Fresia Pareja, MD PhD, Assistant Attending, Department of Pathology and Laboratory Medicine
Co-director of the Lobular Breast Cancer Program, Memorial Sloan Kettering Cancer Center, LBCA Scientific Advisory Board member

First described in 1941 1 , invasive lobular carcinoma (ILC) is the second most common histologic subtype of breast cancer, comprising approximately 15% of all cases.

ILC has a unique appearance under the microscope: cells that do not attach to each other. This stems from a hallmark biological feature – the loss of E-cadherin, a protein that helps cells stick together. Without it, ILC cells grow as single cells or as single cells files, resulting in its characteristic appearance.  ILC, however, is not a single entity, but rather a collection of variants, each with a unique appearance. Although lack of cell-to-cell attachment is their common denominator, ILC variants are defined by differences in their tumor cell appearance or growth pattern 2-4 .

Among ILC variants that exhibit growth patterns that are different from classic ILC, we have:

• Solid ILC: Sheets of tumor cells.
• Alveolar ILC: Small clusters of tumor cells.
• Trabecular ILC: Tumor cells arranged in rope-like strands.
• Tubulolobular carcinoma: Drop-shaped tubules connected to tumor cell cords.

Other ILC variants are defined not by their growth patterns, but rather based on the appearance of their tumor cells, including:

• Pleomorphic ILC: Larger tumor cells with higher degree of variation in size and
  abnormal looking nuclei, and a higher number of actively dividing cells.
• Histiocytoid/apocrine ILC: Tumor cells that are larger than usual and have a pink and cloudy appearance.
• ILC with signet ring cells: Tumor cells contain a substance called mucin that builds up in the cells and pushes their nuclei to the side, creating a signet ring shape.

Other rarer, but equally important, ILC variants include:

• ILC with extracellular mucin: Lobular tumor cells surrounded by pools of mucin.
• Solid papillary ILC: Solid pattern around finger-like projections.
• ILC with tubular elements: A blend of discohesive ILC tumor cells and tubular structures.

Notably, ILC can sometimes display a combination of patterns, further adding to its diversity and complexity. Research studies are revealing that ILC variants are not only distinct under the microscope – they have a different biology and behavior too. For instance, pleomorphic ILC and high grade solid ILC are often of larger size, are more likely to spread to lymph nodes, and tend to be associated with poorer patient outcomes, compared to classic ILC 5 . Furthermore, ILC variants show differences in their genetic makeup, such as the greater complexity in copy number alterations and higher frequency of TP53 and ERBB2 mutations 2,6 reported in pleomorphic and solid ILC, compared to classic ILC.

The diagnosis of ILC variants can be challenging; pathologists do not always agree in their classification and not all variants are systematically reported, as per a recent survey 7 . The future holds promise, however. Artificial intelligence (AI)-based tools have proven useful for the diagnosis of ILC 8,9 and they could be leveraged to assist in the detection of ILC variants. Furthermore, efforts are underway to refine the definitions, standardize the diagnosis and further characterize these challenging but clinically relevant ILC forms. This work will be crucial to deepen our understanding of ILC variants and inform patient care.

ILC is a mosaic of tumors, with each variant contributing a distinct piece to the multifaceted picture of this breast cancer subtype. Each of these variants not only provides new insights into ILC biology, but also offers opportunities to refine diagnosis and unlock novel therapeutic strategies. By recognizing and harnessing these differences, we move towards a future where care for ILC patients is truly personalized – reflecting the uniqueness of ILC variants themselves.

 

REFERENCES
1. Foote, F.W. & Stewart, F.W. Lobular carcinoma in situ: A rare form of mammary cancer. Am J Pathol 17, 491-496 3 (1941).
2. Christgen, M. et al. Lobular Breast Cancer: Histomorphology and Different Concepts of a Special Spectrum of Tumors. Cancers (Basel) 13(2021).
3. Kuba, M.G. & Brogi, E. Update on lobular lesions of the breast. Histopathology 82, 36-52 (2023).
4. WHO Classification of Tumours-Breast Tumours, (International Agency for Research on Cancer, Lyon, 2019).
5. Makhlouf, S., Atallah, N.M., Polotto, S., Lee, A.H.S., Green, A.R. & Rakha, E.A. Deciphering the Clinical Behaviour of Invasive Lobular Carcinoma of the Breast
Defines an Aggressive Subtype. Cancers (Basel) 16(2024).
6. Rosa-Rosa, J.M. et al. High Frequency of ERBB2 Activating Mutations in Invasive Lobular Breast Carcinoma with Pleomorphic Features. Cancers (Basel)
11(2019).
7. De Schepper, M. et al. Results of a worldwide survey on the currently used histopathological diagnostic criteria for invasive lobular breast cancer. Mod
Pathol 35, 1812-1820 (2022).
8. Pareja, F. et al. A Genomics-Driven Artificial Intelligence-Based Model Classifies Breast Invasive Lobular Carcinoma and Discovers CDH1 Inactivating
Mechanisms. Cancer Res 84, 3478-3489 (2024).
9. Sandbank, J. et al. Validation and real-world clinical application of an artificial intelligence algorithm for breast cancer detection in biopsies. NPJ Breast Cancer
8, 129 (2022).