Breast Cancer

Course #30612 - $60 • 15 Hours/Credits


Study Points

  1. Outline the incidence and epidemiology of breast cancer.
  2. Discuss the risk factors for breast cancer, identifying which factors are nonmodifiable versus modifiable.
  3. Review hereditary breast cancers with BRCA1 and BRCA2 mutations and inherited syndromes.
  4. Outline the models used to determine these risks.
  5. Review the anatomy and physiology of normal breast development and the lymphatic system.
  6. Identify screening recommendations for the early detection of breast cancer.
  7. Identify the pathology of benign and malignant breast tumors.
  8. Discuss the diagnostic work-up, incorporating the physical examination, imaging, biopsy, and pertinent family history.
  9. Analyze the various classifications of breast cancer according to pathology and extent of tissue involvement.
  10. Review the staging and grading systems for breast cancers.
  11. Analyze surgical options and interventions as primary treatment, including reconstruction and prostheses.
  12. Discuss lymphedema and measures to avoid this chronic morbidity.
  13. Describe the role of radiation therapy and potential side effects.
  14. Evaluate endocrine therapy for the treatment of estrogen- and progesterone-receptor positive breast cancer.
  15. Review available systemic chemotherapy for breast cancer.
  16. Summarize male breast cancer, outlining risk factors differing to those identified in women.

    1 . How many women will be diagnosed with invasive breast cancer in 2019?
    A) 2,240
    B) 64,640
    C) 268,600
    D) 2.4 million

    INCIDENCE AND EPIDEMIOLOGY OF BREAST CANCER

    Breast cancer is diagnosed more frequently in women than any other cancer (with the exception of skin cancer) and carries the second highest mortality rate after lung cancer [3,4,5,6,7]. An estimated 268,600 women will be diagnosed with an invasive breast cancer in 2019, and an additional 62,930 women will be diagnosed with carcinoma in situ (CIS) breast cancer [3].

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    2 . Which of the following is one of the most significant risk factors for developing breast cancer?
    A) Male sex
    B) White race
    C) Younger age
    D) Familial breast cancer

    RISK FACTORS

    Certain risk factors associated with breast cancer cannot be modified, including age, sex, ethnicity, family history/inherited gene mutations, and hormonal influences. The most significant risk factors for developing breast cancer are female sex, increasing age, and familial breast cancer [3,4,11,13,14,15].

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    3 . Which of the following racial/ethnic groups has the highest odds of being diagnosed with ER/PR-negative breast cancer?
    A) Black
    B) Non-Hispanic white
    C) Asian Indian/Pakistani
    D) American Indian/Alaska Native

    RISK FACTORS

    As noted, breast cancer incidence and mortality rates vary significantly across racial/ethnic groups. According to data from the Surveillance, Epidemiology, and End Results (SEER) program, American Indian/Alaska Native, Asian Indian/Pakistani, Black, Filipino, Hawaiian, Mexican, Puerto Rican, and Samoan women have higher odds of presenting with stage IV breast cancer compared to non-Hispanic white women [19]. Almost all groups were more likely to be diagnosed with ER/PR-negative disease, with black and Puerto Rican women having the highest odds ratios (2.4- and 1.9-fold increases, respectively) compared with non-Hispanic whites. Lastly, black, Hawaiian, Puerto Rican, and Samoan patients had 1.5- to 1.8-fold elevated risks of breast cancer-specific mortality [19].

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    4 . Breast cancer susceptibility genes BRCA1 and BRCA2 are
    A) tumor potentiating genes.
    B) sex-linked dominant tumor suppressor genes.
    C) autosomal dominant tumor suppressor genes.
    D) autosomal recessive tumor suppressor genes.

    RISK FACTORS

    Breast cancer susceptibility genes BRCA1 and BRCA2 are autosomal dominant tumor suppressor genes responsible for 5% to 10% of all cases [21]. BRCA1 is located on chromosome 17q21, consisting of 1,863 amino acids within 24 coding regions. BRCA2 was identified on chromosome 13ql2. It has 27 coding regions, producing a protein more prolific than BRCA1, with 3,418 amino acids [11,13,21,23].

