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Invasive Carcinoma V - Breast



A. Tumor size (See earlier section)

B. Histologic and nuclear grades by Bloom/Richardson (Elston Mod.) Grading Method (See earlier section)

C. Presence of lymphatic space invasion (See earlier section)

D. Surgical margin

When treated by conservative surgery and radiotherapy, the local recurrence rate is 3% when margin is cleared of tumor by more than 1 mm, 2% when margin is cleared by less than 1 mm, 9% when the margin is positive in less than three low power fields, and 28% when the margins is positive in more than three low power fields (Joint Center for Radiation Therapy).

E. Lymph node status

The lymph node status is one of the most important prognostic indicator. In addition, the number of lymph node involved, less than three or four and more, and the amount of metastasis further influence the survival. Tumor cells enter the lymph node via afferent lymphatics. For this reason, metastasis in the early stage occurs predominantly in the subcapsular region (Slide 46). With growth, tumor cells spread to the surrounding extranodal fibroadipose tissue and blood vessels (Slide 47). Extracapsular spread is reported to adversely affect the outcome.



A. Estrogen Receptor (ER) Protein and Progesterone Receptor (PR) Protein

 ER positivity is favorable prognostic indicator, PR positivity alone is a weak favorable prognostic indicator. Patients with ER positive metastatic tumor receiving endocrine therapy had 60% overall clinical response, and 20% reduction in recurrence/mortality (Early Breast Cancer Trialists' Collaborative Group). When ER and PR are combined, the frequency and response rates are summarized as follows (McGuire et al):

ER+/PR+ 58% 77%
ER+/PR- 23% 27%
ER-/PR+ 4% 46%
ER-/PR- 15% 15%

ER/PR status has been based on biochemical ligand assay, which requires fresh tissue frozen immediately following excision. ER/PR status can be obtained on formalin embedded tissue sections by immunohistochemical stains using monoclonal antibodies.

There is 80-90% agreement between biochemical ligand assay and immunohistochemical stains for ER/PR. The result of the latter is reported by the percent of positive tumor cells (Slides 48-49-50).

Immunohistochemical stains for ER/PR have several advantages: precise localization, accurate quantification by visual estimates or by digital imaging technique, possible to perform on routinely processed tissue and archival paraffin block from earlier surgery, workable on cells in effusion or smears obtained by fine needle aspiration. However, laboratory agreement on the type of antibody to use and scoring method is needed.

B. HER-2/neu Oncogen

HER-2/neu is an oncogen and its protein product is located on the cell surface. It may influence growth factor receptor and promote cellular differentiation, adhesion and motility. It is detected by immunohistochemical stain on tissue section. Amplified or over-expression is seen in 20-30% of breast cancers (Slide 51).

HER-2/neu over-expression is a predictive marker for resistance to adjuvant therapy (cytoxan/methotrexate and tamoxifen).

HER-2/neu is over-expressed in high grade DCIS only, therefore cannot be used to distinguish low grade DCIS from atypical ductal hyperplasia (Slides 52 and 53).

C. P-53

Tumor suppressor gene and its protein product is a nuclear transcription factor related to cell cycle regulation and apoptosis. Detected by immunohistochemical stain on tissue section.

Abnormal p53 phenotype in tumor is associated with poor clinical outcome among node negative patients

D. Flow DNA Cytometry

By flow cytometry, the DNA ploidy patterns and ploidy levels of the stem cells and their cell cycle kinetics can be determined. Isolated tumor cells are obtained from the solid tumor by mechanical dispersion or enzyme dissection. Most laboratories currently use tumor tissue embedded in paraffin block.

The tumor cells are stained with dye specific for DNA, suspended in fluid and passed through the laser beam. The DNA content is plotted in a histogram. Benign tissue in the same specimen is processed similarly to serve as diploid control. The Go/G1 peak represent cells in the resting phase. As cells begin to synthesize DNA, the DNA content is increased (S-phase). At the completion of DNA duplication, G2 and M (mitotic) cells produced a second peak with double amount of DNA.

The ploidy level of stem cells is compared with benign diploid cells in the form of DNA index. To allow for instrument error of 5%, the diploid tumors have DNA index of 0.95 to 1.05 (Slide 54), tetraploid tumors 1.90 to 2.1 (Slide 55), and aneuploid tumors outside of diploid and tetraploid ranges (Slide 56).

Flow DNA cytometric analysis provides an objective measure of DNA/chromosome abnormality and rate of cellular proliferation in a more consistent manner than subjective evaluation of histologic features.

In the study of stage I-III breast cancers by Kallioniema et al, the 6-year survival rates for patients with diploid tumor is 80%, tetraploid tumors 60%, hyperdiploid aneuploid tumors (DNA index 1.05-1.8) about 55%, and hypertetrapolid aneuploid tumors 40%. When DNA index and S-phase fraction are combined, the best survival is found among patients with diploid tumors and S-phase fraction of less than 7%. The lowest survival are those with aneuploid tumors with S-phase fraction of greater than 12%. The remaining tumors have intermediate prognosis.

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