Abstract Background: Invasive lobular carcinoma (ILC) accounts for approximately 10-15% of invasive breast cancers and is characterized by a unique histologic growth pattern that often results in subtle imaging findings. Notably, up to 30% of cases may be mammographically occult. ILC is also characterized by an atypical metastatic pattern, with a tendency to spread to sites such as the gastrointestinal tract, peritoneum, and orbit. Presentation as isolated periorbital swelling is exceedingly rare and presents a significant diagnostic challenge, particularly in the context of a negative screening mammogram. Case Presentation: A 56-year-old woman initially presented to her primary care physician with left periorbital swelling, redness, and discomfort. Symptoms were recurrent for over a year, and during this time she was evaluated by optometrists, ophthalmologists, and plastic surgeons without a definitive diagnosis. Empiric treatment for presumed allergic conjunctivitis and sinusitis provided little improvement before symptoms would recur. Screening mammogram during this time was negative for malignancy. She eventually underwent a brain MRI for persistent symptoms which demonstrated nonspecific enhancement of the left orbit. Given ongoing symptoms, she underwent surgical resection of the infraorbital mass, and pathology revealed metastatic ILC. The patient had no breast-related symptoms, and repeat diagnostic mammography and ultrasound failed to identify a primary tumor. Subsequent breast MRI detected a subtle right breast lesion, which was confirmed as ILC on biopsy. Discussion: This case highlights the diagnostic limitations of mammography in detecting ILC and underscores the importance of maintaining clinical suspicion when evaluating persistent orbital symptoms. Orbital metastases are a rare and often an overlooked manifestation of ILC, especially when it is the initial presentation. This case also highlights the value of MRI in the diagnostic workup of ILC, even with negative mammography. Conclusion: Periorbital swelling may represent the initial and sole manifestation of ILC. Given the potential for ILC to spread to atypical sites, providers should be aware of this rare presentation and include breast cancer in the differential diagnosis for unexplained orbital symptoms. Further imaging with MRI should be considered, even in the setting of a negative mammogram, if there is high clinical suspicion for ILC to help avoid delays in diagnosis. Citation Format: S. A. Shaker, D. Ramirez. Atypical Presentation of Invasive Lobular Carcinoma Presenting as Periorbital Swelling Despite Negative Mammogram abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-06-12.
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