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    5 . Which of the following is NOT an inherited genetic mutation that increases breast cancer susceptibility?
    A) Sjögren syndrome
    B) Cowden syndrome
    C) Li-Fraumeni syndrome
    D) Peutz-Jeghers syndrome

    RISK FACTORS

    Genes other than BRCA1 and BRCA2 have also been implicated in increased breast cancer susceptibility [25]. Rarer inherited genetic mutations include those associated with Cowden, Li-Fraumeni, and Peutz-Jeghers syndromes and ataxia telangiectasia [4,26]. Of these, Cowden and Li-Fraumeni syndromes are the most common [27].

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    6 . Which of the following is a disadvantage of the Breast Cancer Risk Assessment Tool (BCRAT), also known as the Gail model?
    A) It does not take into account age at menarche.
    B) The pathology reports from biopsies are included.
    C) It is designed only for women 35 years of age and older.
    D) No questions are related to a family history of breast cancer.

    RISK FACTORS

    Empiric models are appropriate tools for assessing risk when it is improbable there is a hereditary predisposition, which would require genetic testing [4,42]. The National Cancer Institute (NCI) developed the familiar Breast Cancer Risk Assessment Tool (BCRAT), better known as the Gail model, in 1989. The BCRAT predicts the risk of invasive breast cancer within the next five years and up until 90 years of age by incorporating the following data [12,14,42,43,44]:

    • Age at menarche

    • Age at delivery of first live birth

    • Breast biopsies performed previously (negative result)

    • First-degree relatives with breast cancer

    • Race/ethnicity

    • Age of patient

    • History of any breast cancer

    The established cut score for the BCRAT is 1.66%; women who score lower are considered at lower risk, while those who score at or above this are high risk.

    However, there are several disadvantages associated with the BCRAT, as some pertinent information is excluded. The tool is designed only for women 35 years of age or older. No questions are related to a personal or family history of ovarian cancer, and there is no inquiry into distant family members or the age of onset of those with a breast cancer diagnosis. The role of race/ethnicity for African American women and other specific populations is excluded. Finally, the pathology report pertaining to a biopsy is excluded, even though the biopsy report is significantly more valid than the fact a biopsy was performed [17,44].

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    7 . Embryonic breast tissue begins to develop approximately
    A) 5 weeks after conception.
    B) 10 weeks after conception.
    C) 16 weeks after conception.
    D) 24 weeks after conception.

    AN OVERVIEW OF BREAST AND LYMPH ANATOMY

    Approximately five weeks after conception, embryonic breast tissue begins to develop. Cells at this early stage appear as little more than a ridge or thickened area of tissue. At approximately 10 to 16 weeks, more defined tissue forms the foundation for glands for milk production. Muscle cells form the nipple, with the darkened area of areola containing sebaceous glands surrounding the nipple protrusion. As pregnancy advances with hormonal influence from placenta to fetus, the glands with the ability to produce milk form as lobules. From birth to puberty, the 10 to 12 rudimental ducts formed beneath the nipple and areola slowly continue to form into more mature ductal structures.

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    8 . Full breast differentiation is only achieved
    A) at puberty.
    B) after menopause.
    C) with pregnancy and lactation.
    D) at approximately 75 years of age.

    AN OVERVIEW OF BREAST AND LYMPH ANATOMY

    From the onset of puberty, the female breast takes approximately three to four years for glandular maturation. However, full breast differentiation is only achieved with pregnancy and lactation. At puberty, the hypothalamus releases gonadotropin-stimulating hormones, which act on the anterior pituitary gland. The anterior pituitary in turn releases follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH promotes ovarian follicular maturity, with the subsequent production of estrogen, mainly in the form of 17-beta estradiol. Breast tissue enlarges due to the influence of estrogen and the allied growth hormones of glucocorticoids [45,46].

