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1. Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement

Author

Moller, P, Seppala, T, Ahadova, A, Crosbie, E, Holinski-Feder, E, Scott, R, Haupt, S, Moslein, G, Winship, I, Broeke, S, Kohut, K, Ryan, N, Bauerfeind, P, Thomas, L, Evans, D, Aretz, S, Sijmons, R, Half, E, Heinimann, K, Horisberger, K, Monahan, K, Engel, C, Cavestro, G, Fruscio, R, Abu-Freha, N, Zohar, L, Laghi, L, Bertario, L, Bonanni, B, Tibiletti, M, Lino-Silva, L, Vaccaro, C, Valle, A, Rossi, B, da Silva, L, de Oliveira Nascimento, I, Rossi, N, Debniak, T, Mecklin, J, Bernstein, I, Lindblom, A, Sunde, L, Nakken, S, Heuveline, V, Burn, J, Hovig, E, Kloor, M, Sampson, J, Dominguez-Valentin, M, Moller P., Seppala T. T., Ahadova A., Crosbie E. J., Holinski-Feder E., Scott R., Haupt S., Moslein G., Winship I., Broeke S. W. B. -T., Kohut K. E., Ryan N., Bauerfeind P., Thomas L. E., Evans D. G., Aretz S., Sijmons R. H., Half E., Heinimann K., Horisberger K., Monahan K., Engel C., Cavestro G. M., Fruscio R., Abu-Freha N., Zohar L., Laghi L., Bertario L., Bonanni B., Tibiletti M. G., Lino-Silva L. S., Vaccaro C., Valle A. D., Rossi B. M., da Silva L. A., de Oliveira Nascimento I. L., Rossi N. T., Debniak T., Mecklin J. -P., Bernstein I., Lindblom A., Sunde L., Nakken S., Heuveline V., Burn J., Hovig E., Kloor M., Sampson J. R., Dominguez-Valentin M., Moller, P, Seppala, T, Ahadova, A, Crosbie, E, Holinski-Feder, E, Scott, R, Haupt, S, Moslein, G, Winship, I, Broeke, S, Kohut, K, Ryan, N, Bauerfeind, P, Thomas, L, Evans, D, Aretz, S, Sijmons, R, Half, E, Heinimann, K, Horisberger, K, Monahan, K, Engel, C, Cavestro, G, Fruscio, R, Abu-Freha, N, Zohar, L, Laghi, L, Bertario, L, Bonanni, B, Tibiletti, M, Lino-Silva, L, Vaccaro, C, Valle, A, Rossi, B, da Silva, L, de Oliveira Nascimento, I, Rossi, N, Debniak, T, Mecklin, J, Bernstein, I, Lindblom, A, Sunde, L, Nakken, S, Heuveline, V, Burn, J, Hovig, E, Kloor, M, Sampson, J, Dominguez-Valentin, M, Moller P., Seppala T. T., Ahadova A., Crosbie E. J., Holinski-Feder E., Scott R., Haupt S., Moslein G., Winship I., Broeke S. W. B. -T., Kohut K. E., Ryan N., Bauerfeind P., Thomas L. E., Evans D. G., Aretz S., Sijmons R. H., Half E., Heinimann K., Horisberger K., Monahan K., Engel C., Cavestro G. M., Fruscio R., Abu-Freha N., Zohar L., Laghi L., Bertario L., Bonanni B., Tibiletti M. G., Lino-Silva L. S., Vaccaro C., Valle A. D., Rossi B. M., da Silva L. A., de Oliveira Nascimento I. L., Rossi N. T., Debniak T., Mecklin J. -P., Bernstein I., Lindblom A., Sunde L., Nakken S., Heuveline V., Burn J., Hovig E., Kloor M., Sampson J. R., and Dominguez-Valentin M.

Abstract

The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an “average sex “or a pathogenic variant in an “average Lynch syndrome gene” and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host’s adaptive immune system’s ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system’s capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.

