Breast Cancer
Mark D. Pegram
Cristiane Takita
Dennis A. Casciato
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence
1. The American Cancer Society (ACS) estimated that breast cancer was diagnosed in 207,090 women and 1,970 men in the United States during 2010. Another 54,010 women were diagnosed with in situ breast carcinoma. Breast cancer was estimated to be the cause of death in 40,640 women and 450 men during that year.
The death rate from breast cancer in North America has been declining, with a 1.7% annual reduction in mortality since 1992. This decline has occurred despite an increased incidence of the disease over the same time period. Over the last 10 years, mortality caused by breast cancer in the European Union has fallen by 9.8%. These reductions are most likely owing to increased early detection and improved efficacy of adjuvant therapies.
2. Although breast cancer is the most common neoplasm in women, accounting for 26% of all cancers diagnosed annually, it is overall the second leading cause of cancer death (following lung cancer). Breast cancer, however, is the leading cause of cancer death in women aged 65 years.
3. The incidence of breast cancer is highest among women of higher socioeconomic background. Although the incidence of breast cancer is higher in whites, black women are more likely to die from the disease. This disparity may be related both to delay in diagnosis because of restricted access to health care and to differing biology of the disease (e.g., higher frequency of HER2-negative, estrogen receptor [ER]-negative, and progesterone receptor [PR]-negative disease in these populations).
B. Genetic predisposition. Most breast cancers diagnosed are sporadic and not associated with any clear familial genetic predisposition. Approximately 10% of breast cancer patients, however, have tumors that can be attributed to inherited germline mutations in genes that control DNA repair, cell growth regulation, or cell cycle control.
1. Germline genetic defects associated with an increased risk of breast cancer include the following:
a. BRCA-1. First identified in 1990, the BRCA-1 gene is assigned to chromosome 17q21. The gene product is a 1,863 amino acid nuclear protein with pleiotropic activities including sensing or signaling DNA damage, transcriptional regulation, transcription-coupled DNA repair, and ubiquitin ligase activity. Several hundred different mutations have been identified by DNA sequence analysis. Particular BRCA-1 mutations are prevalent in specific populations (e.g., del 185 mutation among patients of Ashkenazi Jewish ancestry). Mutation of BRCA-1 accounts for about 20% of all familial breast cancers.
(1) BRCA-1 mutations are inherited in an autosomal-dominant fashion with variable penetrance and are associated with an increased risk of breast, ovarian, prostate, and possibly colorectal cancers, though two studies published in the Journal of the National Cancer Institute in
2004 failed to demonstrate association between germline BRCA gene mutation and colon cancer risk.
2004 failed to demonstrate association between germline BRCA gene mutation and colon cancer risk.
(2) Breast tumors harboring BRCA-1 mutations frequently lack expression of both ER and PR and lack amplification of the HER2 gene. These tumors very frequently also have somatic mutations in the P53 tumor suppressor gene.
(3) Molecular classification of BRCA-1 mutant tumors by gene expression profiling frequently demonstrates a “basal” breast cancer phenotype (see Section II.B.).
(4) Patients with inherited mutation of BRCA-1 can expect a 50% to 85% lifetime risk for breast cancer and a 15% to 45% risk for ovarian cancer.
b. BRCA-2. First sequenced in 1995, the BRCA-2 gene is assigned to chromosome 13q12. The gene encodes a 3,418 amino acid protein involved in DNA repair. As with BRCA-1, many different mutations have been described in the BRCA-2 gene in affected individuals.
Germline mutations in BRCA-2 are associated with an increased risk of a unique spectrum of human neoplasms, including melanoma, breast cancer (in both men and women), ovarian cancer, and pancreatic cancer. Breast cancers associated with BRCA-2 mutation are frequently ER positive and tend to occur at an older age than with BRCA-1.
c. Li-Fraumeni syndrome is caused by germline mutations in the P53 tumor suppressor gene found on chromosome 17p13. In addition to breast cancer, there is an increased risk of other tumor types (sarcomas, brain tumors, leukemia, and adrenal tumors). The lifetime risk of breast cancer associated with this syndrome is about 50%.
