controlled trials is required to provide an evidence of a higher strength to support or prohibit this treatment strategy.
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Affiliation(s)
- Sarah El-Nakeep
- a Internal Medicine Department, Gastroenterology and Hepatology Division, Faculty of Medicine , Ain Shams University , Cairo , Egypt
| | - Noha Rashad
- b Medical Oncology department , Maadi Military hospital , Cairo , Egypt
| | - Hani Oweira
- c Department of Surgery, Swiss Cancer institute , Zurich , Switzerland.,d Department of General, Visceral and Transplant Surgery , University of Heidelberg , Heidelberg , Germany
| | - Jan Schmidt
- d Department of General, Visceral and Transplant Surgery , University of Heidelberg , Heidelberg , Germany
| | - Daniel Helbling
- e Department of Surgery , OncoCentrum Zurich, Gastrointestinal Tumor Center Zurich (GITZ) , Zurich , Switzerland
| | - Anwar Giryes
- c Department of Surgery, Swiss Cancer institute , Zurich , Switzerland
| | - Ulf Petrausch
- e Department of Surgery , OncoCentrum Zurich, Gastrointestinal Tumor Center Zurich (GITZ) , Zurich , Switzerland
| | - Arianeb Mehrabi
- d Department of General, Visceral and Transplant Surgery , University of Heidelberg , Heidelberg , Germany
| | - Michael Decker
- c Department of Surgery, Swiss Cancer institute , Zurich , Switzerland
| | - Omar Abdel-Rahman
- c Department of Surgery, Swiss Cancer institute , Zurich , Switzerland.,f Clinical Oncology Department, Faculty of Medicine , Ain Shams University , Cairo , Egypt
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Tricoli JV, Bleyer A, Anninga J, Barr R. The Biology of AYA Cancers. CANCER IN ADOLESCENTS AND YOUNG ADULTS 2017. [DOI: 10.1007/978-3-319-33679-4_3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Gelsomino F, Barbolini M, Spallanzani A, Pugliese G, Cascinu S. The evolving role of microsatellite instability in colorectal cancer: A review. Cancer Treat Rev 2016; 51:19-26. [PMID: 27838401 DOI: 10.1016/j.ctrv.2016.10.005] [Citation(s) in RCA: 195] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Revised: 10/17/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023]
Abstract
Microsatellite instability (MSI) is a molecular marker of a deficient mismatch repair (MMR) system and occurs in approximately 15% of colorectal cancers (CRCs), more frequently in early than late-stage of disease. While in sporadic cases (about two-thirds of MSI-H CRCs) MMR deficiency is caused by an epigenetic inactivation of MLH1 gene, the remainder are associated with Lynch syndrome, that is linked to a germ-line mutation of one of the MMR genes (MLH1, MSH2, MSH6, PMS2). MSI-H colorectal cancers have distinct clinical and pathological features such as proximal location, early-stage (predominantly stage II), poor differentiation, mucinous histology and association with BRAF mutations. In early-stage CRC, MSI can select a group of tumors with a better prognosis, while in metastatic disease it seems to confer a negative prognosis. Although with conflicting results, a large amount of preclinical and clinical evidence suggests a possible resistance to 5-FU in these tumors. The higher mutational load in MSI-H CRC can elicit an endogenous immune anti-tumor response, counterbalanced by the expression of immune inhibitory signals, such as PD-1 or PD-L1, that resist tumor elimination. Based on these considerations, MSI-H CRCs seem to be particularly responsive to immunotherapy, such as anti-PD-1, opening a new era in the treatment landscape for patients with metastatic CRC.
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Affiliation(s)
- Fabio Gelsomino
- Division of Oncology, University Hospital of Modena, Via del Pozzo 71, 41124 Modena, Italy.
| | - Monica Barbolini
- Division of Oncology, University Hospital of Modena, Via del Pozzo 71, 41124 Modena, Italy.
| | - Andrea Spallanzani
- Division of Oncology, University Hospital of Modena, Via del Pozzo 71, 41124 Modena, Italy.
| | - Giuseppe Pugliese
- Division of Oncology, University Hospital of Modena, Via del Pozzo 71, 41124 Modena, Italy.
| | - Stefano Cascinu
- Division of Oncology, University Hospital of Modena, Via del Pozzo 71, 41124 Modena, Italy.
