Castleman Disease: A Population Based Study Using the National Cancer Institute's Surveillance, Epidemiology, and End Results Program

Background: Castleman Disease (CD) describes a heterogeneous group of lymphoproliferative disorders that can be divided into various subtypes including unicentric CD (UCD), multicentric CD (MCD), HHV-8 associated multicentric CD, and HHV-8 negative/idiopathic MCD (iMCD). There is lacking data on the epidemiology of CD due to the previous lack of a specific International Classification of Disease (ICD) code or evidence-based diagnostic criteria. As of October 1, 2016, a specific ICD-10 code was created for CD, and a diagnostic criterion for iMCD was established in 2017. The goal of this study was to determine the epidemiology of CD with data available from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. To our knowledge, this is the first study using the SEER database to examine CD.

Methods: Using the SEER 2000-2018 database, 66 cases of CD were identified via the ICD Code 9738 for Large B Cell Lymph HHV8 Multicentric Castleman Disease under the variable histology/behavior. In patients diagnosed with CD who survived at least two months, the Standardized Incidence Ratio (SIR) assessed the overall risk for secondary-primary malignancies (SPMs), while the Standard Mortality Ratio (SMR) assessed the overall risk for mortality. Both of these ratios were calculated using observed to expected (O:E) ratios. The expected number came from the general population. A P value < 0.05 and 95% confidence intervals (CIs) defined statistical significance.

Results: CD survivors had a significantly increased risk of malignancies at all sites(O:E 8.77, 95% CI: 1.06-31.68) and all solid tumors (O:E 10.09, 95% CI: 1.22-36.45) within one year. CD survivors were also at significantly increased risk of malignancy of the urinary system (O:E 45.90, 95% CI: 1.16-255.74) and Kaposi Sarcoma (O:E 2,568.68, 95% CI: 65.03-14,311.75) within one year.

CD survivors had a significantly increased overall risk of mortality from all causes of death (O:E 8.84, 95% CI: 4.24-16.26), all malignant cancers (O:E 9.72, 95% CI: 2.00-28.40), colon cancer excluding the rectum(O:E 45.73, 95% CI: 1.16-254.81), Non-Hodgkin's Lymphoma (O:E 207.27, 95% CI: 25.10-748.72) and infectious and parasitic diseases including HIV (O:E 189.61, 95% CI: 51.66-485.47) across all time periods.

The two most common causes of death in the CD cohort were 1)infectious and parasitic diseases, including HIV, and 2) malignant cancers.

Discussion: Previous data has suggested CD survivors are at higher risk of secondary malignancies, especially lymphomas and Kaposi Sarcoma¹. However, the increased risk of urinary system malignancy has not been previously described. We hypothesize that the increased risk of urinary system malignancy may be due to CD treatment with cyclophosphamide². Current NCCN guidelines recommend screening for Kaposi Sarcoma in the workup of CD, but not urinary or colon malignancies.

It is not surprising that CD survivors are at increased risk of developing solid tumors because, in some cases, it is precisely the solid tumor presentation that leads to the diagnosis of CD³. The causes of death found in the SEER database are consistent with the previous literature³.

Conclusion: With the establishment of a specific ICD code for CD, there is more potential to learn about this disease. Patients with CD were at a significantly increased risk for the development of malignancies at all sites within one year. Increased cancer surveillance aside from Kaposi Sarcoma in this population may be warranted. Greater large-scale, multidisciplinary studies are needed to understand CD epidemiology, increased risk for development of specific secondary malignancies, and increased mortality overall.

References 1. Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood. 2020 Apr 16;135(16):1353-1364. doi: 10.1182/blood.2019000931. PMID: 32106302.

2. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Pharmaceuticals. Lyon (FR): International Agency for Research on Cancer; 2012. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 100A.) CYCLOPHOSPHAMIDE. Available from: https://www.ncbi.nlm.nih.gov/books/NBK304336/

3. Ozsoy M, Ozsoy Z, Sahin S, Arıkan Y. Rare Forms of Castleman Disease Mimicking Malignancy: Mesenteric and Pancreatic Involvement. Cureus. 2018 Mar 12;10(3):e2310. doi: 10.7759/cureus.2310. PMID: 29755906; PMCID: PMC5947929.

No relevant conflicts of interest to declare.