Refractory Hydroa Vacciniforme-like Lymphoma: Biological Insights from Morphoproteomic Analysis

Abstract

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.

Keywords: Epstein-Barr virus; Hydroa vacciniforme-like lymphoma (HVLL); Morphoproteomics; Resistance mechanisms; T-cell lymphoproliferative disorders.

Figure 1

The H&E stained sections of the immediate pretreatment specimen revealed a histopathology comprised mainly of a lymphohistiocytic infiltrate in a perivascular and periadnexal distribution (Figure 1a, 1b, 1c). The nuclei of the tumor cells were strongly positive for EBER-1. The serum EBV DNA level in the post-treatment sera of this patient was recorded at >1,000,000(original magnification for frames A, B and C, x40, x200 and x200, respectively) and Maximum Intensity Projection (MIP) PET Image. A post therapy scan showing innumerable metabolically active cutaneous and subcutaneous nodules and masses throughout the head/neck, extremities, and trunk, a 5.9 x 3.8 cm soft tissue mass extending from the right zygomatic arch, multiple metabolically active cervical lymph nodes, and scattered deeper intermuscular metabolically active soft tissue lesions in the lower extremities

Figure 2

[A] Ki-67 expressed in the nuclei of lesional lymphomonocytic cells in the immediate pretreatment biopsy at >50% and at ~90% of the nuclei in the post-treatment biopsy. [B] Bcl-2,in the pretreatment specimen shows, cytoplasmic expression in ~50% of the lesional cells in the perivascular and periadnexal locations. [C] (mTOR) pathway is constitutively activated in the lesional cells in this immediate pretreatment specimen phosphorylated (p) –mTOR at up to 3+ in the nuclear compartment (see arrow). [D] EZH2, is variably expressed at up to 3+ of the perivascular and periadnexal lesional nuclei in this specimen. [E] CD8 is expressed on up to 90 % of the lesional cells at 1-3+ on their plasmalemmal aspect including those cells with karyomegaly. [F] Less than 10% of programmed cell death receptor protein 1, PD-1 expression exhibited on this same cell population [G] Expression of PD-L1 by the M2 macrophage/histiocytic component of the infiltrate and the patient’s EBV+CD8+ lymphoproliferative disorder in this immediate pretreatment specimen. [H] CD163 expression up to 50% of the lesional cells in this specimen(original magnification of frame C x400 and for A, B, D, E, F, G and H x100).