ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

Paul G. Kemps; Jennifer Picarsic; Benjamin H. Durham; Zofia Hélias-Rodzewicz; Laura Hiemcke-Jiwa; Cor van den Bos; Marianne D. van de Wetering; Carel J.M. van Noesel; Jan A.M. van Laar; Robert M. Verdijk; Uta E. Flucke; Pancras C.W. Hogendoorn; F. J.Sherida H. Woei-A-Jin; Raf Sciot; Andreas Beilken; Friedrich Feuerhake; Martin Ebinger; Robert Möhle; Falko Fend; Antje Bornemann; Verena Wiegering; Karen Ernestus; Tina Méry; Olga Gryniewicz-Kwiatkowska; Bozenna Dembowska-Baginska; Dmitry A. Evseev; Vsevolod Potapenko; Vadim V. Baykov; Stefania Gaspari; Sabrina Rossi; Marco Gessi; Gianpiero Tamburrini; Sébastien Héritier; Jean Donadieu; Jacinthe Bonneau-Lagacherie; Claire Lamaison; Laure Farnault; Sylvie Fraitag; Marie Laure Jullié; Julien Haroche; Matthew Collin; Jackie Allotey; Majid Madni; Kerry Turner; Susan Picton; Pasquale M. Barbaro; Alysa Poulin; Ingrid S. Tam; Dina El Demellawy; Brianna Empringham; James A. Whitlock; Aditya Raghunathan; Amy A. Swanson; Mariko Suchi; Jon M. Brandt; Nabeel R. Yaseen; Joanna L. Weinstein; Irem Eldem; Bryan A. Sisk; Vaishnavi Sridhar; Mandy Atkinson; Lucas R. Massoth; Jason L. Hornick; Sanda Alexandrescu; Kee Kiat Yeo; Kseniya Petrova-Drus; Stephen Z. Peeke; Laura S. Muñoz-Arcos; Daniel G. Leino; David D. Grier; Robert Lorsbach; Somak Roy; Ashish R. Kumar; Shipra Garg; Nishant Tiwari; Kristian T. Schafernak; Michael M. Henry; Astrid G.S. van Halteren; Oussama Abla; Eli L. Diamond; Jean François Emile

doi:10.1182/blood.2021013338

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

Paul G. Kemps, Jennifer Picarsic^*, Benjamin H. Durham, Zofia Hélias-Rodzewicz, Laura Hiemcke-Jiwa, Cor van den Bos, Marianne D. van de Wetering, Carel J.M. van Noesel, Jan A.M. van Laar, Robert M. Verdijk, Uta E. Flucke, Pancras C.W. Hogendoorn, F. J.Sherida H. Woei-A-Jin, Raf Sciot, Andreas Beilken, Friedrich Feuerhake, Martin Ebinger, Robert Möhle, Falko Fend, Antje BornemannVerena Wiegering, Karen Ernestus, Tina Méry, Olga Gryniewicz-Kwiatkowska, Bozenna Dembowska-Baginska, Dmitry A. Evseev, Vsevolod Potapenko, Vadim V. Baykov, Stefania Gaspari, Sabrina Rossi, Marco Gessi, Gianpiero Tamburrini, Sébastien Héritier, Jean Donadieu, Jacinthe Bonneau-Lagacherie, Claire Lamaison, Laure Farnault, Sylvie Fraitag, Marie Laure Jullié, Julien Haroche, Matthew Collin, Jackie Allotey, Majid Madni, Kerry Turner, Susan Picton, Pasquale M. Barbaro, Alysa Poulin, Ingrid S. Tam, Dina El Demellawy, Brianna Empringham, James A. Whitlock, Aditya Raghunathan, Amy A. Swanson, Mariko Suchi, Jon M. Brandt, Nabeel R. Yaseen, Joanna L. Weinstein, Irem Eldem, Bryan A. Sisk, Vaishnavi Sridhar, Mandy Atkinson, Lucas R. Massoth, Jason L. Hornick, Sanda Alexandrescu, Kee Kiat Yeo, Kseniya Petrova-Drus, Stephen Z. Peeke, Laura S. Muñoz-Arcos, Daniel G. Leino, David D. Grier, Robert Lorsbach, Somak Roy, Ashish R. Kumar, Shipra Garg, Nishant Tiwari, Kristian T. Schafernak, Michael M. Henry, Astrid G.S. van Halteren, Oussama Abla, Eli L. Diamond, Jean François Emile

