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When does a new sarcoma exist?

When does a new sarcoma exist? Casali et al. Clin Sarcoma Res (2020) 10:19 Clinical Sarcoma Research https://doi.org/10.1186/s13569-020-00141-9 Open Access EDITORIAL 1,2* 3 1 Paolo G. Casali , Angelo Paolo Dei Tos and Alessandro Gronchi Pathologists diagnose cancers by looking at how their immunohistochemistry confirmed and widened mor - morphological, histochemical and molecular character- phological partitioning. Eventually, molecular biology istics cluster in a single case. Almost always this results is doing the same today with morphological and immu- in a high probability of a known pathologic diagno- nohistochemical entities [3]. Possibly more important, sis. Occasionally, clustering falls so far from any known only to some extent does sarcoma partitioning corre- paradigm that a new nosological entity is needed. If so, a spond to an obvious histogenesis, unlike hematological new diagnostic label is proposed and possibly endorsed neoplasms (in which, say, a subgroup of lymphomas may by the medical community, thus entering the “mor- well correspond to a given stage in normal development phology” 5-digit entities of the World Health Organi- of lymphocytes). By and large, in fact, liposarcoma, leio- zation (WHO) International Classification of Diseases myosarcoma and osteosarcoma correspond to obvious – Oncology (ICD-O) and one of the WHO Classification normal tissues, but this is not the case for several other of Tumours series of books (the WHO “blue books”) sarcoma entities. Synovial sarcoma, Ewing sarcoma or [1]. Just as widely known examples in the sarcoma field, solitary fibrous tumor are examples thereof. In the most liposarcoma, leiomyosarcoma and osteosarcoma are well recent WHO Classification of Tumours—Soft Tissue and consolidated entities. The explosion of molecular biol - Bone Tumours, there is a wide array of soft tissue “tumors ogy, with the increasing use of massive parallel sequenc- of uncertain differentiation”, but others can be found ing, is augmenting our chances to find new clusters and amongst the “fibroblastic and myofibroblastic tumours” thereby create new potential entities. Probably, few can- or the “so-called fibrohistiocytic tumors” [2]. Indeed, cers are more exposed thereto than sarcomas. In the last many sarcoma entities which do not correspond to any years, in fact, several new entities have been added to the known normal tissue have a natural history that is so WHO Classification of Tumours—Soft Tissue and Bone peculiar as to single out them clinically. In other words, Tumours, and many others are legitimate candidates [2]. a synovial sarcoma, a Ewing sarcoma or a solitary fibrous u Th s, in the era of “precision medicine”, sarcomas may be tumor have clinical behaviors which are as specific as a privileged area to speculate about which requirements their pathologic aspects. Therefore, there would be no are needed for a new cancer entity to exist. All this is reason to challenge their nosological autonomy. not just an academic issue. In fact, how we conceptually It is worth noting that the lack of a normal counter- cluster diseases in medicine matters a lot about how we part does not necessarily mean the lack of “any” differ - approach them therapeutically. entiation, atypical though it may be. Just as an example, a Why, amongst cancers, are sarcomas so peculiar? desmoplastic small round cell tumor (DSRCT) does not First, they are highly heterogeneous. Only hematologi- correspond to any known normal tissue, but displays a cal neoplasms do present with so many subgroups. The pathologic differentiation which is highly specific. Prob - pathologic heterogeneity of sarcomas was shaped by ably, it is no coincidence that it is related to an “early” cel- early pathologists on the basis of morphology. Then, lular event crucial to the molecular pathogenesis of the tumor: a fusion transcript activating genes underlying, say, histologic desmoplasia. Desmoplasia is a hallmark of *Correspondence: paolo.casali@istitutotumori.mi.it DSRCT, pathologically and clinically, and underlies some Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy Full list of author information is available at the end of the article features of the natural history of these tumors, such as © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Casali et al. Clin Sarcoma Res (2020) 10:19 Page 2 of 3 their forming gross abdominal masses. In the end, some and unspecific vis-à-vis the rest of soft tissue sarcomas. sarcoma entities, though not resembling any normal line- In other words, NTRK fusions are their molecular fea- age, may present with a specific new differentiation, pos - ture, but there is no specific natural history to the best of sibly related to a known strong molecular pathogenesis. knowledge today. On top of that, there is no distinct line A distinct natural