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

Author

Kemps, P.G., Picarsic, J., Durham, B.H., Hélias-Rodzewicz, Z., Hiemcke-Jiwa, L., Bos, Cor van den, Wetering, M.D. van de, Noesel, C.J. van, Laar, Jacob M. van, Verdijk, R.M., Flucke, U.E., Hogendoorn, P.C., Woei, A.J.F., 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, D.A., Potapenko, V., Baykov, V.V., Gaspari, S., Rossi, S., Gessi, M., Tamburrini, G., Héritier, S., Donadieu, J., Bonneau-Lagacherie, J., Lamaison, C., Farnault, L., Fraitag, S., Jullié, M.L., Haroche, J., Collin, M., Allotey, J., Madni, M., Turner, K., Picton, S., Barbaro, P.M., Poulin, A., Tam, I.S., Demellawy, D. El, Empringham, B., Whitlock, J.A., Raghunathan, A., Swanson, A.A., Suchi, M., Brandt, J.M., Yaseen, N.R., Weinstein, J.L., Eldem, I., Sisk, B.A., Sridhar, V., Atkinson, M., Massoth, L.R., Hornick, J.L., Alexandrescu, S., Yeo, K.K., Petrova-Drus, K., Peeke, S.Z., Muñoz-Arcos, L.S., Leino, D.G., Grier, D.D., Lorsbach, R., Roy, S., Kumar, A.R., Garg, S., Tiwari, N., Schafernak, K.T., Henry, M.M., Halteren, A.G. van, Abla, O., Diamond, E.L., Emile, J.F., Kemps, P.G., Picarsic, J., Durham, B.H., Hélias-Rodzewicz, Z., Hiemcke-Jiwa, L., Bos, Cor van den, Wetering, M.D. van de, Noesel, C.J. van, Laar, Jacob M. van, Verdijk, R.M., Flucke, U.E., Hogendoorn, P.C., Woei, A.J.F., 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, D.A., Potapenko, V., Baykov, V.V., Gaspari, S., Rossi, S., Gessi, M., Tamburrini, G., Héritier, S., Donadieu, J., Bonneau-Lagacherie, J., Lamaison, C., Farnault, L., Fraitag, S., Jullié, M.L., Haroche, J., Collin, M., Allotey, J., Madni, M., Turner, K., Picton, S., Barbaro, P.M., Poulin, A., Tam, I.S., Demellawy, D. El, Empringham, B., Whitlock, J.A., Raghunathan, A., Swanson, A.A., Suchi, M., Brandt, J.M., Yaseen, N.R., Weinstein, J.L., Eldem, I., Sisk, B.A., Sridhar, V., Atkinson, M., Massoth, L.R., Hornick, J.L., Alexandrescu, S., Yeo, K.K., Petrova-Drus, K., Peeke, S.Z., Muñoz-Arcos, L.S., Leino, D.G., Grier, D.D., Lorsbach, R., Roy, S., Kumar, A.R., Garg, S., Tiwari, N., Schafernak, K.T., Henry, M.M., Halteren, A.G. van, Abla, O., Diamond, E.L., and Emile, J.F.

Abstract

Item does not contain fulltext, 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.

Published
2022

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

Author

Kemps, P.G., Picarsic, J., Durham, B.H., Hélias-Rodzewicz, Z., Hiemcke-Jiwa, L., Bos, Cor van den, Wetering, M.D. van de, Noesel, C.J. van, Laar, Jacob M. van, Verdijk, R.M., Flucke, U.E., Hogendoorn, P.C., Woei, A.J.F., 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, D.A., Potapenko, V., Baykov, V.V., Gaspari, S., Rossi, S., Gessi, M., Tamburrini, G., Héritier, S., Donadieu, J., Bonneau-Lagacherie, J., Lamaison, C., Farnault, L., Fraitag, S., Jullié, M.L., Haroche, J., Collin, M., Allotey, J., Madni, M., Turner, K., Picton, S., Barbaro, P.M., Poulin, A., Tam, I.S., Demellawy, D. El, Empringham, B., Whitlock, J.A., Raghunathan, A., Swanson, A.A., Suchi, M., Brandt, J.M., Yaseen, N.R., Weinstein, J.L., Eldem, I., Sisk, B.A., Sridhar, V., Atkinson, M., Massoth, L.R., Hornick, J.L., Alexandrescu, S., Yeo, K.K., Petrova-Drus, K., Peeke, S.Z., Muñoz-Arcos, L.S., Leino, D.G., Grier, D.D., Lorsbach, R., Roy, S., Kumar, A.R., Garg, S., Tiwari, N., Schafernak, K.T., Henry, M.M., Halteren, A.G. van, Abla, O., Diamond, E.L., Emile, J.F., Kemps, P.G., Picarsic, J., Durham, B.H., Hélias-Rodzewicz, Z., Hiemcke-Jiwa, L., Bos, Cor van den, Wetering, M.D. van de, Noesel, C.J. van, Laar, Jacob M. van, Verdijk, R.M., Flucke, U.E., Hogendoorn, P.C., Woei, A.J.F., 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, D.A., Potapenko, V., Baykov, V.V., Gaspari, S., Rossi, S., Gessi, M., Tamburrini, G., Héritier, S., Donadieu, J., Bonneau-Lagacherie, J., Lamaison, C., Farnault, L., Fraitag, S., Jullié, M.L., Haroche, J., Collin, M., Allotey, J., Madni, M., Turner, K., Picton, S., Barbaro, P.M., Poulin, A., Tam, I.S., Demellawy, D. El, Empringham, B., Whitlock, J.A., Raghunathan, A., Swanson, A.A., Suchi, M., Brandt, J.M., Yaseen, N.R., Weinstein, J.L., Eldem, I., Sisk, B.A., Sridhar, V., Atkinson, M., Massoth, L.R., Hornick, J.L., Alexandrescu, S., Yeo, K.K., Petrova-Drus, K., Peeke, S.Z., Muñoz-Arcos, L.S., Leino, D.G., Grier, D.D., Lorsbach, R., Roy, S., Kumar, A.R., Garg, S., Tiwari, N., Schafernak, K.T., Henry, M.M., Halteren, A.G. van, Abla, O., Diamond, E.L., and Emile, J.F.