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Abstract
PURPOSE Colorectal cancer has a distinct clinicopathologic presentation in younger patients. The aim of this paper was to evaluate the outcome of younger (age below 50 y) and older patients with stage IV (advanced) colorectal cancer in the modern era of combination chemotherapy. METHODS Cases of metastatic colorectal cancer reported in Surveillance, Epidemiology, and End Results registry (1973 to 2008) were reviewed. Demographics, tumor characteristics, and overall and cancer-specific survivals in patients below 50 and above 50 years of age were compared by Cox proportional hazard analyses. Joinpoint regression analysis was used to evaluate secular trends in 2-year survival. RESULTS Younger patients had a greater proportion of negative clinicopathologic features (male sex, African American ethnicity, and signet ring or mucinous histology). In multivariate analysis, older age, male sex, African American ethnicity, right-sided tumors, and signet ring histology were associated with higher mortality risk. Younger patients had improved survival (hazard ratio 0.72; 95% confidence interval: 0.70-0.75) compared with older patients, whereas all patients experienced increased 2-year survival by joinpoint analysis beginning in 1999-2000. CONCLUSIONS The results confirm decreased mortality from advanced colorectal cancer in the era of modern combination chemotherapy in younger and older patients. Younger age, non-right-sided tumors, and absence of signet ring histology significantly associate with better survival.
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Tricoli JV, Blair DG, Anders CK, Bleyer WA, Boardman LA, Khan J, Kummar S, Hayes-Lattin B, Hunger SP, Merchant M, Seibel NL, Thurin M, Willman CL. Biologic and clinical characteristics of adolescent and young adult cancers: Acute lymphoblastic leukemia, colorectal cancer, breast cancer, melanoma, and sarcoma. Cancer 2016; 122:1017-28. [PMID: 26849082 DOI: 10.1002/cncr.29871] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 12/03/2015] [Accepted: 12/04/2015] [Indexed: 01/20/2023]
Abstract
Adolescent and young adult (AYA) patients with cancer have not attained the same improvements in overall survival as either younger children or older adults. One possible reason for this disparity may be that the AYA cancers exhibit unique biologic characteristics, resulting in differences in clinical and treatment resistance behaviors. This report from the biologic component of the jointly sponsored National Cancer Institute and LiveStrong Foundation workshop entitled "Next Steps in Adolescent and Young Adult Oncology" summarizes the current status of biologic and translational research progress for 5 AYA cancers; colorectal cancer breast cancer, acute lymphoblastic leukemia, melanoma, and sarcoma. Conclusions from this meeting included the need for basic biologic, genomic, and model development for AYA cancers as well as translational research studies to elucidate any fundamental differences between pediatric, AYA, and adult cancers. The biologic questions for future research are whether there are mutational or signaling pathway differences (for example, between adult and AYA colorectal cancer) that can be clinically exploited to develop novel therapies for treating AYA cancers and to develop companion diagnostics.
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Affiliation(s)
- James V Tricoli
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland
| | - Donald G Blair
- Division of Cancer Biology, National Cancer Institute, Rockville, Maryland
| | - Carey K Anders
- Department of Medicine, University of North Carolina, Chapel Hill, North Carolina
| | - W Archie Bleyer
- Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon
| | - Lisa A Boardman
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Javed Khan
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Shivaani Kummar
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland
| | - Brandon Hayes-Lattin
- Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon
| | - Stephen P Hunger
- Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Melinda Merchant
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Nita L Seibel
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland
| | - Magdalena Thurin
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, Maryland
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de Freitas IN, de Campos FGCM, Alves VAF, Cavalcante JM, Carraro D, Coudry RDA, Diniz MA, Nahas SC, Ribeiro U. Proficiency of DNA repair genes and microsatellite instability in operated colorectal cancer patients with clinical suspicion of lynch syndrome. J Gastrointest Oncol 2015; 6:628-37. [PMID: 26697194 DOI: 10.3978/j.issn.2078-6891.2015.089] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Lynch syndrome (LS) diagnosis is underestimated, and most of the patients remain undetected after colorectal resections. The study aims to assess the frequency of LS in patients undergoing surgical treatment for colorectal cancer (CRC). METHODS A total of 458 CRC patients were operated from January 2005 to December 2008. Positive CRC family history (FH) was present in 118 (25.8%) patients. Histologic sections were reviewed for microsatellite instability (MSI) criteria (Bethesda guidelines), immunohistochemical (IHC) analysis for MLH1, MSH2, MSH6, PMS2 proteins, through the avidin-biotin-peroxidase complex, MSI (BAT-25, BAT-26, NR-21, NR-24 and MONO-27) and BRAF somatic mutation. RESULTS Of the 118 patients with FH, 61 (51.69%) met at least one of the revised Bethesda criteria. IHC was abnormal in 8 (13.1%) and MSI in 12 patients (20%). BRAF was negative in all cases. MSI histopathological included: intratumoral lymphocytes (47.5%), expansive tumors (29.5%) mucinous component (27.8%) and Crohn's like reaction in (14.7%). There was an association between the revised Bethesda criteria with: sex, mucinous histology and Crohn's like reaction; MSI and IHC with PMS2 and MLH1. Revised Bethesda criteria 4 had 10.6 increased chances to display positive MSI. We have proposed a score to contribute as a practical tool in the diagnosis of LS. CONCLUSIONS The frequence of LS in resected CRC patients was 2.6%. The criterion 4 Revised Bethesda was associated more strongly with the presence of MSI.