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed
clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively).
Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and
molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Original language	English
Article number	PMID: 34727172
Pages (from-to)	256-280
Number of pages	25
Journal	Blood
Volume	139
Issue number	2
DOIs	https://doi.org/10.1182/blood.2021013338
Publication status	Published - 13 Jan 2022

Bibliographical note

Funding Information:
P.G.K. received a grant from Leiden University Medical Center. A.G.S.v.H. is supported by Stichting 1000 kaarsjes voor Juultje. E.L.D. is supported by the National Institutes of Health/National Cancer Institute Core Grant (P30 CA008748), National Cancer Institute (R37 CA259260-01), the Frame Fund, Applebaum Foundation, and Joy Family West Foundation. J.-F.E. is supported by the Programme de Recherche Translationnelle sur le Cancer from the French National Cancer Institute (PRT-K19-143).

Publisher Copyright:
© 2022 American Society of Hematology

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10.1182/blood.2021013338

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Kemps, P. G., Picarsic, J., Durham, B. H., Hélias-Rodzewicz, Z., Hiemcke-Jiwa, L., van den Bos, C., van de Wetering, M. D., van Noesel, C. J. M., van Laar, J. A. M., Verdijk, R. M., Flucke, U. E., Hogendoorn, P. C. W., Woei-A-Jin, F. J. S. H., Sciot, R., Beilken, A., Feuerhake, F., Ebinger, M., Möhle, R., Fend, F., ... Emile, J. F. (2022). ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition. Blood, 139(2), 256-280. Article PMID: 34727172. https://doi.org/10.1182/blood.2021013338

@article{5a4cd90252364ef287a0480b1e6fddc6,

title = "ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition",

abstract = "ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailedclinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively).Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic andmolecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.",

author = "Kemps, {Paul G.} and Jennifer Picarsic and Durham, {Benjamin H.} and Zofia H{\'e}lias-Rodzewicz and Laura Hiemcke-Jiwa and {van den Bos}, Cor and {van de Wetering}, {Marianne D.} and {van Noesel}, {Carel J.M.} and {van Laar}, {Jan A.M.} and Verdijk, {Robert M.} and Flucke, {Uta E.} and Hogendoorn, {Pancras C.W.} and Woei-A-Jin, {F. J.Sherida H.} and Raf Sciot and Andreas Beilken and Friedrich Feuerhake and Martin Ebinger and Robert M{\"o}hle and Falko Fend and Antje Bornemann and Verena Wiegering and Karen Ernestus and Tina M{\'e}ry and Olga Gryniewicz-Kwiatkowska and Bozenna Dembowska-Baginska and Evseev, {Dmitry A.} and Vsevolod Potapenko and Baykov, {Vadim V.} and Stefania Gaspari and Sabrina Rossi and Marco Gessi and Gianpiero Tamburrini and S{\'e}bastien H{\'e}ritier and Jean Donadieu and Jacinthe Bonneau-Lagacherie and Claire Lamaison and Laure Farnault and Sylvie Fraitag and Julli{\'e}, {Marie Laure} and Julien Haroche and Matthew Collin and Jackie Allotey and Majid Madni and Kerry Turner and Susan Picton and Barbaro, {Pasquale M.} and Alysa Poulin and Tam, {Ingrid S.} and {El Demellawy}, Dina and Brianna Empringham and Whitlock, {James A.} and Aditya Raghunathan and Swanson, {Amy A.} and Mariko Suchi and Brandt, {Jon M.} and Yaseen, {Nabeel R.} and Weinstein, {Joanna L.} and Irem Eldem and Sisk, {Bryan A.} and Vaishnavi Sridhar and Mandy Atkinson and Massoth, {Lucas R.} and Hornick, {Jason L.} and Sanda Alexandrescu and Yeo, {Kee Kiat} and Kseniya Petrova-Drus and Peeke, {Stephen Z.} and Mu{\~n}oz-Arcos, {Laura S.} and Leino, {Daniel G.} and Grier, {David D.} and Robert Lorsbach and Somak Roy and Kumar, {Ashish R.} and Shipra Garg and Nishant Tiwari and Schafernak, {Kristian T.} and Henry, {Michael M.} and {van Halteren}, {Astrid G.S.} and Oussama Abla and Diamond, {Eli L.} and Emile, {Jean Fran{\c c}ois}",

