Detection of Intratumoral microorganisms in CTCL and patients symptoms and outcomes. Introduction: In CTCL the tumor microenvironment (TME) is a critical component of lymphoma biology and impacts patient outcomes. Intratumoral microorganisms (IMS) constitute a part of the TME in solid tumors and tend to localize in specific niches, influencing response to therapy and outcomes. We hypothesized that IMS may impact presentation and outcomes of patients with CTCL.

Methods: Targeted next-generation sequencing (NGS) was performed on CTCL biopsy samples from 93 patients (pts) followed at our institution with the Memorial Sloan Kettering-Integrated Mutational Profiling of Actionable Cancer Targets (MSK-IMPACT). The control group comprised 177 melanoma biopsies, 49 systemic T-cell lymphoma (TCL) non-cutaneous biopsies and 66 normal lymph nodes. Microbial reads from regions that do not align with the human reference genome were analyzed (Elkrief JCO 2024). Several databases were referenced to exclude contaminations, and IMS were deemed positive if a minimal number of 2 reads was present, and with a higher individualized read threshold for potential contaminants based on the literature. These results were coupled with data on biopsy type (shave vs punch vs excision) lesion characteristics (tumor, plaque, patch), ulceration, pruritus, systemic antibiotics use, ethnicity, and outcomes from our clinical database. Ancestral annotation was inferred using the same MSK-IMPACT NGS platform. We compared variables with Fisher's exact test, the t-test, and LogRank for each IMS present in more than 10% of the samples. ROC curve was used to estimate the AUC and best cut-off value for the IMS/sample.

Results: Median age at diagnosis in the 92 pts was 56 (20 – 90) years, 57 pts were male (52%), 55 pts had limited (IA, IB, IIA) stage CTCL (60%), 33 pts (36%) presented with patches, 41 (45%) with plaques, 13 (14%) with tumors, and 5 (5%) with erythroderma. Twenty-two (24%) were of African American descent, 6 (7%) Asian, 1 (1%) Hawaiian, 53 (58%) white and 10 (11%) had mixed ancestry. Compared to controls, CTCL samples had a similar number of IMS per sample compared to melanoma and systemic TCL, and a significantly higher number of IMS/sample compared to normal lymph nodes. Detection of Escherichia, Erythrobacter, Bordetella, Melothermus Bacillus and Prevotella was typical of melanoma but not found in CTCL samples, while Aquabacterium (p=.0005) and Helicobacter (p=.01) were more prevalent in CTCL. The presence of <9 IMS per sample was associated with worse overall survival (OS), p=.052. The ROC curve demonstrated an AUC of 0.8 for the relation of IMS/sample and OS. Median number of IMS/sample was 13 (3-62) in African American patients and 21 (1-124) in white patients. IMS <9 was associated with non-Caucasian ethnicity (p=.03). Systemic antibiotic use (20 pts, 18%) was associated with worse OS (p=.006) and advanced stage, and with a relative abundance of Prevotella, Streptomyces, Klebsiella. Detection of Staphylococcus was not associated with stage, type of lesion, pruritus or survival. Pruritus was experienced by 48 patients (52%) and was more prevalent in pts with plaques, erythroderma and tumors lesions and localized in the trunk. Acquabacterium detection was associated with less pruritus (p=.002).

Conclusions: Similar to previous findings in solid tumors, our study of IMS in CTCL suggests an increased incidence of intratumoral microbiota detection compared to normal LN, but similar to melanoma and systemic TCL. High number of IMS per sample was associated with improved OS and with Caucasian ethnicity. Further studies in larger independent cohorts are needed to confirm these results and evaluate the interactions of IMS with the lymphoma TME.

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2025
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