Digital pathology in pediatric nodular lymphocyte-predominant Hodgkin lymphoma: correlation with treatment response

Abstract

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) accounts for 10% of all Hodgkin lymphoma cases.1,2 Most patients are diagnosed in the early stages and have excellent survival rates after radio- or chemotherapy, or a combination of the two.3,4 However, radiotherapy is not recommended for pediatric patients because of the late toxicity in aging survivors.5 Instead, low-intensity therapy with cyclophosphamide in combination with vinblastine and prednisone (CVP) is preferred. Only patients with poor treatment response receive more intensive chemotherapy.6 To introduce new treatment concepts based on the biology of the disease, attempts have been made to develop a histological response marker based on the morphometry and distribution of disease-defining LP cells. The classification proposed by Fan et al7 recognizes 6 different histological patterns of NLPHL, with variant patterns C-F being considered high-risk for clinical outcomes.8 However, the prognostic value of this classification is less clear in early-stage patients when compared with those with advanced-stage disease.9,10 Recent research by Hartmann et al11 has shown differences in LP cell nuclear size between early-, intermediate-, and advanced-stage NLPHL, as well as between typical and variant Fan patterns. This analysis was limited to a small number of cells per case. We used deep-learning–based cell detection on digitized biopsy slides from early-stage pediatric patients treated within the EuroNet-PHL-LP1 trial to quantitatively assess LP-cell histology. Through whole-slide spatial analysis, we identified 6 key characteristics of LP cell spatial patterns and correlated them with treatment response to low-intensity CVP chemotherapy. In addition, we explored the relationship between treatment response and various characteristics of B-cell spatial patterns, as well as Fan classification. The formalin-fixed and paraffin-embedded diagnostic lymph node samples of 53 children and adolescents with stage IA or IIA NLPHL who had been enrolled in the EuroNet-PHL-LP1 trial were analyzed. All patients were treated with 3 cycles of CVP chemotherapy (cyclophosphamide 500 mg/m2 intravenously on day 1, vinblastine 6 mg/m2 intravenously on days 1 and 8, and prednisolone 40 mg/m2 orally on days 1-8). The interval between chemotherapy cycles was scheduled for 1 or a maximum of 2 weeks. At the end of chemotherapy, response assessment was performed using positron emission tomography combined with contrast-enhanced computed tomography (PET-CT). The response was