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Inflammatory Myofibroblastic Tumor Driven by Novel NUMA1-ALK Fusion Responds to ALK Inhibition

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Inflammatory Myofibroblastic Tumor Driven by Novel NUMA1-ALK Fusion Responds to ALK Inhibition 115 Molecular Insights in Patient Care Inflammatory Myofibroblastic Tumor Driven by Novel NUMA1-ALK Fusion Responds to ALK Inhibition Nisha Rao, MDa,†; Hans Iwenofu, MDb; Bingfeng Tang, MDc; Jennifer Woyach, MDd; and David A. Liebner, MDe,f Abstract Inflammatory myofibroblastic tumors (IMTs) are soft tissue neoplasms with rare metastatic potential. Approximately half of IMTs are posi- tive for an ALK rearrangement, and ALK inhibitors have been used successfully in the treatment of IMTs with a variety of ALK fusions. This report describes a 21-year-old woman with an aggressive, metastatic IMT with a novel NUMA1-ALK fusion that showed a dramatic response to the ALK inhibitors crizotinib and alectinib. To our knowledge, this report provides the first published description of an IMT with a NUMA1-ALK fusion. The patient’s aggressive IMT responded favorably to crizotinib and alectinib, suggesting that ALK inhibitors may be effective in IMT with NUMA1-ALK fusions. We review published reports of ALK-driven IMTs that have received ALK inhibitor therapy and suggest characteristics that may be associated with favorable response to treatment. We also discuss the strengths and limitations of im- munohistochemistry, fluorescence in situ hybridization, and next-generation sequencing in the diagnosis and management of IMTs. J Natl Compr Canc Netw 2018;16(2):115–121 doi: 10.6004/jnccn.2017.7031 Inflammatory myofibroblastic tumors (IMTs) are rare mary management modality; however, lesions may recur soft tissue neoplasms that usually arise in the lung, abdo- after surgical resection.2 men, or pelvis and affect primarily children and young Recent evidence suggests that the anaplastic lym- 1 adults. IMTs are usually localized and metastatic disease phoma kinase (ALK) gene plays a role in the patho- 2 is rare, accounting for <5% of all cases. IMTs most of- genesis of some IMTs. ALK encodes a receptor tyrosine ten present with signs and symptoms restricted to the kinase normally expressed only in neural tissue,4 and areas affected; however, 15% to 30% of people present rearrangements of ALK can result in inappropriate ac- with fever, weight loss, malaise, microcytic anemia, el- 5 evated erythrocyte sedimentation rate, thrombocytosis, tivation of the ALK receptor tyrosine kinase. Approxi- or polyclonal hypergammaglobulinemia.3 Although the mately half of IMTs are associated with an ALK gene histology of IMT is variable, tumors are generally com- rearrangement.6 Fusions of ALK with TPM3, TPM4, posed of spindle cells in an inflamed stroma of plasma ATIC, CLTC, CARS, RANBP2, EML4, and SEC31L1 cells, lymphocytes, and eosinophils.2 Surgery is the pri- have been described previously.5,7 From the aOhio State University College of Medicine; bDivision of Soft Submitted March 21, 2017; accepted for publication September 5, 2017. Tissue and Bone Pathology, Department of Pathology; cDepartment of Radiology; dDivision of Hematology, Department of Internal Medicine; The authors have disclosed that they have no financial interests, eDivision of Medical Oncology, Department of Internal Medicine; and arrangements, affiliations, or commercial interests with the manufacturers fDivision of Computational Biology and Bioinformatics, Department of any products discussed in this article or their competitors. of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, Ohio. Correspondence: David A. Liebner, MD, Division of Medical Oncology, †Current affiliation: New York Presbyterian Hospital and Columbia Department of Internal Medicine, Ohio State University, 460 West 10th University, New York, New York. Avenue, Columbus, OH 43210. E-mail: [email protected] © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 16 Number 2 | February 2018 116 Molecular Insights in Patient Care Rao et al ALK inhibitors have emerged as a successful staging PET/CT scan showed multiple hypermeta- therapy for ALK-associated IMT in both adult and bolic lesions above and below the diaphragm, in- pediatric patients.8–14 To our knowledge, however, volving the mediastinum and left hemithorax, the response of IMT associated with a NUMA1-ALK bilateral lungs, pleura, liver, left kidney, axial skel- fusion has never been documented. This report de- eton, and musculature (Figure 1A). Differential di- scribes a 21-year-old patient with widely metastatic agnosis at the time included lymphoma and meta- IMT with a NUMA1-ALK fusion who demonstrat- static germ cell tumor. ed a marked response to ALK inhibitor therapy. We Biopsies of a lung mass and a left supraclavicu- then review published reports of ALK-driven IMT lar lymph node were performed. Histologic