history and a distinct clinical behav- of differentiation, nor any reason to regard the molecular ior follow. Under several respects, synovial sarcoma, alteration as clinically relevant, save for the likely activity Ewing sarcoma or solitary fibrous tumor recapitulate this of a class of drugs. Many other cancers will be sensitive to paradigm. these drugs outside sarcomas, that is to say agnostically Today, precision medicine is all about molecularly in regard to histology. On the opposite, a well known characterizing any single case. As from its incepts, the entity such as infantile fibrosarcoma is pathogenetically ambition has been to lead to “a new taxonomy of human related to a gene fusion involving NTRK3, but clearly disease based on molecular biology” [4]. In cancer medi- displays clinical characteristics which are highly specific cine, therapeutically, molecular characterization can (in terms of epidemiology, clinical presentation, evolu- allow to predict sensitivity to treatments, especially tion, prognosis). Its sensitivity to NTRK-inhibitors is just “molecularly targeted therapies”. Many hopes were raised a complement to all that. u Th s, while there is no reason by the introduction of these agents in cancer treatment to challenge the existence of a disease called infantile (in the sarcoma field, this has been eclatant with gastro - fibrosarcoma, one can hardly find reasons, as of today, intestinal stromal tumors), although secondary resistance to regard NTRK-rearranged spindle cell neoplasm as an has proven a formidable limiting factor, such that the autonomous nosological entity. This may be true of other magnitude of clinical benefit has often been limited. On new sarcoma entities. the other hand, medical oncologists are striving to find Our working proposal to the sarcoma community is strong molecular correlates to the activity of the most that new diagnostic entities in the sarcoma field should promising medical therapies in today’s oncology, i.e. never reflect just a new cluster of morphological, those modulating immunity. This said, the idea of preci - immunohistochemical and/or biomolecular character- sion oncology is that medical therapies may effectively istics. Conceptually, when new clusters are appreciated, cut across histologies, as molecular markers do. This is an attempt should be made to correlate them with a widely called “histological agnosticism”. As a result, the distinct natural history. It is true that in rare cancers as first anticancer agents have now received a histologically- sarcomas, all the more in ultrarare cancers as virtually agnostic regulatory approval [5, 6]. An example thereof all new potential sarcoma entities, the low number of are agents inhibiting the neurotrophic tyrosine receptor patients may make it difficult to generate relevant clini - kinase (NTRK), the concept being that a NTRK-inhibitor cal data in due time. Thus, it may be useful to assume may be effective against different malignancies as long as that some specificity in the natural history of disease they harbor a NTRK gene fusion. Then, however, clinical will be more likely if the new cluster corresponds to positioning of the drug will be completely different across either: (1) a normal line of differentiation; (2) a new diseases, being dictated by which is the natural history of clear-cut differentiation, possibly resulting from a the disease, whether at a given stage of disease a medical known strong molecular pathogenesis. In this case, therapy needs to be used, which other agents are available a provisional label could well be accepted, in order to etc. Thus, an NTRK-inhibitor will be used, say, as a last- facilitate clinical data collection. But the simple pres- line therapy in one malignancy and as a first-line therapy ence of a molecular characteristic serving as a predic- in another, and so forth. In other words, the regulatory tor of sensitivity to any anticancer drug should never be approval of a drug may be histologically agnostic, but its enough. This is by no means an obstacle to the fact that clinical use will never be. Indeed, a molecular factor help- it can help tailor medical therapy in any single case and ful to select medical therapies should never become the determine the approval of new agents from the regula- key element to define a disease, powerful though its pre - tory point of view in a histologically-agnostic manner. dictive value may be. This is why one could well challenge We hope that this point of view may be discussed the “emerging” entity named “NTRK-rearranged spindle within the sarcoma community. Possibly, any such dis- cell neoplasm” in the last WHO Classification of Soft Tis - cussion about the “extreme” area of sarcomas could also sue and Bone Tumours [2]. While one may suppose that be of help to other cancer-based communities, at a time these tumors are sensitive to the new NTRK-inhibitors, of precision oncology, which, as a by-product, can gen- the “blue book” depicts their epidemiology, clinical pres- erate so many new molecular clusters. entation, natural history and prognosis as widely variable C asali et al. Clin Sarcoma Res (2020) 10:19 Page 3 of 3 Authors’ contributions 2. The WHO Classification of Tumours Editorial Board. soft tissue and bone All authors discussed, PGC drafted and all authors reviewed the manuscript. tumours. 