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    9 . Which of the following statements regarding the lymphatic system is TRUE?
    A) Damaged lymph nodes cannot regenerate.
    B) Lymphatic vessels are essentially identical to circulatory vessels.
    C) There are approximately 6,000 to 7,000 lymph nodes throughout the body.
    D) None of the above

    AN OVERVIEW OF BREAST AND LYMPH ANATOMY

    Lymphatic vessels differ from those of the circulatory system, as they function within a low pressure system supported by the close proximity of pulsating arteries (with smooth muscle within the larger lymphatic vessels promoting peristalsis). The valves (lymphangions) within the vessels permit the lymph to be transported in one direction only.

    The body is divided into the right and left lymphatic systems. The right lymphatic duct receives lymph from the right side of the head and neck, the right arm, and the right side of the upper trunk. This lymphatic duct then drains into the right venous angle, located between the right internal jugular and right subclavian vein. The right subclavian vein returns lymph to the heart, where it subsequently flows back into the systemic circulation as plasma. The left side of the lymphatic system carries a far greater load and is responsible for the lower extremities, the pelvic area, the left side of the head and neck, the left chest, and the left arm. Lymph returning from the lower extremities and pelvis collects into the cisterna chyli in the mid-abdominal region before being propelled on to the thoracic duct. From the thoracic duct, the lymph continues to the final drainage area in the left venous angle. Parallel with the right, the left subclavian vein returns lymph to the circulation as plasma [49,50,51,52,53,54].

    There are approximately 600 to 700 lymph nodes throughout the body, and damaged nodes cannot regenerate. When a malfunction occurs in the lymphatic system, caused by injury from a surgical intervention or as a side effect from radiation therapy, lymphedema can result. Lymphedema occurs in 5% to 9% of patients undergoing sentinel lymph node biopsy (SLNB) and up to 40% of patients who have had axillary lymph node dissection (ALND) [48,49,51].

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    10 . A category 3 mammogram result indicates
    A) findings are negative.
    B) readings are inconclusive.
    C) abnormality is presumed benign.
    D) findings are highly suspicious for malignancy.

    SCREENING FOR BREAST CANCER

    Mammograms are interpreted through the Breast Imaging Reporting and Data System (BI-RADS). Women receive a written report of their mammogram results, in terms they can understand, within 30 days of their screening. The four descriptions of breast tissue range from fatty to dense. The detection of abnormalities (or lack thereof) is categorized as [64,65,66,67]:

    • 0: Readings are inconclusive; requires further imaging.

    • 1: Findings are negative; continue routine screenings.

    • 2: Findings are benign (e.g., fibroadenoma, cyst); continue routine screenings.

    • 3: Abnormality is presumed benign. Follow-up mammogram in six months, the findings of which may rarely necessitate a biopsy. Possibility of malignancy is less than 2%.

    • 4: Abnormality is suspicious. Biopsy required for histology as malignancy detected in 25% to 50% of masses.

    • 5: Highly suspicious requiring intervention. If first tissue biopsy is benign, re-sample from a different site, as there is a 95% malignancy rate.

    • 6: Imaging with biopsy yielded positive malignancy.

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    11 . Errors in mammogram interpretation may occur due to
    A) less breast density.
    B) extremes of body type.
    C) lack of hormone replacement therapy.
    D) assessment by multiple skilled radiologists.

    SCREENING FOR BREAST CANCER

    Errors in mammogram interpretation do occur, with variations in breast density, extremes of body type (obese or underweight), HRT, and the skill of the radiologist all impacting the findings [64]. In particular, this modality has a general inability to distinguish cysts from solid masses. False-positive results requiring a follow-up study can provoke anxiety, not only during the time before the re-screening but also while waiting for the subsequent results. False-positive results can also result in an unnecessary biopsy and/or overtreatment of a non-aggressive benign lesion. In reality, of the 11% of mammograms requiring further investigation, 90% prove to be benign [59].