sections treated with ALK inhibitors and suggest predictors from both samples revealed a spindle cell prolif- of favorable response to treatment. eration that was variably cellular, with broad areas of fibrosis and obscuring lymphoplasmacytic infil- trates, without evidence of high-grade anaplastic Case Description features, coagulation tumor necrosis, or atypical mi- Clinical Course totic figures (Figure 2). On immunohistochemistry A 21-year-old woman initially presented with left (IHC), lesional cells showed unequivocal, strong, shoulder pain and left arm swelling. She reported and diffuse reactivity for ALK (in a cytoplasmic that she had experienced a 10- to 15-pound weight and perinuclear pattern) and weak focal reactivity loss during the preceding year, a few months of fa- for smooth muscle actin and desmin. Other mark- tigue and dry cough, and a few weeks of shortness of ers, including CD45, CD3, CD20, CD163, CD15, breath and dysphagia. She had also experienced in- CD30, EBER, PAX5, pan cytokeratin-AE1/AE3, termittent night sweats and left-sided pleuritic chest S100, and pan cytokeratin-MNF116, were nega- pain, all of which had worsened acutely over the past tive. Plasma cells stained diffusely for both Kappa month. and Lambda with no evidence of light chain restric- She was diagnosed with an acute deep vein tion. Fluorescence in situ hybridization (FISH) test- thrombosis of her left internal jugular vein. On fur- ing was reported as negative for ALK translocation; ther evaluation, she was found to have a large me- however, next-generation sequencing (NGS) by diastinal mass encasing multiple mediastinal struc- Foundation Medicine (Cambridge, MA) revealed tures and lesions involving the lungs, liver, spleen, a novel NUMA1-ALK fusion. The ALK transloca- kidney, bone, peritoneum, and iliacus muscle. A tion was detected on both DNA and RNA sequenc- A B C Figure 1. PET/CT demonstrating burden of disease. (A) At initial presentation, PET/CT demonstrated multiple hypermetabolic lesions above and below the diaphragm involving the mediastinum, bilateral lungs, left pleura, liver, left kidney, abdomen, axial skeleton, and musculature (maximum standardized uptake value [SUVmax], 48.7). (B) One month after crizotinib therapy initiation, PET/CT demonstrated reduced size and FDG avidity of sev- eral hypermetabolic masses/lesions involving the lung/pleura, liver, and bone, as well as the left perinephric region (SUVmax, 14.1). (C) After 6 months of crizotinib therapy, patient was switched from crizotinib to alectinib for concern for possible contribution of crizotinib to her pneumonitis. A PET/CT performed one month after beginning alectinib demonstrated further reduction in FDG avidity of neck, chest, and bone lesions (SUVmax, 1.9). © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 16 Number 2 | February 2018 Molecular Insights in Patient Care 117 NUMA1-ALK IMT Responds to ALK Inhibition A B C Figure 2. Histology sections from biopsy samples. (A) Sections showing a banal spindle cell proliferation in swirling growth pattern punctuated with sprinkling of chronic inflammatory cells and eosinophils (hematoxylin-eosin, original magnification x200). (B) High power view showing areas with obscuring lymphoplasmacytic infiltrates (hematoxylin-eosin, original magnification x400). (C) Lesional cells demonstrating diffuse and strong ALK reactivity (ALK, original magnification x400). ing analyses. The following fusion was discovered: (Figure 1B). Improvement was specifically noted in 5’-NUMA1(ex1-19 NM_006185)-ALK(ex20-29 a left lower lobe mass (maximum standard uptake NM_004304) (Figure 3). The depth of sequencing value [SUVmax] decreased from 48.7 to 14.1), right was adequate, with a 755 median exon depth for lower lobe lesion (SUVmax, 17.7 to 6.6), left kidney the whole specimen. Taken together, these results mass (SUVmax, 16.7 to 8.0), and right sacral lesion were consistent with an ALK-driven IMT. (SUVmax, 12.4 to 4.2). When the patient was scheduled to begin ther- Six weeks after beginning crizotinib, nivolumab apy, NGS results were still pending. Given the at 3 mg/kg intravenously every 2 weeks was add- strong reactivity for ALK by IHC, she was started ed to her regimen given evidence of high-positive on crizotinib, 250 mg twice daily. At 2-week follow- PD-1 expression in tumor-infiltrating lymphocytes up, the patient’s symptoms had markedly improved: (>25%, clone NAT105 by Cell Marque; Rocklin, her dry cough had resolved, she felt less pressure in CA). She received 12 weeks of combination therapy her chest, and she was able to eat and swallow pills. with crizotinib and nivolumab with continued ra- Apart from lower-abdominal cramping, which was diographic response to therapy. However, she devel- controlled with hyoscyamine, she tolerated crizo- oped grade 2 pneumonitis and grade 3 transaminitis, tinib
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