d. The PTEN gene is assigned to chromosome 10q22-23 and encodes a tumor suppressor. Cowden syndrome is the clinical phenotype resulting from mutations in PTEN. The syndrome is a rare autosomal-dominant disorder characterized by multiple benign hamartomas and malignant tumors (breast and thyroid cancers). The syndrome is recognized by the pathognomonic presentation of facial trichilemmomas and fibromas of the oral mucosa that cause cobblestone appearance of the tongue and acral palmoplantar keratoses. The risk of breast cancer is increased by approximately 50% in subjects with mutation of the gene.
e. CHEK-2. This cell cycle checkpoint kinase gene is an important component of the cellular DNA repair pathway. Mutation of the gene increases the risk of breast cancer in women by twofold and in men by tenfold.
f. RAD-51. RAD51C is essential for homologous recombination repair; a biallelic missense mutation can cause a Fanconi anemia-like phenotype. Six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer were found (exclusively) within 480 pedigrees with the occurrence of both breast and ovarian tumors.
g. Mutations in other genes have been associated with an increased risk of breast cancer (e.g., ATM and STK11—Puetz-Jeghers syndrome). In approximately half of subjects with an apparent familial association with breast cancer based on analysis of the pedigree, no specific gene mutation can be found.
2. Genetic testing for BRCA-1 and BRCA-2 is commercially available but should be interpreted in consultation with a genetic counselor. Factors that indicate an increased likelihood of having germline BRCA mutations include
a. Multiple cases of early onset breast cancer
b. Ovarian cancer with a family history of breast or ovarian cancer
c. Breast and ovarian cancer in the same individual
d. Bilateral breast cancer
e. Male breast cancer
f. Ashkenazi Jewish ancestry
3. American Society of Clinical Oncology (ASCO) guidelines recommend that cancer predisposition genetic testing should be offered when (1) there is a personal or family history suggestive of a genetic cancer susceptibility condition, (2) the test can be adequately interpreted, and (3) the test result will influence medical management. Once a proband has been identified as a carrier for a heritable cancer predisposition condition, it is important that patients and their family members be counseled regarding additional screening and prevention strategies and be alerted to the risk of other primary neoplasms.
4. Prophylactic surgery. Prophylactic bilateral mastectomy reduces the risk of breast cancer among BRCA mutation carriers by more than 90%. Prophylactic bilateral salpingo-oophorectomy reduces the risk of ovarian cancer (although not primary peritoneal carcinoma) by 90% and also reduces the risk of breast cancer by approximately 65% in premenopausal women with BRCA abnormalities.
5. Insurance issues. The United States Health Insurance Portability and Accountability Act (HIPAA) of 1996 states that genetic information may not be treated as a pre-existing medical condition for the purposes of denying insurance coverage or basing the cost of insurance. In addition to federal policy, many states have additional laws to prevent discrimination owing to genetic information. Consequently, most insurance companies will pay for genetic testing and any subsequent treatment that is indicated.
C. Etiologic factors
1. Endogenous estrogen exposure. The following factors affecting endogenous estrogen exposure have been associated with an increased risk of breast cancer in epidemiologic studies.
a. Nulliparity
b. Late first full-term pregnancy (women who completed their first full-term pregnancy after age 30 are two to five times more likely to develop breast cancer compared with those who had had term pregnancies <18 years of age).
c. Early menarche (<12 years of age)
d. Late menopause (>55 years of age)
e. Lactation may reduce the risk of breast cancer
2. Hormone replacement therapy (HRT) following menopause. A preponderance of the evidence from previous historical cohort studies suggested that the risk of breast cancer was increased modestly by long-term estrogen use alone and that women on estrogen plus progestin were more likely to have tumors with more favorable biologic characteristics (hormone receptor positive disease) and lower tumor stage. The Women’s Health Initiative (WHI) study was begun in 1993 with the following results and effects:
a. The WHI was a placebo-controlled study that enrolled 10,739 patients with a history of prior hysterectomy and 16,608 patients with an intact uterus. The former were randomized to receive conjugated equine estrogen (CEE, 0.625 mg/d) versus placebo, and the latter to CEE (0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) versus placebo. The hypothesis being tested in this trial was that long-term CEE + MPA would have more benefit than risk on chronic diseases, such as coronary heart disease.
