Background: Cancer survivorship faces many challenges, including secondary malignancies. Several studies have examined neoplasms after tumor or lymphoma treatments (Josting A, JCO 2003; Kalaycio M, JCO 2006; Donin N, Cancer 2016). However, less is known about second-diagnosed hematologic malignancies (SHM) following solid cancer treatments (Feller A, BMC Cancer 2020). SHM have special biological characteristics (Kayser S, Blood 2011) and given its low incidence, contemporary evidence from large cancer registries may contribute relevant insights to its incidence and risk factors.

Aim: This study aims to investigate the characteristics of SHM, i.e. hematological malignancies following solid cancer diagnosis using data of Germany's largest population-based cancer registry.

Methods: Data from the North Rhine-Westphalia Cancer Registry for the years 2008–2023 was analyzed. Here, cancer diagnosis documentation is mandatory for all pathologists and cancer care departments. Patients aged 15 years and older and diagnosed with a hematologic malignancy (WHO-ICD10 codes, C81 – C96) following any solid cancer (ICD10, C00 – C75, excluding non-melanoma skin cancer, C44) were included. Only patients with metachronous hematologic malignancies after solid cancer diagnosis were enrolled, i.e. with a minimum of 6 months from first cancer diagnosis. Standardized Incidence Ratios (SIR) were calculated to compare the number of observed cases of SHM in patients with prior solid cancer to the much larger number of cases of primary hematological malignancies in the general population (Breslow NE and Day NE, IARC 1987).

Results: Among 1,426,752 eligible persons with diagnosed cancer in the registry, 8,709 cases of synchronous and metachronous SHM were identified. The minimum gap of 6 months between the solid cancer diagnosis and the subsequent SHM reduced the number of analyzable persons to 6,494. The age peak of diagnoses was 75 years. The most frequent SHM was non-Hodgkin's lymphoma (NHL, n=2,723), followed by myeloma (n=1216) and chronic lymphocytic leukemia (n=848). Among the NHL, aggressive NHL (n=1,497) was the largest fraction, with diffuse-large B-cell lymphoma being the main diagnosis (n=897) while the indolent NHL were less frequent (n=833). Cutaneous lymphoma were uncommon. The proportion of cancer diagnoses in these patients differed substantially between the sexes (61% of SHM were diagnosed in men), yet the proportion of diseases was in the expected range of sex-specific differences relating to genetics and risk behavior. Among those 6,494 patients with SHM, the most frequent primary cancer diagnosis was prostate cancer (49% of cancers in men) followed by colorectal cancer (13.8%), melanoma (8%) and lung cancer (5.5%). Besides the genetically encoded sex-specific cancer differences, the proportion of primary urothelial carcinoma was higher in men (4.6%) than in women (1.7%). Certain primary cancer diagnoses had higher, others lower proportions compared to the general cancer population excluding those with SHM. For instance the proportion of lung cancers was lower with 5.4% versus 14.5% in the general registry population (n=1,426,752), while the proportion of prostate cancers was significantly higher in the subgroup that developed SHM (29.9% versus 14.5%). Breast cancer diagnoses were equally distributed in both groups (17-18%). In further analysis, we observed relatively more primary cutaneous lymphoma among patients with prostate cancer as well as indolent NHL. The picture was similar in breast cancer patients with more indolent NHL and comparatively less cases of aggressive NHL.

Interestingly, SHM were most frequently diagnosed at the beginning of the observation period, i.e. the peak of diagnoses was recorded during months 6-12, the incidence subsequently decreased with some oscillations and was half as high after 80 months. The mean standard incidence ratio for SHM was 1.96 and was age dependent. Importantly, we noted several peaks among adolescents and young adults (age 15-20, SIR 2.91, age 25-30, SIR 2.58 and age 30-35, SIR 3.15). Then the SIR rates continuously declined towards older age reaching 0.94 at the age of 80 years.

Conclusion: Aggressive NHL are the most frequent second-diagnosed hematological malignancies in patients with previous solid cancer diagnosis. Adolescents and young adults have the highest SIR of these malignancies, which should be considered in cancer survivorship plans.

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2025
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