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    12 . For a woman with a known history of breast cancer in her mother, the recommended screening is
    A) annual mammogram beginning at 25 years of age.
    B) annual mammogram and MRI beginning at 30 years of age.
    C) annual mammogram and MRI beginning at 40 years of age.
    D) biennial mammogram beginning at 50 years of age.

    SCREENING FOR BREAST CANCER

    Beginning at 30 years of age, annual mammography and MRI are recommended for women if they have [62,70]:

    • A risk assessment score greater than 20% to 25% (e.g., using BRCAPRO)

    • A known history of breast cancer in a first-degree family member

    • An established BRCA mutation

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    13 . The most commonly identified benign breast disease is
    A) phyllodes tumor.
    B) fibrocystic changes.
    C) sclerosing adenosis.
    D) diabetic mastopathy.

    PATHOLOGY OF BREAST LESIONS

    Fibrocystic changes are identified more frequently than any other benign breast mass, and fibroadenoma, comprised of both glandular and structural tissue, is the most common type of benign tumor diagnosed in women 20 to 35 years of age. These tumors arise in the intralobular fibrous stroma of breast tissue. Surveillance with routine screening is usually sufficient treatment if there is absolute assurance that it is not a phyllodes tumor [73].

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    14 . The main utility of ultrasound in the diagnosis of breast cancer is
    A) to aid in guiding biopsy.
    B) to identify microcalcifications.
    C) its ability to distinguish a cyst from a solid mass.
    D) its ability to visualize the mass without any discomfort.

    DIAGNOSTIC EVALUATION

    After the initial mammogram, an ultrasound may be completed, if necessary [82]. The main utility of ultrasound is its ability to distinguish a cyst from a solid mass. The order for an ultrasound should summarize the location of the detectable lump and describe the findings. If the mass is solid, the location (described by placement on a clock face) and distance from the nipple should be noted. The order should also indicate if the mass should be aspirated or biopsied.

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    15 . Fine-needle aspiration is used to biopsy a breast mass that is BI-RADS category
    A) 0.
    B) 1.
    C) 2.
    D) 3.

    DIAGNOSTIC EVALUATION

    Percutaneous fine-needle aspiration (FNA) is used when a mass, usually a cyst, is palpable and does not require imaging to locate the site. An FNA is used to biopsy BI-RADS category 3, 4, or 5 lesions.

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    16 . A core-needle biopsy is appropriate for
    A) DCIS.
    B) microcalcifications.
    C) BI-RADS category 4 lesions with suspicious, nonpalpable masses.
    D) palpable breast masses that do not require imaging to locate the site.

    DIAGNOSTIC EVALUATION

    A core-needle biopsy is appropriate for BI-RADS category 4 lesions with suspicious, nonpalpable masses. A core sample is more substantial compared to the amount of tissue obtained with FNA. The procedure is minimally invasive, and anticoagulants do not need to be put on hold. The area is numbed with local anesthesia, and a large-gauge needle and an automated biopsy gun obtain the core tissue. Women generally prefer this method to the stereotactic biopsy, as it is less time consuming and no x-ray is required. Ultrasound can be used for guidance if needed [65,84,85,86].

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    17 . Most sentinel lymph nodes in the axilla are located
    A) below the clavicle.
    B) against the chest wall.
    C) posterior to the pectoralis muscle.
    D) lateral and inferior to the pectoralis minor muscle.

    DIAGNOSTIC EVALUATION

    The axilla houses approximately 40 lymph nodes. Among these, three levels of lymph nodes have been identified [92]:

    • Level I nodes: Approximately 65% of nodes are lateral and inferior to the pectoralis minor muscle. Most sentinel nodes (83%) are identified in this area.

    • Level II nodes: About 30% of nodes are located posterior to the pectoralis minor muscle, with the axillary vein below this cluster. More than 15% of sentinel nodes are identified in this area.