5th ed. Lyon: International Agency for Research on Cancer; All authors read and approved the final manuscript. 2020. 3. Dei Tos AP. a pattern-based approach to diagnosis. Cambridge: Cam- Competing interests bridge University Press; 2019. PGC received honoraria for speaker, consultancy or advisory role from: Bayer, 4. National Research Council (US) Committee on A Framework for Develop- Deciphera, Eisai, Eli Lilly, Pfizer. His Unit received funds from: Advenchen Labo - ing a New Taxonomy of Disease. Toward Precision Medicine: Building a ratories, Amgen Dompé, AROG Pharmaceuticals, Bayer, Blueprint Medicines, Knowledge Network for Biomedical Research and a New Taxonomy of Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Glaxo, Karyopharm Phar- Disease. Washington: National Academies Press; 2011. maceuticals, Novartis, Pfizer, PharmaMar. APDT received honoraria for advisory 5. Seligson ND, Knepper TC, Ragg S, Walko CM. Developing drugs for tissue- role from: Bayer, Roche, PharaMar. AG received compensation for advisory agnostic indications: a paradigm shift in leveraging cancer biology for role from: Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorkd, Nanobiotix. precision medicine. Clin Pharmacol Ther. 2020. https ://doi.org/10.1002/ He received honoraria from: Lilly, PharmaMar. His Unit received funds from: cpt.1946. PharmaMar. 6. Pestana RC, Sen S, Hobbs BP, Hong DS. considering issues beyond the tissue. Nat Rev Clin Oncol. 2020. https ://doi.org/10.1038/s4157 Author details 1-020-0384-0. 1 2 Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy. University of Milan, Milano, Italy. University of Padova, Padova, Italy. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. References 1. Fritz A, Percy C, Andrew J, Shanmugaratnam K, Sobin L, Parkin DM, Whelan S, editors. International Classification of Diseases for Oncology. 3rd ed. Geneva: World Health Organization; 2013. Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

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Abstract

Casali et al. Clin Sarcoma Res (2020) 10:19 Clinical Sarcoma Research https://doi.org/10.1186/s13569-020-00141-9 Open Access EDITORIAL 1,2* 3 1 Paolo G. Casali , Angelo Paolo Dei Tos and Alessandro Gronchi Pathologists diagnose cancers by looking at how their immunohistochemistry confirmed and widened mor - morphological, histochemical and molecular character- phological partitioning. Eventually, molecular biology istics cluster in a single case. Almost always this results is doing the same today with morphological and immu- in a high probability of a known pathologic diagno- nohistochemical entities [3]. Possibly more important, sis. Occasionally, clustering falls so far from any known only to some extent does sarcoma partitioning corre- paradigm that a new nosological entity is needed. If so, a spond to an obvious histogenesis, unlike hematological new diagnostic label is proposed and possibly endorsed neoplasms (in which, say, a subgroup of lymphomas may by the medical community, thus entering the “mor- well correspond to a given stage in normal development phology” 5-digit entities of the World Health Organi- of lymphocytes). By and large, in fact, liposarcoma, leio- zation (WHO) International Classification of Diseases myosarcoma and osteosarcoma correspond to obvious – Oncology (ICD-O) and one of the WHO Classification normal tissues, but this is not the case for several other of Tumours series of books (the WHO “blue books”) sarcoma entities. Synovial sarcoma, Ewing sarcoma or [1]. Just as widely known examples in the sarcoma field, solitary fibrous tumor are examples thereof. In the most liposarcoma, leiomyosarcoma and osteosarcoma are well recent WHO Classification of Tumours—Soft Tissue and consolidated entities. The explosion of molecular biol - Bone Tumours, there is a wide array of soft tissue “tumors ogy, with the increasing use of massive parallel sequenc- of uncertain differentiation”, but others can be found ing, is augmenting our chances to find new clusters and amongst the “fibroblastic and myofibroblastic tumours” thereby create new potential entities. Probably, few can- or the “so-called fibrohistiocytic tumors” [2]. Indeed, cers are more exposed thereto than sarcomas. In the last many sarcoma entities which do not correspond to any years, in fact, several new entities have been added to the known normal tissue have a natural history that is so WHO Classification of Tumours—Soft Tissue and Bone peculiar as