note = "Funding Information: P.G.K. received a grant from Leiden University Medical Center. A.G.S.v.H. is supported by Stichting 1000 kaarsjes voor Juultje. E.L.D. is supported by the National Institutes of Health/National Cancer Institute Core Grant (P30 CA008748), National Cancer Institute (R37 CA259260-01), the Frame Fund, Applebaum Foundation, and Joy Family West Foundation. J.-F.E. is supported by the Programme de Recherche Translationnelle sur le Cancer from the French National Cancer Institute (PRT-K19-143). Publisher Copyright: {\textcopyright} 2022 American Society of Hematology",

year = "2022",

month = jan,

day = "13",

doi = "10.1182/blood.2021013338",

language = "English",

volume = "139",

pages = "256--280",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier",

number = "2",

}

Kemps, PG, Picarsic, J, Durham, BH, Hélias-Rodzewicz, Z, Hiemcke-Jiwa, L, van den Bos, C, van de Wetering, MD, van Noesel, CJM, van Laar, JAM, Verdijk, RM, Flucke, UE, Hogendoorn, PCW, Woei-A-Jin, FJSH, Sciot, R, Beilken, A, Feuerhake, F, Ebinger, M, Möhle, R, Fend, F, Bornemann, A, Wiegering, V, Ernestus, K, Méry, T, Gryniewicz-Kwiatkowska, O, Dembowska-Baginska, B, Evseev, DA, Potapenko, V, Baykov, VV, Gaspari, S, Rossi, S, Gessi, M, Tamburrini, G, Héritier, S, Donadieu, J, Bonneau-Lagacherie, J, Lamaison, C, Farnault, L, Fraitag, S, Jullié, ML, Haroche, J, Collin, M, Allotey, J, Madni, M, Turner, K, Picton, S, Barbaro, PM, Poulin, A, Tam, IS, El Demellawy, D, Empringham, B, Whitlock, JA, Raghunathan, A, Swanson, AA, Suchi, M, Brandt, JM, Yaseen, NR, Weinstein, JL, Eldem, I, Sisk, BA, Sridhar, V, Atkinson, M, Massoth, LR, Hornick, JL, Alexandrescu, S, Yeo, KK, Petrova-Drus, K, Peeke, SZ, Muñoz-Arcos, LS, Leino, DG, Grier, DD, Lorsbach, R, Roy, S, Kumar, AR, Garg, S, Tiwari, N, Schafernak, KT, Henry, MM, van Halteren, AGS, Abla, O, Diamond, EL & Emile, JF 2022, 'ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition', Blood, vol. 139, no. 2, PMID: 34727172, pp. 256-280. https://doi.org/10.1182/blood.2021013338

TY - JOUR

T1 - ALK-positive histiocytosis

T2 - a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

AU - Kemps, Paul G.

AU - Picarsic, Jennifer

AU - Durham, Benjamin H.