b. Published in 2003, the study demonstrated a 24% increase in the risk of breast cancer among the women with an intact uterus randomized to receive CEE + MPA (P = 0.003). Moreover, tumors detected in the CEE + MPA group had a larger mean tumor size (1.7 vs. 1.5 cm, P = 0.038) and were more likely to have lymph node metastasis (25.9% vs. 15.8%, P = 0.033). In addition, more women in the CEE + MPA group had abnormal mammograms at 1 year (9.4% vs. 5.4%, P <0.0001). The study further demonstrated that the risk both of ER/PR positive as well as ER/PR negative disease was increased similarly, contrary to previous reports from non-placebo-controlled cohort studies. With longer follow-up (median = 11 years), breast cancer mortality also appears to be increased with combined use of estrogen plus progestin. Finally, the use of CEE + MPA was found to decrease the risk of colorectal cancer, although the colorectal cancers that were diagnosed were of more advanced stage.
c. The WHI study concluded that combined CEE + MPA increases the number of abnormal mammograms and the risk of invasive breast cancer, and that breast cancers are diagnosed at a later stage. This increased risk of invasive breast cancer was not seen in the women with prior hysterectomy who were randomized to receive CEE alone. The use of CEE alone increased the risk of stroke, decreased the risk of hip fracture, and did not affect the risk of coronary heart disease.
d. It is important to note that patients with prior hysterectomy in this study were more likely to report past or current hormone use, had a higher body mass index, and that 41% had prior bilateral oophorectomy.
e. Together, these data led to a revised view of postmenopausal HRT because use of CEE + MPA potentially leads to delay in diagnosis of two of the three most common cancers in postmenopausal women:
(1) HRT with CEE + MPA should be used at the lowest possible dose and shortest duration sufficient to control vasomotor or vaginal symptoms.
(2) Women with prior hysterectomy treated with CEE for a short-term have no significant increase in breast cancer risk, although the risk of stroke is increased.
f. Subsequent to publication of findings from the WHI study, there was a sharp decline in the number of new prescriptions for HRT in the United States from 22.8 million in the first quarter of 2001 to 15.2 in the first quarter of 2003. Coincident with this practice was a sharp (7%) decrease in the breast cancer incidence, especially among older women with hormone receptor positive disease, suggesting a possible link between decreased incidence and decreased exogenous estrogen and progestin exposure in the form of HRT.
3. Age. The incidence of breast cancer increases steadily with age. Approximately 75% of all cases are diagnosed in postmenopausal women. The risk of developing breast cancer at age 25 years is 1 of 19,608, whereas the lifetime risk is 1 of 8 for women living into their 80s.
4. Benign breast disease. Most forms of benign breast disease, such as fibrocystic disease, are not associated with increased risk. Hyperplasia with atypia, papillomas, sclerosing adenosis, and lobular carcinoma in situ have been reported to be associated with an increased risk. Hyperplasia with atypia is felt to be a proliferative disease that is associated with an 8% risk of developing invasive breast cancer in patients with a negative family history and a 20% risk in patients with a positive family history of breast cancer.
5. Physical activity. Most cohort studies suggest an inverse association between physical activity and breast cancer risk, regardless of the age at which the physical activity occurred.
6. Ionizing radiation. Exposure to radiation increases the risk of breast cancer. Medical radiation therapy (RT) to the chest, for example to a mantle field for Hodgkin lymphoma, can increase subsequent risk of breast cancer. Exposure to fallout from nuclear weapons also appears to increase risk. Recent epidemiologic data following the Chernobyl nuclear power plant disaster suggest higher incidence of breast cancer in the years following the disaster. Breast cancers following radiation exposure typically have long latency, often a decade or more following the exposure.
7. Ethanol. Studies have shown a positive linear relationship between incremental alcoholic beverage intake and increasing breast cancer risk.
II. PATHOLOGY, MOLECULAR CLASSIFICATION, AND NATURAL HISTORY.
Breast cancer is a highly heterogeneous disease. Classification based on clinical and pathologic features have historically been used to guide in the treatment of patients. Although classic histopathologic classification of breast cancer remains important, molecular characterization of the disease is rapidly emerging as a vital tool for understanding clinical prognosis, as well as predicting response to systemic therapies.
