Posts tagged ALK fusions

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

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 involv..... READ ARTICLE

Blood DOI:10.1182/blood.2021013338

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

Real-World OutcomesKirk SmithJanuary 13, 2022ALK-positive histiocytosis, clinicopathologic spectrum, neurologic involvement and responses, ALK inhibition, ALK fusions, CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, DCTN1-ALK, KIF5B-ALK

ALK rearrangements in infantile fibrosarcoma-like spindle cell tumors of soft tissue and kidney

Recurrent alterations in receptor tyrosine kinase (RTK) and downstream effectors are described in infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) and a subset of spindle cell sarcomas, provisionally designated “NTRK-rearranged” spindle cell neoplasms. These two groups of tumors demonstrate overlapping morphologies and harbor alterations in NTRK1/2/3, RET, MET, ABL1, ROS1, RAF1, and BRAF, although their relationship is not fully elucidated. We describe herein a cohort of pediatric tumors with clinicopathologic features not typical for inflammatory myofibroblastic tumor, but rather with similarities to cCMN/IFS harboring ALK fusions.
Clinicopathologic features were assessed and partner agnostic targeted RNA sequencing on clinically validated platforms were performed. Tumors occurred in patients from 2 to 10 years (median age 2 years) with a 2:2 male to female ratio and an average size of 8.4 cm. Two tumors arose in soft tissues and 2 in the kidney. Morphologi..... READ ARTICLE

Histopathology DOI:10.1111/his.14603

Authors: Serena Y. Tan, Alyaa Al-Ibraheemi, William A. Arhens, Javier E. Oesterheld, Julie C. Fanburg-Smith, Yajuan J. Liu, Sheri L. Spunt, Erin R. Rudzinski, Cheryl Coffin, Jessica L. Davis

Case Study, group2Kirk SmithNovember 29, 2021infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN), spindle cell sarcomas, pediatric tumors, ALK fusions

Superficial ALK-rearranged myxoid spindle cell neoplasm: a cutaneous soft tissue tumor with distinctive morphology and immunophenotypic profile

Gene rearrangements involving the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase gene have been identified in various neoplasms, including inflammatory myofibroblastic tumor and epithelioid fibrous histiocytoma. We present an ALK-rearranged cutaneous soft tissue tumor with unique morphologic and immunophenotypic features that are not shared by other entities with ALK rearrangements. The six cases involved two females and four males, aged 18–84 (mean 51) years old. Three tumors were on the back and three on the lower extremities (thigh, knee, shin); ranging from 0.5 to 5.6 (mean 2.1) cm. Four were confined to the dermis; two involved the subcutis. All six cases were characterized by the presence of spindled to ovoid cells arranged in concentric whorls and cords against a myxoid to myxohyaline stroma and relatively cellular aggregates of plump ovoid to epithelioid cells. Four cases showed distinct hyalinized blood vessels. Both cases that involved the subcutis showed peripheral lipofibromatosis-like areas. Tumor-infiltrating lymphocytes were absent to moderate. Severe cytologic atypia or conspicuous mitotic activity was not identified. Immunohistochemically, all tumors diffusely expressed ALK (D5F3) and CD34. All but one tumor was diffusely positive for S100 protein. All tumors were negative for EMA, AE1/AE3, SMA, and SOX10. Next-generation sequencing revealed ALK fusions with FLNA (3 cases), MYH10 (2 cases), and HMBOX1 (1 case) as the partner genes. In all six cases, the breakpoints involved exon 20 of ALK, which preserves the receptor tyrosine kinase domains of ALK in the fusion product. Of the four cases with limited follow-up information (2–18 months), none recurred. In conclusion, we report an ALK-rearranged cutaneous soft tissue tumor characterized by the presence of myxoid spindle cell whorls and cords, and co-expression of ALK, CD34, and frequently S100 protein, we term “superficial ALK-rearranged myxoid spindle cell neoplasm”. READ ARTICLE

Modern Pathology

Authors: Josephine K. Dermawan, Elizabeth M. Azzato, John R. Goldblum, Brian P. Rubin, Steven D. Billings and Jennifer S. Ko

Case Study, group5Kirk SmithJune 4, 2021FLNA-ALK, MYH10-ALK, HMBOX1-ALK, ALK fusions