Abstract

Item does not contain fulltext, 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.

Published
2022

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

Author

Kemps, P.G., Picarsic, J., Durham, B.H., Hélias-Rodzewicz, Z., Hiemcke-Jiwa, L., Bos, Cor van den, Wetering, M.D. van de, Noesel, C.J. van, Laar, Jacob M. van, Verdijk, R.M., Flucke, U.E., Hogendoorn, P.C., Woei, A.J.F., 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, D.A., Potapenko, V., Baykov, V.V., Gaspari, S., Rossi, S., Gessi, M., Tamburrini, G., Héritier, S., Donadieu, J., Bonneau-Lagacherie, J., Lamaison, C., Farnault, L., Fraitag, S., Jullié, M.L., Haroche, J., Collin, M., Allotey, J., Madni, M., Turner, K., Picton, S., Barbaro, P.M., Poulin, A., Tam, I.S., Demellawy, D. El, Empringham, B., Whitlock, J.A., Raghunathan, A., Swanson, A.A., Suchi, M., Brandt, J.M., Yaseen, N.R., Weinstein, J.L., Eldem, I., Sisk, B.A., Sridhar, V., Atkinson, M., Massoth, L.R., Hornick, J.L., Alexandrescu, S., Yeo, K.K., Petrova-Drus, K., Peeke, S.Z., Muñoz-Arcos, L.S., Leino, D.G., Grier, D.D., Lorsbach, R., Roy, S., Kumar, A.R., Garg, S., Tiwari, N., Schafernak, K.T., Henry, M.M., Halteren, A.G. van, Abla, O., Diamond, E.L., Emile, J.F., Kemps, P.G., Picarsic, J., Durham, B.H., Hélias-Rodzewicz, Z., Hiemcke-Jiwa, L., Bos, Cor van den, Wetering, M.D. van de, Noesel, C.J. van, Laar, Jacob M. van, Verdijk, R.M., Flucke, U.E., Hogendoorn, P.C., Woei, A.J.F., 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, D.A., Potapenko, V., Baykov, V.V., Gaspari, S., Rossi, S., Gessi, M., Tamburrini, G., Héritier, S., Donadieu, J., Bonneau-Lagacherie, J., Lamaison, C., Farnault, L., Fraitag, S., Jullié, M.L., Haroche, J., Collin, M., Allotey, J., Madni, M., Turner, K., Picton, S., Barbaro, P.M., Poulin, A., Tam, I.S., Demellawy, D. El, Empringham, B., Whitlock, J.A., Raghunathan, A., Swanson, A.A., Suchi, M., Brandt, J.M., Yaseen, N.R., Weinstein, J.L., Eldem, I., Sisk, B.A., Sridhar, V., Atkinson, M., Massoth, L.R., Hornick, J.L., Alexandrescu, S., Yeo, K.K., Petrova-Drus, K., Peeke, S.Z., Muñoz-Arcos, L.S., Leino, D.G., Grier, D.D., Lorsbach, R., Roy, S., Kumar, A.R., Garg, S., Tiwari, N., Schafernak, K.T., Henry, M.M., Halteren, A.G. van, Abla, O., Diamond, E.L., and Emile, J.F.

Abstract

Contains fulltext : 249882.pdf (Publisher’s version ) (Closed access), 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.

Published
2022

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