A. Classic histopathologic classification. Based on cellular morphology, breast tumors can be broadly categorized as tumors composed of cells of ductal origin (ductal adenocarcinomas) or of lobular origin (lobular carcinomas). Breast malignancies are further classified into invasive (infiltrating) carcinomas capable of metastasizing, and noninvasive disease that can invade beyond the basement membrane (ductal carcinoma in situ, [DCIS], also known as intraductal carcinoma).
1. Ductal adenocarcinoma (70% to 80%) is the most common invasive histology. The clinical prognosis is highly variable, ranging from indolent to rapidly progressive. Prognosis may be estimated by evaluation of cellular morphologic characteristics and molecular markers, such as expression of ER, PR, Ki67 (a marker of cell proliferation, see Section V.B.5), and HER2.
2. Lobular carcinoma (10% to 15%). Invasive lobular carcinoma is capable of metastasis and has a stage-adjusted prognosis similar to infiltrating ductal carcinoma. Invasive lobular carcinomas may be especially difficult to diagnose because of their unique single cell radial pattern of tissue invasion (the so-called Indian-filing on light microscopy) rendering them frequently nonpalpable or mammographically silent. Invasive lobular carcinomas are somewhat more likely to be bilateral compared with infiltrating ductal carcinomas. Metastases from lobular breast carcinomas have a predilection for pleuropericardial surfaces.
To be distinguished from invasive lobular carcinoma, lobular carcinoma in situ (LCIS) is a benign lesion associated with an increase risk of developing subsequent invasive disease, either ductal or lobular. LCIS, in and of itself, is of no clinical consequence, however.
3. Special subtypes with a favorable prognosis (<10%) include papillary, tubular, mucinous, and pure medullary carcinomas.
4. Inflammatory breast cancer (approximately 1%) is a particularly aggressive subtype that can be recognized microscopically based on presence of dermolymphatic invasion. Clinically, this is often associated with cutaneous erythema of the breast (which can mimic mastitis) and cutaneous edema (“peau d’orange”).
5. Paget disease of the breast, which is characterized by unilateral eczematous change of the nipple, is frequently seen in association with underlying DCIS.
6. Cystosarcoma phyllodes constitutes <1% of all breast neoplasms. About 90% of phyllodes tumors are benign and about 10% are malignant. Although these tumors rarely metastasize, they can recur locally. Surgical resection with ample margins is necessary to optimize local control.
7. Rare tumors include squamous cell carcinoma, lymphoma, and sarcoma.
B. Molecular classification of breast malignancy. Molecular classification of breast tumors can be based on single gene assays, such as ER, PR, HER2 gene copy numbers, proliferation index, and Ki67; or on multigene expression platforms, which can measure dozens to even thousands of gene transcripts simultaneously. Multigene transcript profiles use either real-time quantitative polymerase chain reaction (RT-PCR) or gene chip expression microarray. An example of the former is the Oncotype DX assay (see Section VIII.A.2.b), and Mammaprint is an example of the latter (see Section VIII.A.2.c).
The classification of breast cancer based on gene expression profiling has not yet been completely reconciled with classic histopathologic classification. Gene expression profiling using DNA microarrays have, however, defined new molecular subtypes of breast cancer associated with the cell-of-origin distinction. Recent reports indicate distinct gene expression profiles for inflammatory breast cancer, lobular breast cancer, HER2-positive breast cancer, and BRCA-mutant breast cancer. Based on these observations, breast cancer has been divided into at least five subgroups with distinct biologic features and clinical outcomes.
1. Luminal A. The luminal tumors express cytokeratins 8 and 18, have the highest levels of ER expression, tend to be low grade, will most likely respond to endocrine therapy, and have a favorable prognosis. They tend to be less responsive to chemotherapy.
2. Luminal B. Tumor cells are also of luminal epithelial origin, but with a gene expression pattern distinct from luminal A. Prognosis is somewhat worse than luminal A.
3. Normal-like breast tumors. These tumors have a gene expression profile reminiscent of nonmalignant “normal” breast epithelium. Prognosis is similar to the luminal B group.
4. HER2-amplified. These tumors have amplification of the HER2 gene on chromosome 17q and frequently exhibit coamplification and overexpression of other genes adjacent to HER2. HER2-positive cases have significantly decreased expression of ER and PR and have upregulation of vascular endothelium growth factor (VEGF). Historically, the clinical prognosis of such tumors was poor. With the advent of trastuzumab therapy, however, the clinical outcome for patients with HER2-positive tumors has markedly improved.