to single out them clinically. In other words, Tumours, and many others are legitimate candidates [2]. a synovial sarcoma, a Ewing sarcoma or a solitary fibrous u Th s, in the era of “precision medicine”, sarcomas may be tumor have clinical behaviors which are as specific as a privileged area to speculate about which requirements their pathologic aspects. Therefore, there would be no are needed for a new cancer entity to exist. All this is reason to challenge their nosological autonomy. not just an academic issue. In fact, how we conceptually It is worth noting that the lack of a normal counter- cluster diseases in medicine matters a lot about how we part does not necessarily mean the lack of “any” differ - approach them therapeutically. entiation, atypical though it may be. Just as an example, a Why, amongst cancers, are sarcomas so peculiar? desmoplastic small round cell tumor (DSRCT) does not First, they are highly heterogeneous. Only hematologi- correspond to any known normal tissue, but displays a cal neoplasms do present with so many subgroups. The pathologic differentiation which is highly specific. Prob - pathologic heterogeneity of sarcomas was shaped by ably, it is no coincidence that it is related to an “early” cel- early pathologists on the basis of morphology. Then, lular event crucial to the molecular pathogenesis of the tumor: a fusion transcript activating genes underlying, say, histologic desmoplasia. Desmoplasia is a hallmark of *Correspondence: paolo.casali@istitutotumori.mi.it DSRCT, pathologically and clinically, and underlies some Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy Full list of author information is available at the end of the article features of the natural history of these tumors, such as © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Casali et al. Clin Sarcoma Res (2020) 10:19 Page 2 of 3 their forming gross abdominal masses. In the end, some and unspecific vis-à-vis the rest of soft tissue sarcomas. sarcoma entities, though not resembling any normal line- In other words, NTRK fusions are their molecular fea- age, may present with a specific new differentiation, pos - ture, but there is no specific natural history to the best of sibly related to a known strong molecular pathogenesis. knowledge today. On top of that, there is no distinct line A distinct natural history and a distinct clinical behav- of differentiation, nor any reason to regard the molecular ior follow. Under several respects, synovial sarcoma, alteration as clinically relevant, save for the likely activity Ewing sarcoma or solitary fibrous tumor recapitulate this of a class of drugs. Many other cancers will be sensitive to paradigm. these drugs outside sarcomas, that is to say agnostically Today, precision medicine is all about molecularly in regard to histology. On the opposite, a well known characterizing any single case. As from its incepts, the entity such as infantile fibrosarcoma is pathogenetically ambition has been to lead to “a new taxonomy of human related to a gene fusion involving NTRK3, but clearly disease based on molecular biology” [4]. In cancer medi- displays clinical characteristics which are highly specific cine, therapeutically, molecular characterization can (in terms of epidemiology, clinical presentation, evolu- allow to predict sensitivity to treatments, especially tion, prognosis). Its sensitivity to NTRK-inhibitors is just “molecularly targeted therapies”. Many hopes were raised a complement to all that. u Th s, while there is no reason by the introduction of these agents in cancer treatment to challenge the existence of a disease called infantile (in the sarcoma field, this has been eclatant with gastro - fibrosarcoma, one can hardly find reasons, as of today, intestinal stromal tumors), although secondary resistance to regard NTRK-rearranged spindle cell neoplasm as an has proven a formidable limiting factor, such that the autonomous nosological entity. This may be true of other magnitude of clinical benefit has often been limited. On new sarcoma entities. the other hand, medical oncologists are striving to find Our working proposal to the sarcoma community is strong molecular correlates to the activity of the most that new diagnostic entities in the sarcoma field should promising medical therapies in today’s oncology, i.e. never reflect just a new cluster of morphological, those modulating immunity. This said, the idea of preci - immunohistochemical and/or biomolecular character- sion oncology is that medical therapies may effectively istics. Conceptually, when new clusters are appreciated, cut across histologies, as molecular markers do. This is an attempt should be made to correlate them with a widely called “histological agnosticism”. As a result, the distinct natural history. It is true that in rare cancers as first anticancer agents have now received a histologically- sarcomas, all the more in ultrarare