Tehran University of Medical Sciences International Journal of Hematology-Oncology and Stem Cell Research 2008-2207 16 3 2022 07 09 177 183 EN Rohit Goswamy Department of Internal Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, United States Helen Ajufo Department of Internal Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, United States Abhishek Maiti Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, United States Robert Brown Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, United States Harinder Juneja Department of Internal Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, United States Effrosyni Apostolidou Department of Internal Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, United States 2020 12 02 2021 04 26 T-cell/natural killer cell lymphoproliferative disorders are rare, associated with poor overall survival, and have limited treatment options. We report a case of a patient who developed hydroa vacciniforme-like lymphoma (HVLL, an EBV-peripheral T-cell lymphoma), refractory to multiple lines of systemic therapy including methotrexate, mycophenolate mofetil, dapsone, thalidomide, prednisone, and romidepsin. We conducted morphoproteomic analysis of the patient’s tumor which provided important biological insights. Histopathology showed primarily lymphohistiocytic infiltrates strongly positive EBV expression with a Ki-67 of >50% in the pretreatment biopsy and approximately 90% in the post-treatment biopsy, strong expression of Enhancer of Zester Homolog 2 (EZH2), a constitutively active mTOR pathway, 50% cytoplasmic BCL-2 expression; largely negative PD-1 positive CD8 T-cells. Based on this morphoproteomic analysis and published literature, we postulated that novel agents including venetoclax, tazemetostat, and other agents may provide a targeted approach for treating HVLL. This case illustrates the use of morphoproteomic analysis to better understand the biology of tumors.   https://ijhoscr.tums.ac.ir/index.php/ijhoscr/article/view/1485 https://ijhoscr.tums.ac.ir/index.php/ijhoscr/article/download/1485/944