Drug-induced sarcoidosis-like reactions (DISR) are non-caseating granulomatous processes temporally and causally related to systemic therapy, classically described with immune checkpoint inhibitors, anti-TNF-α agents and tyrosine kinase inhibitors, and increasingly reported with monoclonal antibodies and antibody-drug conjugates (ADCs).[1] Trastuzumab deruxtecan (T-DXd) is a HER2-directed ADC that links trastuzumab to a topoisomerase I inhibitor. Its main pulmonary toxicity is interstitial lung disease (ILD)/pneumonitis, reported in approximately 11% of patients, whereas granulomatous reactions are not addressed in current multidisciplinary guidance, which focuses on ILD/pneumonitis.[2] We report, to our knowledge, the first published case of mediastinal sarcoidosis-like reaction attributable to T-DXd in metastatic breast cancer.

A 48-year-old woman (former smoker, less than10 pack-years) diagnosed in 2020 with ER-positive, HER2-positive metastatic breast cancer, previously treated with multiple lines of therapy including trastuzumab, pertuzumab, docetaxel, capecitabine, palbociclib, fulvestrant, and letrozole, started treatment with T-DXd in January 2025. A surveillance 18F-FDG PET-CT in March 2025 revealed new bilateral upper-lobe micronodules and FDG-avid hilar and mediastinal lymphadenopathy, initially suspicious for disease progression. EBUS cryo-biopsies of hilar and subcarinal nodes showed a non-necrotising epithelioid granulomatous reaction with abundant giant cells, consistent with sarcoid granulomas. Microbiological work-up (including mycobacteria) was negative. Ocular involvement was excluded by ophthalmological assessment and cardiac involvement by electrocardiography, echocardiography and PET-CT. Given the temporal relationship with T-DXd and the absence of alternative aetiologies, DISR was diagnosed. T-DXd was discontinued and the patient was switched to sacituzumab govitecan in May 2025. Oral prednisone (60mg/day, subsequently tapered) was administered for a total of 6 months until complete discontinuation. The patient remained respiratorily stable, with preserved pulmonary function (FEV1 2.64L [93%], FVC 3.29L [93%], DLCO 76% [haemoglobin-corrected]), and complete radiological resolution of the micronodular pattern and lymphadenopathy on follow-up PET-CT (Fig. 1). No recurrence occurred on surveillance PET-CT after the switch.

Fig. 1.

18F-FDG PET-CT before and after corticosteroid therapy for trastuzumab deruxtecan-induced sarcoidosis-like reaction. (A) Diagnostic study (left column, panels 1–4): axial CT lung-window images showing a bilateral, predominantly upper-lobe perilymphatic micronodular pattern, the morphological correlate of the FDG-avid hilar and mediastinal lymphadenopathy. (B) Control study after 6 months of corticosteroid treatment (right column, panels 5–8): fused PET-CT images demonstrating complete resolution of the pulmonary micronodules and of the mediastinal and hilar uptake. The residual focal FDG uptake in the manubrium sternum corresponds to a lytic bone metastasis from the breast carcinoma, unrelated to the sarcoidosis-like reaction.

DISR has been reported with anti-HER2 monoclonal antibodies, including trastuzumab,[3] and with pertuzumab–trastuzumab combinations, where mediastinal granulomatous reactions may mimic disease progression on PET-CT.[4] The HER2-directed antibody backbone of T-DXd plausibly shares immunological mechanisms with these monoclonals, likely involving CD4+ Th1-driven granuloma formation, while the cytotoxic payload may contribute through immunogenic cell death. The short latency in our patient (∼2 months) is consistent with the wide interval reported for DISR, from weeks to over a year. Distinguishing DISR from metastatic progression is critical, since misclassification may prompt unwarranted treatment escalation or premature discontinuation of effective oncological therapy; in published cohorts, sarcoid-like reactions have mimicked metastases in over 20% of immunotherapy-treated patients.[5] Histological confirmation by EBUS-guided cryo-biopsy is the diagnostic cornerstone, and the course is generally favourable, with resolution after drug withdrawal and corticosteroids. Although dose-reduced rechallenge may be considered, the extent of involvement led us to opt for definitive discontinuation and a switch to sacituzumab govitecan, which shares a topoisomerase I inhibitor payload but has not been associated with granulomatous reactions. With the expanding use of HER2-targeted ADCs across breast and other solid tumours, clinicians should consider sarcoidosis-like reaction in the differential diagnosis of new pulmonary nodules or lymphadenopathy arising during T-DXd therapy.