Published
2023

2. Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database

Author

Dominguez-Valentin, M, Haupt, S, Seppälä, T, Sampson, J, Sunde, L, Bernstein, I, Jenkins, M, Engel, C, Aretz, S, Nielsen, M, Capella, G, Balaguer, F, Evans, D, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Dębniak, T, Fruscio, R, Lopez-Koestner, F, Alvarez-Valenzuela, K, Katz, L, Laish, I, Vainer, E, Vaccaro, C, Carraro, D, Monahan, K, Half, E, Stakelum, A, Winter, D, Kennelly, R, Gluck, N, Sheth, H, Abu-Freha, N, Greenblatt, M, Rossi, B, Bohorquez, M, Cavestro, G, Lino-Silva, L, Horisberger, K, Tibiletti, M, Nascimento, I, Thomas, H, Rossi, N, Apolinário da Silva, L, Zaránd, A, Ruiz-Bañobre, J, Heuveline, V, Mecklin, J, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, P, Therkildsen, C, Madsen, M, Burgdorf, S, Hopper, J, Win, A, Haile, R, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, P, Figueiredo, J, Buchanan, D, Thibodeau, S, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schröck, E, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hüneburg, R, Redler, S, Büttner, R, Weitz, J, Pineda, M, Duenas, N, Vidal, J, Moreira, L, Sánchez, A, Hovig, E, Nakken, S, Green, K, Lalloo, F, Hill, J, Crosbie, E, Mints, M, Goldberg, Y, Dominguez-Valentin M., Haupt S., Seppälä T. T., Sampson J. R., Sunde L., Bernstein I., Jenkins M. A., Engel C., Aretz S., Nielsen M., Capella G., Balaguer F., Evans D. G., Burn J., Holinski-Feder E., Bertario L., Bonanni B., Lindblom A., Levi Z., Macrae F., Winship I., Plazzer J. P., Sijmons R., Laghi L., Della Valle A., Heinimann K., Dębniak T., Fruscio R., Lopez-Koestner F., Alvarez-Valenzuela K., Katz L. H., Laish I., Vainer E., Vaccaro C., Carraro D. M., Monahan K., Half E., Stakelum A., Winter D., Kennelly R., Gluck N., Sheth H., Abu-Freha N., Greenblatt M., Rossi B. M., Bohorquez M., Cavestro G. M., Lino-Silva L. S., Horisberger K., Tibiletti M. G., Nascimento I. d., Thomas H., Rossi N. T., Apolinário da Silva L., Zaránd A., Ruiz-Bañobre J., Heuveline V., Mecklin J. P., Pylvänäinen K., Renkonen-Sinisalo L., Lepistö A., Peltomäki P., Therkildsen C., Madsen M. G., Burgdorf S. K., Hopper J. L., Win A. K., Haile R. W., Lindor N., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J., Buchanan D. D., Thibodeau S. N., von Knebel Doeberitz M., Loeffler M., Rahner N., Schröck E., Steinke-Lange V., Schmiegel W., Vangala D., Perne C., Hüneburg R., Redler S., Büttner R., Weitz J., Pineda M., Duenas N., Vidal J. B., Moreira L., Sánchez A., Hovig E., Nakken S., Green K., Lalloo F., Hill J., Crosbie E., Mints M., Goldberg Y., Dominguez-Valentin, M, Haupt, S, Seppälä, T, Sampson, J, Sunde, L, Bernstein, I, Jenkins, M, Engel, C, Aretz, S, Nielsen, M, Capella, G, Balaguer, F, Evans, D, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Dębniak, T, Fruscio, R, Lopez-Koestner, F, Alvarez-Valenzuela, K, Katz, L, Laish, I, Vainer, E, Vaccaro, C, Carraro, D, Monahan, K, Half, E, Stakelum, A, Winter, D, Kennelly, R, Gluck, N, Sheth, H, Abu-Freha, N, Greenblatt, M, Rossi, B, Bohorquez, M, Cavestro, G, Lino-Silva, L, Horisberger, K, Tibiletti, M, Nascimento, I, Thomas, H, Rossi, N, Apolinário da Silva, L, Zaránd, A, Ruiz-Bañobre, J, Heuveline, V, Mecklin, J, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, P, Therkildsen, C, Madsen, M, Burgdorf, S, Hopper, J, Win, A, Haile, R, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, P, Figueiredo, J, Buchanan, D, Thibodeau, S, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schröck, E, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hüneburg, R, Redler, S, Büttner, R, Weitz, J, Pineda, M, Duenas, N, Vidal, J, Moreira, L, Sánchez, A, Hovig, E, Nakken, S, Green, K, Lalloo, F, Hill, J, Crosbie, E, Mints, M, Goldberg, Y, Dominguez-Valentin M., Haupt S., Seppälä T. T., Sampson J. R., Sunde L., Bernstein I., Jenkins M. A., Engel C., Aretz S., Nielsen M., Capella G., Balaguer F., Evans D. G., Burn J., Holinski-Feder E., Bertario L., Bonanni B., Lindblom A., Levi Z., Macrae F., Winship I., Plazzer J. P., Sijmons R., Laghi L., Della Valle A., Heinimann K., Dębniak T., Fruscio R., Lopez-Koestner F., Alvarez-Valenzuela K., Katz L. H., Laish I., Vainer E., Vaccaro C., Carraro D. M., Monahan K., Half E., Stakelum A., Winter D., Kennelly R., Gluck N., Sheth H., Abu-Freha N., Greenblatt M., Rossi B. M., Bohorquez M., Cavestro G. M., Lino-Silva L. S., Horisberger K., Tibiletti M. G., Nascimento I. d., Thomas H., Rossi N. T., Apolinário da Silva L., Zaránd A., Ruiz-Bañobre J., Heuveline V., Mecklin J. P., Pylvänäinen K., Renkonen-Sinisalo L., Lepistö A., Peltomäki P., Therkildsen C., Madsen M. G., Burgdorf S. K., Hopper J. L., Win A. K., Haile R. W., Lindor N., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J., Buchanan D. D., Thibodeau S. N., von Knebel Doeberitz M., Loeffler M., Rahner N., Schröck E., Steinke-Lange V., Schmiegel W., Vangala D., Perne C., Hüneburg R., Redler S., Büttner R., Weitz J., Pineda M., Duenas N., Vidal J. B., Moreira L., Sánchez A., Hovig E., Nakken S., Green K., Lalloo F., Hill J., Crosbie E., Mints M., and Goldberg Y.