AU - Hélias-Rodzewicz, Zofia

AU - Hiemcke-Jiwa, Laura

AU - van den Bos, Cor

AU - van de Wetering, Marianne D.

AU - van Noesel, Carel J.M.

AU - van Laar, Jan A.M.

AU - Verdijk, Robert M.

AU - Flucke, Uta E.

AU - Hogendoorn, Pancras C.W.

AU - Woei-A-Jin, F. J.Sherida H.

AU - Sciot, Raf

AU - Beilken, Andreas

AU - Feuerhake, Friedrich

AU - Ebinger, Martin

AU - Möhle, Robert

AU - Fend, Falko

AU - Bornemann, Antje

AU - Wiegering, Verena

AU - Ernestus, Karen

AU - Méry, Tina

AU - Gryniewicz-Kwiatkowska, Olga

AU - Dembowska-Baginska, Bozenna

AU - Evseev, Dmitry A.

AU - Potapenko, Vsevolod

AU - Baykov, Vadim V.

AU - Gaspari, Stefania

AU - Rossi, Sabrina

AU - Gessi, Marco

AU - Tamburrini, Gianpiero

AU - Héritier, Sébastien

AU - Donadieu, Jean

AU - Bonneau-Lagacherie, Jacinthe

AU - Lamaison, Claire

AU - Farnault, Laure

AU - Fraitag, Sylvie

AU - Jullié, Marie Laure

AU - Haroche, Julien

AU - Collin, Matthew

AU - Allotey, Jackie

AU - Madni, Majid

AU - Turner, Kerry

AU - Picton, Susan

AU - Barbaro, Pasquale M.

AU - Poulin, Alysa

AU - Tam, Ingrid S.

AU - El Demellawy, Dina

AU - Empringham, Brianna

AU - Whitlock, James A.

AU - Raghunathan, Aditya

AU - Swanson, Amy A.

AU - Suchi, Mariko

AU - Brandt, Jon M.

AU - Yaseen, Nabeel R.

AU - Weinstein, Joanna L.

AU - Eldem, Irem

AU - Sisk, Bryan A.

AU - Sridhar, Vaishnavi

AU - Atkinson, Mandy

AU - Massoth, Lucas R.

AU - Hornick, Jason L.

AU - Alexandrescu, Sanda

AU - Yeo, Kee Kiat

AU - Petrova-Drus, Kseniya

AU - Peeke, Stephen Z.

AU - Muñoz-Arcos, Laura S.

AU - Leino, Daniel G.

AU - Grier, David D.

AU - Lorsbach, Robert

AU - Roy, Somak

AU - Kumar, Ashish R.

AU - Garg, Shipra

AU - Tiwari, Nishant

AU - Schafernak, Kristian T.

AU - Henry, Michael M.

AU - van Halteren, Astrid G.S.

AU - Abla, Oussama

AU - Diamond, Eli L.

AU - Emile, Jean François

N1 - Funding Information: P.G.K. received a grant from Leiden University Medical Center. A.G.S.v.H. is supported by Stichting 1000 kaarsjes voor Juultje. E.L.D. is supported by the National Institutes of Health/National Cancer Institute Core Grant (P30 CA008748), National Cancer Institute (R37 CA259260-01), the Frame Fund, Applebaum Foundation, and Joy Family West Foundation. J.-F.E. is supported by the Programme de Recherche Translationnelle sur le Cancer from the French National Cancer Institute (PRT-K19-143). Publisher Copyright: © 2022 American Society of Hematology

PY - 2022/1/13

Y1 - 2022/1/13

N2 - ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailedclinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively).Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic andmolecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

AB - ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailedclinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively).Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic andmolecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

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U2 - 10.1182/blood.2021013338

DO - 10.1182/blood.2021013338

M3 - Article

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AN - SCOPUS:85122787125

SN - 0006-4971

VL - 139

SP - 256

EP - 280

JO - Blood

JF - Blood

IS - 2

M1 - PMID: 34727172

ER -

ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

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