Characteristic nuclear membrane <scp>ALK</scp> reactivity in chronic myelomonocytic leukemia with <scp><i>RANBP2</i>‐<i>ALK</i></scp> fusion
Authors: Christopher B. Hergott, Paola Dal Cin, Jason L. Hornick, Eric S. Winer, Ruben D. Carrasco, Annette S. Kim
Journal: American Journal of Hematology (2021)

A 62-year-old male presented to an outside hospital with dyspnea, macrocytic anemia (Hgb 6.8 g/dL; MCV 109 fL), thrombocytopenia (91 000/μL), and leukocytosis (50 140/μL) with monocytosis (10 028/μL; 20%) and 2% circulating immature myelomonocytic cells. Bone marrow examination subsequently revealed an expansion of left-shifted myelomonocytic elements, myeloid dysplasia, and 6% blasts/promonocytes. Karyotype analysis identified 46,XY,inv (2)(p23;q13)[20], a finding initially interpreted as a likely constitutional alteration. The patient was diagnosed with chronic myelomonocytic leukemia-1 (CMML-1) and began decitabine hypomethylating therapy. Following three cycles of decitabine, the patient was referred to our institution for subsequent management. A post-treatment biopsy revealed a variably cellular bone marrow (IMAGE 1A) with relative myeloid hypoplasia and left-shifted maturation (IMAGE 1B). Blasts and promonocytes were not increased. Recognizing that inv (2)(p23;q13) can drive ALK overexpression, we hypothesized that ALK immunohistochemistry (IHC) could highlight persistent disease in this patient. We observed ALK reactivity among early myeloid precursors and myelomonocytic elements with distinctive nuclear membrane staining that is seen with RANBP2-ALK fusions (IMAGE 1C).1 Conventional karyotyping (IMAGE 1D) and metaphase FISH analysis for ALK (IMAGE 1E) ultimately confirmed residual involvement by the patient's myeloid neoplasm. The patient subsequently underwent allogeneic bone marrow transplantation and remains in remission. The RANBP2-ALK fusions were first characterized in the context of epithelioid inflammatory myofibroblastic sarcoma, a malignant soft tissue neoplasm in which RANBP2's native nucleoporin function generates a characteristic pattern of ALK expression at the nuclear membrane.1-3 This staining localization distinguishes RANBP2 from other ALK fusion partners (which produce cytoplasmic, nuclear, and/or perinuclear staining),4-7 portends aggressive disease behavior, and predicts sensitivity to ALK inhibitors.8-10 The RANBP2-ALK fusions are comparatively rare among myeloid malignancies but have been reported in pediatric leukemia patients, often in association with monosomy 7.11, 12 RANBP2-ALK fusions are rarer still in adults.13, 14 Interestingly, leukemias bearing these fusions appear to exhibit myelomonocytic differentiation invariably. Multiple reports also suggest RANBP2-ALK-rearranged leukemias exhibit at least transient responses to the ALK inhibitor crizotinib, which has been used effectively as a bridge to allogeneic transplant.15-17 This case illustrates the immediately recognizable immunohistochemical findings for RANBP2-ALK-rearranged myeloid neoplasia and underscores the utility of IHC in monitoring disease behavior and response to therapy. This application has not been documented previously and may be especially useful when bone marrow aspirate quality is suboptimal or when only post-therapy specimens are available. Furthermore, it provides a cost-effective case-screening tool to study the clinicopathologic sequelae of RANBP2-ALK fusion and the responses of myeloid disease to new generations of ALK inhibitors. The authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.