We examined a cohort of patients with mycosis fungoides (MF) treated at the University of Minnesota (UMN) from 2005-2017 to elucidate the pathophysiology of second malignancies in MF. A number of previous studies have demonstrated a link between MF and development of second primary malignancies.1
A natural language search of all charts for the terms “mycosis fungoides,” “cutaneous lymphoma,” “cutaneous T-cell lymphoma,” and “CTCL” was performed.2 Seborrheic dermatitis (SD) was selected as a control group as SD is a benign dermatologic condition rarely associated with malignancy.3 Cases of MF were matched to cases of SD by age, sex, and follow-up. Fine and Gray regression was used to model the probability of a subsequent malignancy in the presence of competing risks and other covariates, including duration of follow-up.4 Multivariable Cox proportionate hazard modelling, chi square, two-tailed student’s t-test, and ANOVA were used. P-values <0.05 were considered statistically significant. This project was approved by the IRB at the University of Minnesota.
We identified 172 patients with MF along with 172 matched control patients with SD (Table 1). Among patients with MF and SD, 24 and 3 developed second malignancies, respectively (p<0.0002).
Table 1.
Demographics of mycosis fungoides patients seen at the University of Minnesota.
| MF (n=172) | SD (n=172) | P value | |
|---|---|---|---|
| Age in years, median (range) | 59 (8-89) | 61.5 (14-88) | 0.34 |
| Gender, n (%) | |||
| Male | 99 (57.5) | 99 (57.5) | 1.0 |
| Female | 73 (42.4) | 73 (42.4) | |
| Follow up in years, median (range) | 5 (0-40) | 4.1 (0-24) | <0.00001 |
| Second malignancy (%) | 24 (14) | 3 (2) | <0.00002 |
| Pre-existing malignancy, n (%) | 18 (10) | 19 (10) | 0.91 |
| Malignancies identified | ALCL Bladder (2) Breast (2) Cholangiocarcinoma CLL Colon Endometrial Hodgkin’s Melanoma (3) Melanoma in situ NHL Pancreatic Prostate (3) Renal cell (3) Tongue Uterine |
Breast Prostate (2) |
ALCL—anaplastic large cell lymphoma, CLL—chronic lymphocytic leukemia, NHL—non-Hodgkin lymphoma
In univariate analysis, patients with MF were significantly more likely to develop a second malignancy than patients with SD (relative risk [RR] 8.1, CI 5.1-13.2, p<0.0005, Figure 1). Additionally, patients with tumor stage MF were more likely to develop a second malignancy (9/26) than those with patch/plaque stage disease (14/110, RR 3.2, CI 2.6-10.4, p<0.01). Similarly, patients with stage IIB or higher disease were significantly more likely to develop a second malignancy (11/37) than those with early stage disease (13/131, RR 3.0, CI 3.1-13.5, p<0.003).
Figure 1. Incidence of second malignancies in patients with mycosis fungoides.
Cumulative incidence of subsequent malignancies in patients with mycosis fungoides (MF) vs. seborrheic dermatitis (SD)
In multivariate analysis, patients with MF were at significantly higher risk of developing a subsequent MF were significantly more likely to develop a second malignancy than those with patch/plaque stage disease (HR 4.2; 95% CI 1.27-12.5; p=0.018). However, there was no statistically significant difference between patients with advanced vs early stage disease (HR 1.1; CI 0.8-1.3 p = 0.797).
Analysis of treatments and imaging undergone by each patient revealed no significant difference in systemic, topical, or phototherapy received between patients who did and did not develop second malignancies.
Means of diagnosis of second malignancy was documented in 19 of 24 cases (79.1%). The majority of the malignancies were found based on patient-reported symptoms (13/19, 68.4%) or screening studies (2/19, 10.5%), rather than MF-related screening exams (4/19, 21.1%). None of the 19 cases of second malignancy with known means of diagnosis were found incidentally on imaging.
In conclusion, patients with MF may have underlying immune dysregulation, including defects in T-cell mediated immunity. 5 Decreased immune surveillance in the setting of MF may be a contributor to increased risk of malignancy. Our data show that patients with MF are at increased risk of developing second malignancies, particularly patients with advanced stage disease or tumors.
Acknowledgements:
We would like to thank the American Society of Hematology for their support of this project as part of the HONORS research grant, which funded data collection and analysis.
Research reported in this publication was supported by NIH grant P30 CA77598 utilizing the Biostatistics and Bioinformatics Core shared resource of the Masonic Cancer Center, University of Minnesota and by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114. This funded the statistical analysis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
IRB statement: This project was approved by the IRB at the University of Minnesota.
Conflicts of Interest: The authors report no conflicts of interest
Financial Disclosure: The authors report no conflicts of interest relevant to this manuscript and have no other financial relationships to disclose.
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References
- 1.Huang KP et al. Second Lymphomas and Other Malignant Neoplasms in Patients With Mycosis Fungoides and Sézary Syndrome. Arch. Dermatol 143, (2007). [DOI] [PubMed] [Google Scholar]
- 2.Ford E, Carroll JA, Smith HE, Scott D & Cassell JA Extracting information from the text of electronic medical records to improve case detection: a systematic review. J. Am. Med. Informatics Assoc 23, 1007–1015 (2016). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Okada K et al. Refractory Seborrheic Dermatitis of the Head in a Patient with Malignant Lymphoma. Case Rep. Dermatol 6, 279–282 (2014). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Fine JP & Gray RJ A Proportional Hazards Model for the Subdistribution of a Competing Risk. J. Am. Stat. Assoc 94, 496 (1999). [Google Scholar]
- 5.Lee BN et al. Dysregulated synthesis of intracellular type 1 and type 2 cytokines by T cells of patients with cutaneous T-cell lymphoma. Clin. Diagn. Lab. Immunol 6, 79–84 (1999). [DOI] [PMC free article] [PubMed] [Google Scholar]