Abstract

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We ackno

Published
2023

5. Perineurioma versus meningioma. A multi-institutional immunohistochemical and ultrastructural studY.

Author

Domínguez-Malagón, H. R., Serrano-Arévalo, M. L., Maldonado, J., Chávez, J., Toussaint-Caire, S., de Almeida, O. P. D., and Lino-Silva, L. S.

Subjects
CELL junctions, MENINGIOMA, PROGESTERONE receptors, CLAUDINS, ULTRASTRUCTURE (Biology), DESMOSOMES
Abstract

The differential diagnosis between perineurioma (PN) and meningioma (MEN) can be difficult by histology and immunohistochemistry (IHC) because the perineurium and arachnoid have the same embryological origin. However, there are no comparative studies determining conclusive parameters for the differential diagnosis. The aim of this study is to compare IHC of PN and MEN and their ultra-structural characteristics to elucidate which are the useful data that allow differentiate both entities. Thirty-five MEN were analyzed, and 15 PN, (11 skin and soft tissues and four oral cavity). IHC for epithelial membrane antigen (EMA), Claudin-1, GLUT-1, somatostatin-2 receptor (SSTR-2), and progesterone receptor (RP) was performed. Ultrastructural studies were performed on 8 MEN and 15 PN. Only in PN Claudin-1 was positive in 9/11 (90%) cases and GLUT-1 in 7/11 (63%) cases. In MEN, the progesterone receptor was expressed in 21/35 (60%) cases and no case expressed Claudin-1 and GLUT-1; EMA was expressed in all MEN cases and 93% of PN. SSTR-2 was expressed weakly in six cases of MEN (17%), and it was not considered useful for differential diagnosis. On ultrastructure, PN showed thin and parallel processes, some caveolae, and lacked cell junctions. The cellular processes were surrounded by a collagenous stroma in 94% of the cases. MEN were characterized by curved cytoplasmic cell processes showing desmosomes in 75% of cases. Ultrastructural findings aid in the differential diagnosis between PN and MEN, especially if molecular studies are not available. [ABSTRACT FROM AUTHOR]

Published
2021
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6. Mantle cell lymphoma with involvement of the digestive tract.

Author

Oña-Ortiz FM, Sánchez-Del Monte J, Ramírez-Solís ME, de la Mora-Levy JG, Alonso-Larraga JO, Lino-Silva LS, Herrera-Servín MA, Jiménez-Morales M, Manzano-Robleda MC, Yañez-Cruz M, and Hernández-Guerrero AI

Subjects
Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Retrospective Studies, Digestive System Neoplasms pathology, Endoscopy, Gastrointestinal, Lymphoma, Mantle-Cell pathology
Abstract

Introduction and Aim: Mantle cell lymphoma is an aggressive subtype of B-cell non-Hodgkin lymphoma and its incidence is 0.5/100,000 inhabitants. Gastrointestinal involvement at diagnosis is 15-30%. The aim of our study was to analyze the clinical and endoscopic characteristics of mantle cell lymphoma affecting the digestive tract., Material and Methods: A retrospective study was conducted, based on a case series of patients with mantle cell lymphoma affecting the gastrointestinal tract that were diagnosed over a 10-year period., Results: Ten patients (11.7%) had gastrointestinal tract involvement. The upper endoscopic findings were polypoid lesions (66%), thickened folds (44%), and nonspecific changes in the mucosa (33%). At colonoscopy, polypoid lesions were viewed in 100% of the patients and ulcerated lesions in 40%., Conclusion: Polypoid lesions are the most common endoscopic characteristics in patients with mantle cell lymphoma of the gastrointestinal tract. Upper endoscopy and colonoscopy should be carried out on patients with mantle cell lymphoma, even those with nonspecific symptoms, to check their gastrointestinal status. Gastrointestinal involvement has an impact on disease staging., (Copyright © 2018 Asociación Mexicana de Gastroenterología. All rights reserved.)

Published
2019
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7. Primary laryngeal sarcomas in a Mexican population: Case series of eleven cases.

Author

Luna-Ortiz K, Navarro-Santiesteban S, Villavicencio-Valencia V, Salcedo-Hernandez RA, Lino-Silva LS, and Delgado JA

Subjects
Adult, Aged, Aged, 80 and over, Cohort Studies, Disease-Free Survival, Female, Humans, Laryngeal Neoplasms mortality, Laryngeal Neoplasms pathology, Male, Mexico, Middle Aged, Sarcoma mortality, Sarcoma pathology, Survival Rate, Treatment Outcome, Young Adult, Laryngeal Neoplasms surgery, Sarcoma surgery
Published
2017
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