5. Basal. These ER- or PR-negative and HER2-negative tumors (the so-called triple negative) are characterized by markers of basal or myoepithelial cells. They tend to be high grade and express cytokeratins 5/6 and 17 as well as vimentin, p63, CD10, smooth muscle actin, and epidermal growth factor receptor (EGFR). It is likely that the basal group is still somewhat heterogeneous; for example, patients with BRCA-1 mutant tumors also fall within this molecular subtype. Overall, patients with basal breast cancers have a poor prognosis, although they likely benefit to some extent from chemotherapy.
C. Location and mode of spread. The most common anatomic presentation of breast cancer is in the upper outer quadrant. Breast cancers spread by contiguity, lymphatic channels, and blood-borne metastases. The most common organs involved with symptomatic metastases are regional lymph nodes, skin,
bone, liver, lung, and brain. Internal mammary nodes have evidence of tumor in 25% of patients with inner quadrant lesions and 15% with outer quadrant lesions. Internal mammary node metastases rarely occur in the absence of axillary node involvement.
bone, liver, lung, and brain. Internal mammary nodes have evidence of tumor in 25% of patients with inner quadrant lesions and 15% with outer quadrant lesions. Internal mammary node metastases rarely occur in the absence of axillary node involvement.
D. Clinical course. The clinical course of breast cancer is heterogeneous at best, but, generally, there are trends based on stage. Early breast cancer is curable, but has a chance of distant metastases occurring even 10 to 20 years after treatment. Locally advanced cancer has an increased risk of latent distant metastasis. In some women, the course is quite rapid, particularly in women with aggressive tumors having indicators of a poor prognosis. Metastatic breast cancer (except in rare cases) is not curable but typically has a course of stable or responsive disease on therapy, sometimes for months, and then progression in a stepwise fashion.
III. SCREENING AND EARLY DETECTION
A. Mammography detects about 85% of breast cancers. A distinction should be made between diagnostic mammography and screening mammography. A screening mammogram is an x-ray study of the breast used to detect breast changes in women who have no signs or symptoms of breast cancer. A diagnostic mammogram is an x-ray study of the breast that is used to check for breast cancer after a lump or other sign or symptom of breast cancer has been found. Although 15% of breast cancers cannot be visualized with mammography, 45% of breast cancers can be seen on mammography before they are palpable. A normal mammographic result must not dissuade the physician from obtaining a biopsy of a suspicious mass.
Digital mammography is gradually replacing film mammography. Digital mammography takes an electronic image of the breast and uses less radiation than film mammography. Digital mammography allows improvement in image storage and transmission because images can be stored and sent electronically. Diagnostic software may also be used to help interpret digital mammograms. Digital systems, however, currently cost approximately one and a half to four times more than film systems.
1. The American College of Radiology BI-RADS System for reporting mammographic findings is as follows:
Category 1: Negative
Category 2: Benign finding
Category 3: Probably benign finding. Short interval follow-up is suggested. The findings have a very high probability of being benign, but the radiologist would prefer to establish stability.
Category 4: Suspicious abnormality: biopsy should be considered. These are lesions that do not have characteristic findings of breast cancer, but have a definite probability of being malignant.
Category 5: Highly suggestive of malignancy.
2. Meta-analysis of eight randomized mammogram screening trials has shown a 24% reduction in the mortality rate of breast cancer. Mortality reductions have been observed in trials of women aged 40 to 69 years with mammography performed at intervals of 12 and 24 months.
3. The ACS recommends an annual mammogram for women at average risk beginning at age 40. Breast cancer mammographic screening should continue annually regardless of age as long as the woman is in reasonably good health, has a life expectancy of at least 3 to 5 years, and would be willing to undergo therapy. Chronologic age alone should not be used as a reason to discontinue screening mammography.
B. Breast physical examinations. Despite the lack of data showing a reduction in risk of death from breast cancer owing to clinical breast examination (CBE) or breast self-examination (BSE), the ACS has maintained recommendations related to both of these screening modalities.