    • Level III nodes: Fewer than 10% of nodes are located medially to the pectoralis minor muscle below the clavicle and against the chest wall. Rarely is a sentinel node detected here.

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    18 . Axillary lymph node dissection should supersede sentinel lymph node biopsy when
    A) nodes are not palpable in the axilla.
    B) in situ breast cancer has been diagnosed.
    C) inflammatory breast cancer has been diagnosed.
    D) the treatment plan involves mastectomy with simultaneous removal of the nodes.

    DIAGNOSTIC EVALUATION

    In the majority of cases, an ALND will be conducted after the sentinel node has been identified. However, ALND may supersede SLNB when nodes are palpable in the axilla or if inflammatory breast cancer has been diagnosed. With inflammatory breast cancer, the flow of lymph to the axilla is obstructed, which can result in a false-negative result with SLNB. Women who are pregnant or breastfeeding will require ALND, as they are ineligible for SLNB [90,92]. A decision not to pursue ALND may be appropriate if the plan is to proceed with a mastectomy while simultaneously removing the nodes.

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    19 . Ductal carcinoma in situ arises in the
    A) nipple.
    B) basement membrane.
    C) terminal duct lobular units.
    D) upper outer quadrant of the breast.

    CLASSIFICATION OF BREAST CANCERS

    DCIS constitutes 20% of all newly diagnosed breast cancers [71]. The malignancy arises in the TDLUs; the malignant epithelial cells tend to grow in medium to larger-sized ducts but do not extend through the basement membrane [84,89].

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    20 . If they develop breast cancer, survivors of childhood Hodgkin lymphoma are usually diagnosed with what type of carcinoma?
    A) DCIS
    B) Basal-like breast cancer
    C) Invasive ductal carcinoma
    D) Inflammatory breast cancer

    CLASSIFICATION OF BREAST CANCERS

    DCIS is usually diagnosed between the ages of 49 and 69 years. The challenge with DCIS is not only whether the in situ mass will progress to an invasive tumor, but when the progression will occur. DCIS is considered a precursor to invasive breast cancer and is related to a mutation in the BRCA genes and the allied risk factors of familial breast cancer, obesity, increased breast density, and nulliparity. Survivors of childhood Hodgkin lymphoma are usually diagnosed with this form of tumor if they develop breast cancer [35].

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    21 . An invasive ductal carcinoma with a histologic grade of 3 is characterized by
    A) differentiation in the glandular tissue.
    B) uniform nuclei and absent mitotic activity.
    C) infiltration of the supporting breast tissue.
    D) tumors that are solid clusters or nests and no gland formation.

    CLASSIFICATION OF BREAST CANCERS

    Breast examination may reveal a fixed, immobile mass. The firmness of the mass results from a fibrous response that ultimately produces the hard gritty tumor. Pathologically, the tumors have a gray-white appearance. The invasive ductal carcinomas are histologically graded as [84,93]:

    • Well differentiated (grade 1): The cells are usually ER/PR-positive and HER2 is not overexpressed. Solid clusters of cells infiltrate the supporting breast tissue. Mitotic activity is absent, and the nuclei are uniform.

    • Moderately differentiated (grade 2): A solid cluster of cells plus differentiation in the glandular tissue. There is evidence of pleomorphic nuclei and increased mitotic activity.

    • Poorly differentiated (grade 3): The tumors are solid clusters or nests; there is no gland formation. Atypical nuclei and mitotic activity are very evident.

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    22 . Which of the following is part of the criteria established for the diagnosis of inflammatory breast cancer?
    A) Absence of a palpable mass
    B) A time frame of one year or more
    C) Biopsy-confirmed invasive carcinoma
    D) Cyanosis and skin that is cool to the touch

    CLASSIFICATION OF BREAST CANCERS

    The criteria established by the American Joint Committee on Cancer (AJCC) and the International Union for Cancer Control for the diagnosis of inflammatory breast cancer include [70,98,99]:

    • A time frame of six months or less

    • Biopsy-confirmed invasive carcinoma

    • May or may not have a palpable mass

    • Erythema, warmth, and peau d'orange are included in the rapidly presenting symptoms

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    23 . Paget disease is
    A) a major cause of breast cancer in men.
    B) identified by ulcerated lesions on the nipple.
    C) often manifested with some nipple retraction.
    D) most common in women younger than 30 years of age.

