Mayor WHO 6th Edition Updates in Invasive Lobular Carcinoma

Summary of the major updates in the WHO Classification of Tumors of the Breast, 6th Edition (2026) as they pertain to invasive lobular carcinoma (ILC) and related changes
Key ILC-Specific Changes:
- ILC with Extracellular Mucin (ILCEM) — New Diagnostic Entity:
  - The most significant ILC-related change is the formal recognition of ILC with extracellular mucin (ILCEM) as a distinct diagnostic entity with prognostic implications:
    - This rare subtype, first described in 2009, is characterized by lobular-phenotype tumor cells (single cells, cords, nests, trabeculae) floating within pools of extracellular mucin
  - Key features include:
    - Typically presents as a large mass (> 2 cm) in postmenopausal women:
      - Often shows high nuclear grade (grade 2 to 3), signet-ring cell morphology, pleomorphic features, solid growth patterns
    - E-cadherin is absent or aberrant on IHC, with cytoplasmic p120 catenin localization confirming lobular phenotype in both mucinous and non-mucinous components
    - All reported cases are ER-positive, with a higher rate of HER2 positivity than classic ILC
    - Molecularly, ILCEM harbors CDH1 alterations in ~ 92% of cases, along with PIK3CA, RUNX1, AKT1, and PTEN mutations:
      - Cases with recurrences show additional ERBB2, ERBB3, TP53, and FGFR1 alterations
  - Worse prognosis than classic ILC:
    - 52% recurrence rate and ~ 30% disease-specific mortality in reported series
The WHO 6th Edition (2026) introduces a critical terminological change for ILC:
- The term “variant” is now reserved exclusively for molecular / genetic alterations:
- While morphological differences in ILC are reclassified as architectural patterns or cytomorphological subtypes rather than “variants”;
  - This represents a significant conceptual shift from the 5th edition framework
Terminology Update: “Variant” vs. “Pattern/Subtype”:
- In the WHO 5th edition, ILC morphological forms were called “variants”
- The 6th edition clarifies that “variant” should now refer only to molecular / genetic alterations (e.g., CDH1 mutations, PIK3CA mutations):
  - While the morphological diversity of ILC is described using terms like “pattern” or “subtype”:
    - This aligns breast pathology terminology with broader WHO classification principles across organ systems
Architectural Patterns of ILC:
- ILC architectural patterns are categorized based on growth pattern and cytomorphology:
  - Growth pattern-based:
    - Classic:
      - The most common pattern, characterized by small, dyscohesive cells with monomorphic nuclei and scant cytoplasm
      - Arranged in single cells, single files, and targetoid infiltrations around ducts and lobules, with little or no stromal reaction
      - Two cell types exist within classic ILC:
      - Type A cells – monomorphic, pleomorphism score 1
      - Type B cells – larger, vesicular, pleomorphism score 2
    - Solid:
      - Sheets of dyscohesive lobular cells growing in solid nests without fibrovascular cores or a fibrous capsule
      - Associated with higher Ki67 and more aggressive behavior
      - High-grade solid ILC is grouped with pleomorphic ILC as an aggressive subtype
    - Alveolar:
      - Cells arranged in rounded nests of ~ 20 cells resembling alveolar structures; often mixed with other patterns
    - Tubulolobular:
      - Features small tubular structures admixed with classic lobular single-file growth
    - Trabecular:
      - Trabeculae mainly 2 to 3 cells thick (first described by Martinez and Azzopardi in 1979)
      - Prognosis appears similar to classic ILC
    - Solid papillary:
      - A recently described pattern with circumscribed nodules containing fibrovascular cores, distinct from solid ILC (which lacks fibrovascular cores)
      - May express neuroendocrine markers (synaptophysin, chromogranin)
      - Shows higher post-endocrine therapy Ki67 levels
    - ILC with tubular elements (ILC-TE):
      - A recently identified pattern defined by noncohesive carcinoma cells mixed with cohesive tubular elements, with complete E-cadherin loss but P-cadherin upregulation (E-cadherin to P-cadherin switch, or EPS) in tubular areas
      - Accounts for ~ 7.5% of ILC and is associated with less-aggressive features (lower grade, lower Ki67, cT1, cN0)
  - Cytomorphology-based:
    - Pleomorphic:
    - High nuclear grade (pleomorphism score 3), accounting for < 1% of all breast cancers
    - Associated with worse prognosis than classic ILC and even IBC-NST, with frequent ERBB2 and PIK3CA mutations
  - Histiocytoid / apocrine:
    - Cells with abundant eosinophilic or granular cytoplasm resembling histiocytes
New Entity: ILC with Extracellular Mucin (ILCEM):
- The 6th edition formally recognizes ILCEM as a distinct diagnostic entity:
  - Lobular-phenotype cells floating within pools of extracellular mucin, confirmed by absent /aberrant E-cadherin and cytoplasmic p120 catenin
  - This carries worse prognosis than classic ILC (52% recurrence rate)
Prognostic Stratification by Pattern:
- A large cohort study (n = 7,140) identified that pleomorphic ILC and high-grade solid ILC together comprise ~ 14% of ILC cases and constitute an aggressive subtype with worse breast cancer-specific survival and disease-free survival compared to both classic ILC and IBC-NST:
  - Notably, adjuvant chemotherapy did not improve outcomes in this aggressive subgroup
- Classic ILC and its related patterns (alveolar, trabecular, papillary, tubulolobular) had significantly better survival than IBC-NST in the first 10 to 15 years of follow-up