1. CBE is recommended for women at average risk of breast cancer beginning in their 20s. CBE should be part of a periodic health examination and should occur at least every 3 years. Women aged 40 years and older should receive CBE, preferably annually, and, ideally, before, or in conjunction with, the annual screening mammogram.
2. Women should be told about the benefits and limitations of BSE in their 20s. Women who choose to do BSE should receive instruction and have their technique reviewed on the occasion of a periodic health examination.
C. High-risk patients. The ACS reported that women at increased risk for breast cancer might benefit from additional screening strategies beyond those offered to women at average risk. These interventions may include initiation of screening at a younger age, shorter screening intervals, or the addition of other radiologic investigations in addition to mammography, including magnetic resonance imaging (MRI) or ultrasound.
1. ACS guidelines recommend MRI screening in addition to mammograms for women who have at least one of the following conditions:
a. A BRCA1 or BRCA2 mutation
b. A first-degree relative (parent, sibling, child) with a BRCA1 or BRCA2 mutation, even if they have yet to be tested themselves
c. A lifetime risk of breast cancer that has been scored at 20% to 25% or greater based on one of several accepted risk assessment tools that evaluate family history and other factors
d. A history of radiation to the chest between the ages of 10 and 30 years
e. Germline p53 mutation (Li-Fraumeni syndrome), or hamartoma syndromes associated with PTEN mutation (Cowden syndrome or Bannayan— Riley-Ruvalcaba syndrome), or one of these syndromes based on a history in a first-degree relative
2. The ACS guideline indicates that sufficient evidence still does not exist to recommend for or against MRI screening in women who have
a. A 15% to 20% lifetime risk of breast cancer, based on one of several accepted risk assessment tools that evaluate family history and other factors
b. LCIS or atypical lobular hyperplasia (ALH)
c. Atypical ductal hyperplasia (ADH)
d. Very dense breasts or unevenly dense breasts (when viewed on a mammogram)
e. Already had breast cancer, including DCIS
3. Contralateral breast cancer. A study published in the New England Journal of Medicine shows that MRI scans can be a useful adjunct for finding contralateral breast tumors in women with newly diagnosed disease. In this report, 969 newly diagnosed breast cancer patients were studied; MRI found 30 early-stage tumors that mammograms and physical examinations could not detect and missed only three tumors (see Lehman et al., 2007).
IV. DIAGNOSIS
A. Physical findings and differential diagnosis
1. Breast lumps are detectable in many patients with breast cancer and constitute the most common sign on history and physical examination. The typical malignant breast mass tends to be solitary, unilateral, solid, hard, irregular, and nontender.
2. Spontaneous nipple discharge through a mammary duct is the second most common sign of breast cancer. Nipple discharge develops in about 3% of women and 20% of men with breast cancer, but is a manifestation of benign disease in 90% of patients. Discharge in patients >50 years of age is more likely to represent cancer rather than benign conditions. Milky or purulent discharges are associated with a negligible chance of being cancer.
3. Other presenting manifestations include skin changes, axillary lymphadenopathy, or signs of locally advanced or disseminated disease. A painful breast is a common symptom, but it is usually a result of something other than the cancer. Paget carcinoma appears as unilateral eczema of the nipple. Inflammatory carcinoma appears as skin erythema, edema, and underlying induration in the absence of infection.
B. Evaluation of a breast mass
1. Breast lump or mass in women <30 years of age. Ultrasound is the preferred diagnostic modality for young women with a breast mass. If the mass is solid and suspicious, then mammography followed by tissue diagnosis is recommended. If the mass is thought to be benign ultrasonographically, then the option of tissue diagnosis versus observation with frequent physical and ultrasonographic surveillance is appropriate. If the breast mass appears to be a simple cyst on ultrasound, no intervention is required. If it appears to be a complex cyst, then aspiration is appropriate. If the mass disappears with aspiration and the aspirate is not bloody, then routine screening can again begin.
2. Breast lump or mass in women >30 years of age. Diagnostic mammography should be performed. If the mammographic features are indeterminate, then ultrasonography should be performed. If the mammogram or ultrasound shows a suspicious lesion, tissue sampling is required.
