This patient underwent a core needle biopsy (CNB) before definitive management was undertaken. CNB showed morphological features consistent with classic invasive lobular carcinoma (ILC), with tumor cells arranged in cords, clusters, and single-file arrangements. Loss of cohesion is apparent. The nuclei are round to oval to notched with a high nuclear:cytoplasmic ratio. Occasional signet ring cells are noted (Post test images 3-4). On immunohistochemistry, the tumor cells were ER and PR positive, HER2neu negative with the Ki67 proliferation index being 1-2%. E-cadherin was very focally positive (Post test image 5). A diagnosis of ILC was confirmed.

Breast cancer is the most prevalent cancer detected in between women worldwide (1). Among its subtypes, ILC ranks as the second most common type with invasive ductal carcinoma (IDC) being the most common (2,3). The median age range for of ILC patients is wide, spanning from 28 to 86 years of age (2-7). ILC exhibits a unique clinical, radiological, morphologic, molecular, and treatment profile, distinct from other invasive breast cancers (8). Originating from breast lobular structures, ILC's individual tumor cells infiltrate the surrounding tissue (9). This distinctive growth pattern poses challenges in clinical and radiological detection, resulting in later presentation and possible metastases at the time of diagnosis (10). Patients with ILC may present with skin thickening and dimpling, with a mass lesion not always present (2,11). Additionally, ILC often affects both breasts. Metastases to body cavities and meninges are well-described (2,9,12-16).

Mammogram, ultrasound, and MRI can be used to diagnose ILC, together with clinical and FNA/biopsy findings. Mammography's overall sensitivity in detecting breast cancer ranges from 63% to 98%. However, this sensitivity decreases to 57-81% for ILC and can be as low as 30% in dense breast tissue (9). The mammographic findings include a poorly spiculated and ill-defined lesion with microcalcifications not often seen (2,9,11). The sensitivity of ultrasound in detecting ILC ranges from 68% to 98% (2,9). Typical ultrasound features include an irregular, hypoechoic mass with ill-defined margins and posterior shadowing (2). MRI has a sensitivity of 93% in detecting ILC and is useful for diagnosing, assessing the extent of the disease, and planning surgery. MRI features include solitary masses with irregular margins or multiple enhancing lesions connected by strands or clusters (2,17). Contrast-enhanced spectral mammography (CESM) is a new diagnostic modality that has shown comparable diagnostic value to MRI in diagnosing ILC (9).

The cytological assessment of classic ILC typically reveals an infiltrating, low-grade tumor with a distinctive pattern and varying cellularity, often reduced due to the desmoplastic response elicited by the tumor cells. The architectural pattern ranges from single-lying isolated cells to linear arrangements, small clusters, swirling patterns, and rarely, solid growth (4,11,18). The tumor cells appear discohesive, consisting of small to medium-sized, uniform cells with minimal nuclear atypia. Other observable characteristics include an increased nuclear-to-cytoplasmic (N:C) ratio, oval to round, irregular, triangular, or indented nuclei with coarsely granular, hyperchromatic chromatin and inconspicuous nucleoli. Additionally, scant cytoplasm with poorly defined cell borders is typically present. Some cases may show signet ring cells with a targetoid appearance of the cytoplasm. (2,4,9,19,20). Apart from the classic variant, ILC also displays several other subtypes, each exhibiting distinct features and behaviors (2). These subtypes include solid, alveolar, histiocytoid, tubule-lobular, signet ring, apocrine, and pleomorphic (2,15, 16).

The false negative rate of FNA in the diagnosis of ILC ranges from 4% to 39.5% (12). Several factors contribute to this false negative rate, including inadequate sampling, low cellularity, mild atypia, small cell size and cytopathologist expertise (4,12). Despite these challenges, FNA remains a valuable, swift, safe, minimally invasive, and cost-effective diagnostic tool for ILC (12,20). The false negative rate of CNB in lobular carcinoma doesn’t appear to be well-described.

ILC displays a significant loss of cadherin-1 (CDH1) expression, the gene responsible for encoding E-cadherin (5). The majority of ILC cases show positivity for ER and positivity for PR in approximately 60-70% of instances, while HER2 overexpression is relatively uncommon (2, 12,21). Positive staining for p120 catenin is generally observed, and the expression of KI67 is typically low (2). Other mutations include PTEN, TBX3 and FOXA1, 1q gain, 16p gain and 16q loss (22,23).

With the upcoming WHO system for reporting breast cytopathology and its attendant well-defined criteria and diagnostic management for breast lesions, there is expected to be renewed interest in breast FNA. Accurate recognition of lobular carcinoma is essential on both breast FNA and in a metastatic site. ILC is more likely than IDC to be bilateral, potentially influencing management decisions. The treatment for ILC is unique due to its relative lack of chemosensitivity, with endocrine therapy being the preferred approach (2), further emphasizing the importance of accurate ILC diagnosis.