    CLASSIFICATION OF BREAST CANCERS

    Paget disease of the breast accounts for 1% to 3% of breast malignancies in women and less than 1% in men. Paget disease is identified by ulcerated, raw, scaly vesicular lesions visible on the nipple and extending to the areola. Paget cells, classified as large, high-grade adenocarcinoma, are present within the nipple epidermis. Advanced disease may manifest with some nipple retraction, but this is an infrequent finding [46,66,84]. The malignancy is generally ipsilateral.

    The average age at diagnosis is 50 to 60 years of age. Any appearance of eczematous skin changes, nipple involvement, or discharge from the nipple should be investigated to rule out the possibility of an underlying malignancy [66]. Initial symptoms of pain and itching may exist for months and precede any visible signs of the disease. Steroids or antibiotics may provide a temporary improvement in the skin appearance; a biopsy is necessary to confirm the diagnosis. In 85% to 88% of patients who present with typical symptoms, an invasive or in situ malignancy will be detected [86]. Roughly 50% have a detectable mass within 2 cm of the affected nipple. An estimated 25% have an intraductal occult malignancy, with no abnormality seen on mammogram and no detectable mass. Another 20% have no palpable mass but an abnormality is detectable on mammogram; this finding confers a greater risk for invasive cancer. Paget disease must be distinguished from malignant melanoma and Bowman disease, a type of squamous cell carcinoma [101].

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    24 . All of the following are risk factors for triple-negative breast cancer, EXCEPT:
    A) Underweight
    B) Younger age at menarche
    C) Short interval of breastfeeding
    D) Full-term pregnancy at a younger age

    CLASSIFICATION OF BREAST CANCERS

    Triple-negative breast cancers are more common among premenopausal women and are diagnosed with greater frequency in African American and Hispanic women [107]. Other risk factors, some of which are modifiable, include:

    • A younger age at the onset of menstruation

    • Full-term pregnancy at a younger age

    • A short interval of breastfeeding

    • Lactation halted through medication

    • Obesity

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    25 . According to the AJCC staging system, a tumor that is 16 mm in greatest dimension would be graded
    A) Tis.
    B) T1a.
    C) T1c.
    D) T3.

    STAGING AND GRADING BREAST CANCERS

    AMERICAN JOINT COMISSION ON CANCER TUMOR CLASSIFICATION FOR BREAST CANCER

    GradeEvidence
    TXPrimary tumor cannot be assessed
    T0No evidence of primary tumor
    TisCarcinoma in situTis (DCIS): Ductal carcinoma in situ
    Tis (Paget): Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted.
    T1Tumor ≤20 mm in greatest dimensionT1mi: ≤1 mm in greatest dimension
    T1a: >1 mm but ≤5 mm in greatest dimension
    T1b: >5 mm but ≤10 mm in greatest dimension
    T1c: >10 mm but ≤20 mm in greatest dimension
    T2Tumor >20 mm but ≤50 mm in greatest dimension
    T3Tumor >50 mm in greatest dimension
    T4Tumor of any size with direct invasion to the chest wall and/or to the skin (ulceration or skin nodules)aT4a: Extension to the chest wall, not including only pectoralis muscle adherence/invasion
    T4b: Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange) of the skin, which does not meet the criteria for inflammatory breast carcinoma
    T4c: Both T4a and T4b
    T4d: Inflammatory carcinomab
    a Invasion of the dermis alone does not qualify as T4.
    b Inflammatory breast cancer is clinically defined when one-third or more of the skin is involved; this requires a tissue diagnosis to determine tumor markers.
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    26 . A patient assigned a grade of NX on the AJCC staging system has
    A) regional lymph nodes that cannot be assessed.
    B) no evidence of regional lymph node metastases.
    C) metastases in ipsilateral infraclavicular lymph nodes.
    D) metastases to movable ipsilateral level I, II axillary lymph nodes.

