Long-Term Risk of Subsequent Malignant Neoplasms Among Childhood and Adolescent Lymphoma Survivors (1975-2013): A Population-Based Predictive Nomogram

Abstract

Background: Studies are needed to assess risk factors pertinent to the incidence of secondary malignancies among childhood and adolescent lymphoma survivors. We aimed to identify risk factors pertinent to the incidence of secondary malignancies and subsequently establish a clinically practical predictive nomogram.

Methods: A total of 5561 patients who were diagnosed with primary lymphoma below the age of 20 years between 1975 and 2013 and survived for at least 5 years were identified. Standardized incidence ratio (SIR) and excess risk (ER) analysis were performed by sex, age, and year when primary lymphoma was diagnosed, sites and types of primary lymphoma, and therapy strategies. Univariable and multivariable logistic regression were used to identify independent risk factors for adolescent and childhood lymphoma-related secondary malignancies. Based on 5 factors (age, time from lymphoma diagnosis, gender, lymphoma type, and therapy), a nomogram for predicting the risk of a secondary malignancy for patients with childhood and adolescent primary lymphoma was established.

Results: Among 5561 lymphoma survivors, 424 developed a secondary malignancy. Females (SIR = 5.34, 95% CI, 4.73-5.99; ER = 50.58) exhibited a higher SIR and ER than males (SIR = 3.28, 95% CI, 2.76-3.87; ER = 15.53). Blacks were at a higher risk than Caucasians or others. Nodular lymphocyte-predominant Hodgkin lymphoma survivors exhibited typically high SIR (13.13, 95% CI, 6-24.92) and ER (54.79) among all lymphoma classifications. Lymphoma survivors who underwent radiotherapy, whether they received chemotherapy or not, had typically higher SIR and ER. Among all types of secondary malignancies, "bone and joint neoplasms" (SIR = 11.07, 95% CI, 5.52-19.81) and "soft tissue neoplasms" (SIR = 12.27, 95% CI, 7.59-18.76) presented significantly high SIR whereas "breast cancer" and "endocrine cancer" associated with higher ER. The median diagnosis age of secondary malignancies was 36 years old, and the median time interval between the diagnosis of two malignancies was 23 years. A nomogram was constructed to predict the risk of secondary malignancies in patients diagnosed with primary lymphoma before 20 years of age. After internal validation, the AUC and C-index of the nomogram are 0.804 and 0.804, respectively.

Conclusion and relevance: The established nomogram provides a convenient and reliable tool for predicting the risk of a secondary malignancy among childhood and adolescent lymphoma survivors, concluding significant concern for lymphoma survivors with high-risk estimates.

Keywords: adolescent lymphoma; childhood lymphoma; nomogram; secondary malignancies.

Figure 1.

The relative and absolute risk of developing a secondary malignancy for childhood and adolescent lymphoma survivors. Abbreviations: ER: excess risk; SIR: standard incidence ratio; CI: confidence interval; NLPHL: nodular lymphocyte-predominant Hodgkin lymphoma; R: radiotherapy; NR: no/unknown radiotherapy; C: chemotherapy; NC: no/unknown chemotherapy.

Figure 2.

The risk analysis and cumulative incidence rate of a secondary malignancy for lymphoma patients of different intervals between diagnosis of primary lymphoma (PL) and a secondary malignancy (SMN) (n = 424). (A) The relative and absolute risk analysis of secondary malignancies for lymphoma patients of different intervals between diagnosis of primary lymphoma and a secondary malignancy. (B) The distribution of intervals between the diagnosis of primary lymphoma and a secondary malignancy. (C) Cumulative incidence rate of a secondary malignancy for primary lymphoma patients with treatment modalities include NR+C, NR+NC, R+C, and R+NC, respectively. Abbreviations: SIR: standard incidence ratio; CI: confidence interval; ER: excess risk; R: radiotherapy; C: chemotherapy; NR: No/unknown radiotherapy; NC: No/unknown chemotherapy.

Figure 3.

Nomogram constructed for predicting the risk of a lymphoma-related secondary malignancy among childhood and adolescent primary lymphoma patients and its validation. (A) Nomogram for predicting the risk of a lymphoma-related secondary malignancy. Each level of different factors corresponds to a point. By adding all these points according to the real condition of a patient, we can obtain a total number that has a corresponding decimal on the “Risk of subsequent cancer” line. Therefore, the risk probability for SMN is (the decimal × 100)%. Mark: 1, classical Hodgkin lymphoma; 2, nodular lymphocyte predominance Hodgkin lymphoma (NLPHL); 3, non-Hodgkin lymphoma, B-cell; 4, non-Hodgkin lymphoma, T-cell; 5, non-Hodgkin lymphoma, unknown lineage; 6, lymphoid neoplasm, none of specific. (B) Receiver operating characteristic (ROC) curve. (C) Calibration curve. Abbreviations: R: Radiotherapy; C: Chemotherapy; NR: No/unknown Radiotherapy; NC: No/unknown Chemotherapy.