Pathology of Triple Negative Breast Cancer Part 3

Adenoid cystic carcinoma:
- 0.1% to 1% of all breast cancers
- Low aggressive malignant potential
- Myoepithelial differentiation
- Exhibit tubular, trabecular, cribriform, and / or solid patterns
- Cribriform is the classic pattern
- Characterized by MYB-NFIB t(6;9)(q22-23;p23-24)

Tumor infiltrating lymphocytes (TIL):
- Recommendations for assessing TILS in breast cancer:
  - Evaluated for the stromal component (% of stromal TIL)
  - Evaluated with the borders of the invasive tumor
  - Exclude TILs outside of the tumor border, around DCIS and normal lobules
  - Lymphocytes and plasma cells, exclude neutrophils
  - Full sections are preferred over biopsies:
    - Cores can be used in the pre therapeutic neoadjuvant setting
  - Average TILs in the tumor area (do not focus on hotspots)
  - The number of TILS correlate with complete pathologic response in the neoadjuvant setting
  - No formal recommendations for a clinically relevant TILS threshold(s) can be given at this stage
PD-L1 and Breast Cancer:
- The PD-L1 on tumor cells, when combined with its PD-1 on immune cells:
  - Causes an inhibition of immune response mediated by CD8+ T cells
- Breast tumor that have PD-L1 tend to have high number of TILs, and the majority are of the triple negative type
Tumors arising in BRCA 1 carriers:
- BRCA 1 is involved in:
  - DNA repair
  - Cell cycle regulation
  - Transcriptional regulation
  - Chromatin remodeling
- Loss of BRCA 1 leads to:
  - Deficiency in repair of DNA doble-strand breaks
- 75% of all tumors developing in BRCA 1 germ line mutation carriers are TNBC:
  - High histologic grade
  - High proliferation rate
Residual cancer burden after neoadjuvant chemotherapy (NAC):
- Parameters required to calculate residual cancer burden (RCB):
  - Submission of the entire area of the tumor bed
  - Tumor dimensions (at least in two dimensions)
  - Percentage invasive carcinoma in the tumor bed
  - Percentage of the in situ carcinoma in the tumor bed
  - The number of positive lymph nodes
  - The largest diameter of nodal metastasis

In these diagrams, the macroscopic tumor bed dimensions in examples A, C, D also define the final dimensions of the residual tumor bed after microscopic review. However, the macroscopic tumor bed dimensions in example B overestimate the extent of residual cancer, and so the dimensions of the residual tumor bed (d1 and d2) would be revised after microscopic evaluation of the extent of residual cancer in the corresponding slides from the gross tumor bed. In a different example (E), microscopic residual cancer extends beyond the confines of the macroscopic tumor bed. Again, the dimensions of the residual tumor bed (d1 and d2) would be revised after microscopic evaluation of the recognizable extent of residual cancer beyond the macroscopic tumor bed.
This approach accounts for differences in the concentration and distribution of residual cancer within a tumor bed. In the illustration above, the estimated % CA in example A would be high (in a small area), whereas the estimated % CA for examples C and D would be lower (in a larger area). In examples C and D, the estimated % CA would likely be similar, even though the distribution of cancer within the residual tumor bed is different in those two examples.

A practical way to estimate % CA in a slide is to encircle with ink dots the tumor bed on each slide from the grossly defined residual tumor bed (e.g., slides A1-A5 in the example above). Then use the microscope to estimate the cellularity in each microscopic field across the area of tumor bed. In each microscopic field, % CA can be estimated by comparing the proportion of residual tumor bed area containing cancer (invasive or in situ). Estimate an average of the readings for % CA in the cross-sectional area. The same can be done for in situ component (% CIS). Estimates are to the nearest 10%, but include 0%, 1%, and 5% for areas with low cellularity. The average cellularity within the tumor bed from each slide across the tumor bed can then be estimated (illustrated above).

It is recommended to repeat ER, PR, and HER2 on invasive TNBC after neoadjuvant therapy
Distant metastasis in patient with residual disease after NAC:
- Factors associated with increased distant metastatic rate:
  - Positive pathologic LN status
  - Lymphovascular space invasion (LVSI)
  - Increasing clinical T and N stage
  - Multifocality
  - Extranodal extension