    STAGING AND GRADING BREAST CANCERS

    AMERICAN JOINT COMISSION ON CANCER LYMPH NODE CLASSIFICATION FOR BREAST CANCER

    GradeEvidence
    Clinicala
    NXRegional lymph nodes cannot be assessed (prior removal)
    N0No regional lymph node metastases
    N1Metastases to movable ipsilateral level I, II axillary lymph node(s)N1mi: Micrometastases (approx. 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)b
    N2Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastasesN2a: Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures
    N2b: Metastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases
    N3Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement; or in ipsilateral internal mammary lymph node(s) with level I, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph nodes with or without axillary or internal mammary lymph node involvementN3a: Metastases in ipsilateral infraclavicular lymph node(s)
    N3b: Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
    N3c: Metastases in ipsilateral supraclavicular lymph node(s)
    Pathologic (pN)c
    pNXRegional lymph nodes cannot be assessed (e.g., previously removed or not removed for pathologic study)
    pN0No regional lymph node metastasis identified histologicallypN0(i+): ITCs only (malignant cell clusters in regional lymph node(s) no larger than 0.2 mm)
    pN0(mol+): Positive molecular findings (RT-PCR); no ITCs detected
    pN1Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or clinically negative internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsypN1mi: Micrometastases (approx. 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)
    pN1a: Metastases in 1–3 axillary lymph nodes, at least one metastasis greater than 2.0 mm
    pN1b: Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs
    pN1c: pN12a and pN1b combined
    pN2Metastases in 4–9 axillary lymph nodes or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastasespN2a: Metastases in 4–9 axillary lymph nodes (at least one tumor deposit greater than 2.0 mm)
    pN2b: Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary lymph nodes
    pN3Metastases in 10 or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive level I, II axillary nodes; or in more than three axillary lymph nodes and micrometastases or macrometastases detected by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodespN3a: Metastases in 10 or more axillary lymph nodes (at least one tumor deposit larger than 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) nodes
    pN3b: pN1a or pN2a in the presence of N2b (positive internal mammary nodes by imaging); or pN2a in the presence of pN1b
    pN3c: Metastases in ipsilateral supraclavicular lymph nodes
    aThe suffixes (sn) and (f) should be added to the N category to denote confirmation of metastasis by sentinel lymph node biopsy or FNA/core-needle biopsy, respectively, with no further resection of nodes.
    bN1mi is rarely used but may be appropriate in cases where sentinel node biopsy is performed before tumor resection, most likely in cases treated with neoadjuvant therapy.
    cIsolated tumor cell clusters (ITC) are defined as small clusters of cells not greater than 0.2 mm, or single tumor cells, or a cluster of fewer than 200 cells in a single histologic cross-section. ITCs may be detected by routine histology or by immunohistochemical (IHC) methods. Nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the total number of nodes evaluated.
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    27 . The breast cancer grade of T1N1M1 is stage
    A) IB.
    B) IIA.
    C) IIIC.
    D) IV.