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Affiliation(s)
- Isabella Nicácio de Freitas
- 1 Department of Gastroenterology and Pathology, University of São Paulo School of Medicine, São Paulo, SP, Brazil ; 2 Hospital A.C. Camargo, São Paulo, SP, Brazil
| | | | - Venâncio Avancini Ferreira Alves
- 1 Department of Gastroenterology and Pathology, University of São Paulo School of Medicine, São Paulo, SP, Brazil ; 2 Hospital A.C. Camargo, São Paulo, SP, Brazil
| | - Juliana Magalhães Cavalcante
- 1 Department of Gastroenterology and Pathology, University of São Paulo School of Medicine, São Paulo, SP, Brazil ; 2 Hospital A.C. Camargo, São Paulo, SP, Brazil
| | - Dirce Carraro
- 1 Department of Gastroenterology and Pathology, University of São Paulo School of Medicine, São Paulo, SP, Brazil ; 2 Hospital A.C. Camargo, São Paulo, SP, Brazil
| | - Renata de Almeida Coudry
- 1 Department of Gastroenterology and Pathology, University of São Paulo School of Medicine, São Paulo, SP, Brazil ; 2 Hospital A.C. Camargo, São Paulo, SP, Brazil
| | - Márcio Augusto Diniz
- 1 Department of Gastroenterology and Pathology, University of São Paulo School of Medicine, São Paulo, SP, Brazil ; 2 Hospital A.C. Camargo, São Paulo, SP, Brazil
| | - Sérgio Carlos Nahas
- 1 Department of Gastroenterology and Pathology, University of São Paulo School of Medicine, São Paulo, SP, Brazil ; 2 Hospital A.C. Camargo, São Paulo, SP, Brazil
| | - Ulysses Ribeiro
- 1 Department of Gastroenterology and Pathology, University of São Paulo School of Medicine, São Paulo, SP, Brazil ; 2 Hospital A.C. Camargo, São Paulo, SP, Brazil
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Heterogenous MSH6 Loss Is a Result of Microsatellite Instability Within MSH6 and Occurs in Sporadic and Hereditary Colorectal and Endometrial Carcinomas. Am J Surg Pathol 2015; 39:1370-6. [DOI: 10.1097/pas.0000000000000459] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Exploring the role and diversity of mucins in health and disease with special insight into non-communicable diseases. Glycoconj J 2015; 32:575-613. [PMID: 26239922 DOI: 10.1007/s10719-015-9606-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 06/18/2015] [Indexed: 12/11/2022]
Abstract
Mucins are major glycoprotein components of the mucus that coats the surfaces of cells lining the respiratory, digestive, gastrointestinal and urogenital tracts. They function to protect epithelial cells from infection, dehydration and physical or chemical injury, as well as to aid the passage of materials through a tract i.e., lubrication. They are also implicated in the pathogenesis of benign and malignant diseases of secretory epithelial cells. In Human there are two types of mucins, membrane-bound and secreted that are originated from mucous producing goblet cells localized in the epithelial cell layer or in mucous producing glands and encoded by MUC gene. Mucins belong to a heterogeneous family of high molecular weight proteins composed of a long peptidic chain with a large number of tandem repeats that form the so-called mucin domain. The molecular weight is generally high, ranging between 0.2 and 10 million Dalton and all mucins contain one or more domains which are highly glycosylated. The size and number of repeats vary between mucins and the genetic polymorphism represents number of repeats (VNTR polymorphisms), which means the size of individual mucins can differ substantially between individuals which can be used as markers. In human it is only MUC1 and MUC7 that have mucin domains with less than 40% serine and threonine which in turn could reduce number of PTS domains. Mucins can be considered as powerful two-edged sword, as its normal function protects from unwanted substances and organisms at an arm's length while, malfunction of mucus may be an important factor in human diseases. In this review we have unearthed the current status of different mucin proteins in understanding its role and function in various non-communicable diseases in human with special reference to its organ specific locations. The findings described in this review may be of direct relevance to the major research area in biomedicine with reference to mucin and mucin associated diseases.
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