Sarcoidosis and Cancer: The Role of the Granulomatous Reaction as a Double-Edged Sword

Abstract

Background/Objectives: The relationship between sarcoidosis and the occurrence of neoplasia deserves to be investigated, but this relation has been observed in different and heterogeneous populations, leading to conflicting data. To clarify the causal relationship between these two diseases, different risk factors (e.g., smoking), concurrent comorbidities, corticosteroid therapy, and metastasis development-as an expression of cancer aggressiveness-were investigated. Methods: In a retrospective study on 287 sarcoidosis outpatients at the Pneumological Department of the Gemelli Foundation (Rome, Italy) between 2000 and 2024, the diagnosis of cancer was recorded in 36 subjects (12.5%). Results: The reciprocal timeline of the diseases showed three different scenarios: (1) cancer preceding sarcoidosis or sarcoid-like reactions (63.8%); (2) cancer arising after sarcoidosis diagnosis (8.3%); and (3) sarcoidosis accompanying the onset of malignancy (27.8%). Only two subjects with sarcoidosis and cancer showed metastasis, and one of them was affected by lymphoma. Conclusions: These data suggest that granulomatous inflammation due to sarcoidosis may assume an ambivalent role as a "double-edged sword", according to the M1/M2 macrophage polarization model: it represents a protective shield, preventing the formation of metastasis through the induction of immune surveillance against cancer while, on the other hand, it can be a risk factor for carcinogenesis due to the persistence of a chronic active inflammatory status. Low-dose steroid treatment was administered in only 31.6% of the cancer-sarcoidosis subjects for less than six months to control inflammation activity, with no promotive effect on carcinogenesis observed.

Keywords: cancer; granulomatous reaction; sarcoidosis.

Figure 1

Cancer subjects (36 out of 287) distributed with respect to temporal relationship between cancer and sarcoidosis onset.

Figure 2

Percentage of subjects with and without cancer in the total sarcoidosis population (287 subjects). The temporal relationship between cancer and sarcoidosis onset is indicated in the cancer populations.

Figure 3

Summary of the main macrophage polarization states of activated macrophages in relation to functional roles and human diseases. M1-like or M2-like activation states can be induced by different stimuli and signaling pathways. In humans, distinct defensive or healing schemas are reported to be related to M1-like or M2-like polarization. Inducing factors are indicated on the arrows; antigens and receptors expression is represented in red; cytokines and chemokines production is shown in bold. LPS: lipopolysaccharide; MR: mannose receptor; TNF: tumor necrosis factor; TLR: Toll Like Receptor; Arg 1: arginase 1; IFNγ: interferon gamma; IL: interleukin; MCP: monocyte chemoattractant protein; TGF: transforming growth factor; MCSF: macrophage colony stimulating-factor; ROS: reactive oxygen species; MHC: major histocompatibility complex; VEGF: vascular endothelial growth factor. Modified from J. Novais Barbosa, D. Pereira Vasconcelos, Macrophage response to biomaterials, Handbook of Biomaterials Biocompatibility, 2020 [68].