Sabrina Rossi1, Marco Gessi2, Sabina Barresi1, Gianpiero Tamburrini3, Isabella Giovannoni1, Antonio Ruggiero4, Giovanna Stefania Colafati5, Paolo Frassanito3, Alessia Carboni5, Andrea Alexandre6, Antonella Cacchione7, Pietro Trombatore6, Francesca Diomedi-Camassei1, Stefania Gaspari7, Francesca Gianno8,9, Carlo Efisio Marras10, Valerio Cecinati11, Andrea Carai10, Angela Mastronuzzi7, Rita Alaggio1. 1. Pathology Unit, Department of Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 2. Neuropathology Unit, Pathology Division, Fondazione Policlinico Universitario A.Gemelli IRCCS, Università Cattolica S.Cuore, Rome, Italy. 3. Pediatric Neurosurgery Unit, Fondazione Policlinico Universitario A.Gemelli IRCCS, Università Cattolica S.Cuore, Rome, Italy. 4. Pediatric Oncology Division, Fondazione Policlinico Universitario A.Gemelli IRCCS, Università Cattolica S.Cuore, Rome, Italy. 5. Neuroradiology Unit, Imaging Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 6. Radiology and Neuroradiology Division, Fondazione Policlinico Universitario A.Gemelli IRCCS, Università Cattolica S.Cuore, Rome, Italy. 7. Department of Onco-Hematology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 8. Department of Radiology, Oncology and Anatomic Pathology, University La Sapienza, Rome, Italy. 9. IRCCS Neuromed, Pozzilli, Isernia, Italy. 10. Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 11. Pediatrics and Pediatric Oncoematology Unit, Ospedale Santissima Anninziata, Taranto, Italy.
Abstract
AIMS: Histiocytoses are a heterogeneous group of localized or disseminated diseases. Clinical presentation and patients' outcome vary greatly, ranging from mild to life-threatening disorders. Rare cases of systemic or localized histiocytosis harboring ALK rearrangement have been reported. METHODS: Two cases of CNS histiocytosis were thoroughly investigated by implementing multiple molecular tests, i.e. FISH, RT-qPCR, NGS analysis. RESULTS: In a 10-month old girl (patient #1), MRI showed two left hemispheric lesions and a right fronto-mesial lesion histologically consisting of a moderately cellular infiltrative proliferation, composed by CD68(PGM1)+/CD163+ spindle cells. ALK 5'/3'-imbalance and a KIF5B(exon 24)-ALK(exon 20) fusion were documented by RT-qPCR and NGS analysis, respectively. A subsequent CT scan showed multiple hepatic and pulmonary lesions. The patient was started on chemotherapy (vinblastine) associated to an ALK-inhibitor (Alectinib) with remarkable response. In a 11-year-old girl (patient #2), MRI showed a right frontal 1.5 cm lesion. Neuropathological examination revealed a histiocytic proliferation composed by medium sized CD68(PGM1)+/HLA-DR+ cells, showing moderate ALK1 positivity. ALK rearrangement and a KIF5B(exon 24)-ALK(exon 20) fusion were demonstrated also in this case. Subsequent CT, 18F-FDG-PET and MRI scans showed the presence of a single right femoral lesion, proved to be a fibrous cortical defect. CONCLUSIONS: In ALK-histiocytoses, CNS involvement may occur as part of a systemic disease or, rarely, as its only primary disease localization, which could remain otherwise asymptomatic. The diagnosis often relies on neuropathological examination of brain biopsy, which may pose a diagnostic challenge due to the variable histopathological features. An integrated histological and molecular approach in such cases is recommended.
AIMS: Histiocytoses are a heterogeneous group of localized or disseminated diseases. Clinical presentation and patients' outcome vary greatly, ranging from mild to life-threatening disorders. Rare cases of systemic or localized histiocytosis harboring ALK rearrangement have been reported. METHODS: Two cases of CNS histiocytosis were thoroughly investigated by implementing multiple molecular tests, i.e. FISH, RT-qPCR, NGS analysis. RESULTS: In a 10-month old girl (patient #1), MRI showed two left hemispheric lesions and a right fronto-mesial lesion histologically consisting of a moderately cellular infiltrative proliferation, composed by CD68(PGM1)+/CD163+ spindle cells. ALK 5'/3'-imbalance and a KIF5B(exon 24)-ALK(exon 20) fusion were documented by RT-qPCR and NGS analysis, respectively. A subsequent CT scan showed multiple hepatic and pulmonary lesions. The patient was started on chemotherapy (vinblastine) associated to an ALK-inhibitor (Alectinib) with remarkable response. In a 11-year-old girl (patient #2), MRI showed a right frontal 1.5 cm lesion. Neuropathological examination revealed a histiocytic proliferation composed by medium sized CD68(PGM1)+/HLA-DR+ cells, showing moderate ALK1 positivity. ALK rearrangement and a KIF5B(exon 24)-ALK(exon 20) fusion were demonstrated also in this case. Subsequent CT, 18F-FDG-PET and MRI scans showed the presence of a single right femoral lesion, proved to be a fibrous cortical defect. CONCLUSIONS: In ALK-histiocytoses, CNS involvement may occur as part of a systemic disease or, rarely, as its only primary disease localization, which could remain otherwise asymptomatic. The diagnosis often relies on neuropathological examination of brain biopsy, which may pose a diagnostic challenge due to the variable histopathological features. An integrated histological and molecular approach in such cases is recommended.
Authors: 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 Journal: Blood Date: 2022-01-13 Impact factor: 22.113