cancers as virtually agnostic regulatory approval [5, 6]. An example thereof all new potential sarcoma entities, the low number of are agents inhibiting the neurotrophic tyrosine receptor patients may make it difficult to generate relevant clini - kinase (NTRK), the concept being that a NTRK-inhibitor cal data in due time. Thus, it may be useful to assume may be effective against different malignancies as long as that some specificity in the natural history of disease they harbor a NTRK gene fusion. Then, however, clinical will be more likely if the new cluster corresponds to positioning of the drug will be completely different across either: (1) a normal line of differentiation; (2) a new diseases, being dictated by which is the natural history of clear-cut differentiation, possibly resulting from a the disease, whether at a given stage of disease a medical known strong molecular pathogenesis. In this case, therapy needs to be used, which other agents are available a provisional label could well be accepted, in order to etc. Thus, an NTRK-inhibitor will be used, say, as a last- facilitate clinical data collection. But the simple pres- line therapy in one malignancy and as a first-line therapy ence of a molecular characteristic serving as a predic- in another, and so forth. In other words, the regulatory tor of sensitivity to any anticancer drug should never be approval of a drug may be histologically agnostic, but its enough. This is by no means an obstacle to the fact that clinical use will never be. Indeed, a molecular factor help- it can help tailor medical therapy in any single case and ful to select medical therapies should never become the determine the approval of new agents from the regula- key element to define a disease, powerful though its pre - tory point of view in a histologically-agnostic manner. dictive value may be. This is why one could well challenge We hope that this point of view may be discussed the “emerging” entity named “NTRK-rearranged spindle within the sarcoma community. Possibly, any such dis- cell neoplasm” in the last WHO Classification of Soft Tis - cussion about the “extreme” area of sarcomas could also sue and Bone Tumours [2]. While one may suppose that be of help to other cancer-based communities, at a time these tumors are sensitive to the new NTRK-inhibitors, of precision oncology, which, as a by-product, can gen- the “blue book” depicts their epidemiology, clinical pres- erate so many new molecular clusters. entation, natural history and prognosis as widely variable C asali et al. Clin Sarcoma Res (2020) 10:19 Page 3 of 3 Authors’ contributions 2. The WHO Classification of Tumours Editorial Board. soft tissue and bone All authors discussed, PGC drafted and all authors reviewed the manuscript. tumours. 5th ed. Lyon: International Agency for Research on Cancer; All authors read and approved the final manuscript. 2020. 3. Dei Tos AP. a pattern-based approach to diagnosis. Cambridge: Cam- Competing interests bridge University Press; 2019. PGC received honoraria for speaker, consultancy or advisory role from: Bayer, 4. National Research Council (US) Committee on A Framework for Develop- Deciphera, Eisai, Eli Lilly, Pfizer. His Unit received funds from: Advenchen Labo - ing a New Taxonomy of Disease. Toward Precision Medicine: Building a ratories, Amgen Dompé, AROG Pharmaceuticals, Bayer, Blueprint Medicines, Knowledge Network for Biomedical Research and a New Taxonomy of Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Glaxo, Karyopharm Phar- Disease. Washington: National Academies Press; 2011. maceuticals, Novartis, Pfizer, PharmaMar. APDT received honoraria for advisory 5. Seligson ND, Knepper TC, Ragg S, Walko CM. Developing drugs for tissue- role from: Bayer, Roche, PharaMar. AG received compensation for advisory agnostic indications: a paradigm shift in leveraging cancer biology for role from: Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorkd, Nanobiotix. precision medicine. Clin Pharmacol Ther. 2020. https ://doi.org/10.1002/ He received honoraria from: Lilly, PharmaMar. His Unit received funds from: cpt.1946. PharmaMar. 6. Pestana RC, Sen S, Hobbs BP, Hong DS. considering issues beyond the tissue. Nat Rev Clin Oncol. 2020. https ://doi.org/10.1038/s4157 Author details 1-020-0384-0. 1 2 Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy. University of Milan, Milano, Italy. University of Padova, Padova, Italy. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. References 1. Fritz A, Percy C, Andrew J, Shanmugaratnam K, Sobin L, Parkin DM, Whelan S, editors. International Classification of Diseases for Oncology. 3rd ed. Geneva: World Health Organization; 2013. Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions

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Clinical Sarcoma ResearchSpringer Journals

Published: Sep 13, 2020

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