3. Breast biopsy. When a tissue diagnosis is required, then a choice must be made among the differing techniques.
a. Fine-needle aspiration (FNA) cytology may be performed if both technical and cytopathologic expertise are available. The method is easy, quick, and safe. Seeding tumor cells along the needle track is not a consideration in breast cancer. The sensitivity in diagnosing malignancy has been reported to be 90% to 95%, with 98% specificity. It is, however, impossible to distinguish invasive from in situ carcinoma because only cells are obtained; the architecture of the tissue cannot be assessed with FNA.
b. Ultrasound or stereotactic core biopsy. These techniques are increasingly used as an alternative to excisional biopsy or FNA and are the standard for mammographic changes without accompanying mass; wire- or needle-guided lumpectomies can follow the procedure. In addition, the core biopsy allows sufficient tissue to be removed to appropriately characterize the histology of the specimen. ER, PR, and HER2 testing may be performed if an invasive malignancy is diagnosed.
c. Excisional biopsy is the standard technique for diagnosis of a breast mass if stereotactic or ultrasound-guided core biopsy is unavailable. If excisional biopsy is performed, an adequate amount of normal tissue should be removed around the suspicious lesion so that the biopsy serves as a segmental mastectomy in the event that a malignancy is found. This tactic allows for complete excision with clear margins and full histologic evaluation.
C. Pretreatment staging procedures for invasive breast cancer. Should an invasive breast cancer be found, pretreatment staging may be considered before definitive surgical therapy of the breast and axillary lymph nodes.
1. Complete blood count, liver function tests
2. Chest radiograph, diagnostic bilateral mammography
3. Bone scan and radiologic evaluation of the liver may be considered if the patient is symptomatic or is found to have an elevated alkaline phosphatase.
4. Bone marrow aspiration if there is unexplained cytopenia or a leukoerythroblastic blood smear
5. The role of positron emission tomography (PET), with or without computed tomography, in the initial staging of breast cancer is being evaluated. In general, PET can accurately detect sites of distant disease with a sensitivity of 80% to 97% and specificity of 75% to 94%.
V. STAGING AND PROGNOSIS
A. Staging system. The American Joint Committee on Cancer (AJCC) implemented the current TNM staging system for breast cancer in 2003. The T and M descriptors and prognostic stage groupings are shown in Table 10.1. The N substage descriptors are shown in Table 10.2.
B. Prognostic factors
1. Tumor grade is an important prognostic variable; the higher the grade, the more guarded the prognosis. The Nottingham combined histologic grade (Elston-Ellis modification of the Bloom-Scarff-Richardson grading system) is recommended by the AJCC staging system. A tumor is graded by assessing three morphologic features (tubule formation, nuclear pleomorphism, and count of mitoses). A value of 1 (favorable) to 3 (unfavorable) is assigned to each feature. A combined score of 3 to 5 points is designated grade 1, 6 to 7 points is grade 2, and 8 to 9 points is grade 3.
2. Pathologic stage has a clear impact on expected survival.
a. Tumor size. The risk of recurrence increases linearly with tumor size for patients with fewer than four lymph nodes involved with metastases; thereafter, the prognostic weight of lymph node metastases generally supersedes tumor size. The effect of tumor size on prognosis is reflected by the following SEER 5-year survival data (adapted from Carter et al., 1989).
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The 20-year breast cancer-specific, disease-free survival for node-negative patients treated with mastectomy alone is about 92% for pT1a-b tumors and 75% to 80% for pT1c tumors. Tumor grade affects these probabilities.
b. Lymph node involvement is the greatest prognostic indicator for breast cancer recurrence. Because of the changes in staging systems for breast cancer, the potential for confusion exists regarding the long-term prognosis for patients by pathologic stage. The 1988 staging system did not differentiate breast cancer stage by numbers of lymph nodes involved. The 2003 TNM staging system and subsequent revisions as shown in Table 10.2 does address this issue.
c. Distant metastases. Many patients with stage IV disease survive 2 to 4 years, or even longer, depending on sites of metastases, their rate of progression, and response to therapy. Prolonged survival can be achieved, particularly in patients with hormone receptor-positive disease with boneonly metastasis.
Table 10.1 Postoperative-Pathologic TNM Staging System for Breast Cancer | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Table 10.2 Posteropative-Pathologic TNM Staging System for Breast Cancer: Regional Lymph Nodes (N)a | ||||||||||||||||||||||||||||||||||||||||||||||||
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