Minor Prognostic Factors.

Most women with nodal involvement and/or carcinomas over 1 cm in diameter will benefit from some form of systemic therapy. In this group, minor prognostic factors can be used to

decide among chemotherapy regimens and/or hormonal therapies. For node-negative women with small carcinomas, minor prognostic factors are used to identify the women most likely

to benefit from systemic therapy and those who might not need any additional treatment.[74] Three of these factors—estrogen receptor, progesterone receptor, and HER2/neu—are most

useful as predictive factors for response to specific therapeutic agents.

1. Histologic subtypes.The 30-year survival rate of women with special types of invasive carcinomas (tubular, mucinous, medullary, lobular, and papillary) is greater than 60%,

compared with less than 20% for women with cancers of no special type.[75]

2. Tumor grade.The most commonly used grading system to assess the degree of tumor differentiation (Scarff Bloom Richardson) combines nuclear grade, tubule formation, and

mitotic rate. Eighty-five per cent of women with well-differentiated grade I tumors, 60% of women with moderately differentiated grade II tumors, and 15% of women with

poorly differentiated grade III tumors survive for 10 years.

3. Estrogen and progesterone receptors.Current assays use immunohistochemistry to detect the receptors in the nucleus ( Fig. 23-27A ). Fifty per cent to 85% of carcinomas

express estrogen receptors, and such tumors are more common in postmenopausal women. Women with hormone receptor-positive cancers have a slightly better prognosis than

do women with hormone receptor-negative carcinomas. The evaluation of hormone receptors is most valuable to predict response to therapy. Eighty per cent of tumors with

estrogen receptors and progesterone receptors respond to hormonal manipulation, whereas only about 40% of those with only one type of receptor respond. Tumors with neither

estrogen nor progesterone receptors have a less than 10% likelihood of responding.

4. HER2/neu. HER2 (human epidermal growth factor receptor 2 or c-erb B2 or neu) is a transmembrane glycoprotein involved in cell growth control.[76] [77] It does not appear to

have a specific ligand but acts as a coreceptor for multiple growth factors. HER2/neu is overexpressed in 20% to 30% of breast carcinomas. In over 90% of cases, overexpression

is associated with amplification of the gene on 17q21, and this can be determined either by evaluating protein content using immunohistochemistry or by determining gene copy

number by using FISH ( Figs. 23-27B and C ). Although not all studies have come to the same conclusion, many have shown that overexpression of HER2/neu is associated with

a poor prognosis. In addition, ongoing studies are addressing the possibility that HER2/neu-over-expressing tumors respond differently to hormonal or anthracycline

chemotherapy regimens. However, evaluation of HER2/neu is most important to determine response to therapy targeted to this protein.

Trastuzumab (Herceptin) is a humanized monoclonal antibody to HER2/neu developed to specifically target tumor cells and, it is hoped, spare normal cells. In clinical trials, the

combination of Trastuzumab with chemotherapy improved response in patients with carcinomas overexpressing HER2/neu. Unfortunately, cardiac toxicity, due to an unknown

mechanism, could limit its usefulness. However, as the first gene-targeted therapeutic agent for a solid tumor, the results have been very promising.

5. Lymphovascular invasion (LVI).Tumor cells may be seen within vascular spaces (either lymphatics or small capillaries) surrounding tumors. This finding is strongly

associated with the presence of lymph node metastases and is a poor prognostic factor in women without lymph node metastases. The presence of tumor cells in lymphatics of

the dermis is strongly associated with the clinical appearance of inflammatory cancer and bodes a very poor prognosis. LVI must be strictly defined to have prognostic

significance.

6. Proliferative rate.Proliferation can be measured by flow cytometry (as the S-phase fraction), by thymidine labeling index, by mitotic counts, or by immunohistochemical

detection of cellular proteins (e.g., cyclins, Ki-67) produced during the cell cycle. Cyclin E content, when both full-length and low-molecular-weight isoforms are detected, is a

very strong predictor of survival. [78] Tumors with high proliferation rates have a worse prognosis, but the most reliable method to assess proliferation has not yet been

established. Mitotic counts are included as part of the standard grading system.

7. DNA content.The amount of DNA per tumor cell can be determined by flow cytometric analysis or by image analysis of tissue sections. Tumors with a DNA index of 1 have

the same total amount of DNA as normal diploid cells, although marked karyotypic changes may be present. Aneuploid tumors are those with abnormal DNA indices and have a

slightly worse prognosis.

Figure 23-27Predictive markers. A, Estrogen receptor is detected in the nucleus by immunohistochemical studies. Progesterone receptor has the same appearance. B, HER2/neu

overexpression is detected on the cell membrane by immunohistochemistry. C, Amplification of the HER2/neu gene can be detected by FISH analysis with a fluorescent probe for the

gene. A normal cell has two copies of the gene. These tumor cells have over 25 signals, indicating amplification of the gene for HER2/neu. (Courtesy of Dr. Jonathan Fletcher, Brigham

and Women's Hospital, Boston, MA.)

Figure 23-28 A, This mammogram shows a well-circumscribed mass. (Courtesy of Dr. Jack Meyer, Brigham and Women's Hospital, Boston, MA.) Although the most common lesion

would be a fibroadenoma, other benign (e.g., fibrous lesions or PASH) and malignant (e.g., medullary or mucinous carcinomas) lesions can also have this appearance. B, Fibroadenoma.

A rubbery, white, well-circumscribed mass is clearly demarcated from the surrounding yellow adipose tissue. The fibroadenoma does not contain adipose tissue and therefore appears

denser than the surrounding normal tissue on mammogram.

Figure 23-29Fibroadenoma. The lesion consists of a proliferation of intralobular stroma surrounding and often pushing and distorting the associated epithelium. The border is sharply

delimited from the surrounding tissue.

Figure 23-30Phyllodes tumor. Compared to a fibroadenoma, there is increased stromal cellularity, cytologic atypia, and stromal overgrowth, giving rise to the typical leaflike

architecture.

Figure 23-31Gynecomastia. Terminal ducts (without lobule formation) are lined by a multilayered epithelium with small papillary tufts. There is typically surrounding periductal

hyalinization and fibrosis.

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