    STAGING AND GRADING BREAST CANCERS

    AMERICAN JOINT COMMISSION ON CANCER ANATOMIC STAGE/PROGNOSTIC GROUPS FOR BREAST CANCER

    StageTNM
    0TisN0M0
    IAT1aN0M0
    IB
    T0
    T1a
    N1mi
    N1mi
    M0c
    M0
    IIA
    T0
    T1a
    T2
    N1b
    N1b
    N0
    M0
    M0
    M0
    IIB
    T2
    T3
    N1
    N0
    M0
    M0
    IIIA
    T0
    T1a
    T2
    T3
    T3
    N2
    N2
    N2
    N1
    N2
    M0
    M0
    M0
    M0
    M0
    IIIB
    T4
    T4
    T4
    N0
    N1
    N2
    M0
    M0
    M0
    IIICAny TN3M0
    IVAny TAny NM1
    aT1 includes T1mi.
    bT0 and TI tumors with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB.
    cM0 includes M0(i+)
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    28 . For metastasized stage IV breast cancer, surgery is
    A) contraindicated.
    B) usually curative.
    C) completed after chemotherapy and/or radiation to shrink the tumor.
    D) primarily for palliation of pain or prevention/amelioration of symptoms.

    SURGICAL INTERVENTIONS

    The majority of breast cancers are diagnosed at stage I or stage II, but approximately 10% are at a more advanced stage when they are identified. Women with locally advanced breast cancer (stage III) generally require neoadjuvant chemotherapy and/or radiation prior to any surgery to promote tumor shrinkage and allow for a more manageable surgical procedure [59,60,114]. Surgery may also be indicated for metastasized stage IV breast cancer, but primarily only for palliation of pain or prevention/amelioration of symptoms of the disease. It is important to note that surgery with radiation therapy is generally not curative for these patients.

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    29 . Modified radical mastectomy involves removal of the
    A) affected quadrant of the breast and the identified sentinel node.
    B) entire breast, leaving the axillary nodes and pectoralis muscles intact.
    C) entire breast and skin, the pectoralis muscles, and level I, II, and III lymph nodes.
    D) entire breast, the fascia underlying the pectoralis major muscle, and level I and II axillary nodes.

    SURGICAL INTERVENTIONS

    Mastectomies may be radical, modified radical, or simple. Radical mastectomy is rarely performed today due to the morbidity associated with removal of the entire breast and skin. With this approach, level I, II, and III axillary nodes plus the pectoralis major and minor muscles are removed. A modified radical mastectomy involves removal of the entire breast, the fascia underlying the pectoralis major muscle, and level I and II axillary nodes. A modified radical mastectomy is appropriate for patients with two or more primary tumors in the same breast but in separate quadrants and malignant micro-calcifications in diffuse areas. The tumor(s) should be large in relation to the area of breast tissue. Re-excision of breast tissue that fails to produce negative margins is an indication for this type of surgery. It is the surgical intervention of choice for patients previously administered radiation therapy for breast cancer or mantle radiation therapy for childhood Hodgkin lymphoma.

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    30 . Free TRAM flap breast reconstruction differs from the pedicled TRAM flap procedure in what way?
    A) There is a greater risk of flap loss with TRAM flap than with free TRAM flap.
    B) The free TRAM flap procedure requires only one area of surgical intervention.
    C) With free TRAM flap, the tissue is fully resected and transplanted; no pedicle is included.
    D) With free TRAM flap procedures, the transplanted flap receives vascular support through an intact blood supply, while the TRAM flap procedure relies on microvascular anastomosis.

    SURGICAL INTERVENTIONS

    Similar to the pedicled TRAM flap procedure, the free TRAM flap involves a mastectomy and resection of a portion of the lower rectus abdominus muscle, skin, and fat for the reconstructed breast. However, the tissue is fully resected and transplanted; no pedicle is included. Microvascular anastomosis connects the perforators to either the internal mammary or thoracodorsal blood vessels, enabling the transplanted breast tissue to remain viable [116,120].

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    31 . Gluteal free flap breast reconstruction is a good option for women
    A) who prefer a less visible scar.
    B) with excessive abdominal fat.
    C) with less firm gluteal muscles.
    D) who require a shorter surgery time.

    SURGICAL INTERVENTIONS

    One alternative to using abdominal or back muscles is to use the gluteal muscle from the buttock to create a flap. This may be a good option for women with insufficient abdominal fat or who prefer a less visible scar.

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    32 . Today, the prevalence of lymphedema 15 years after breast cancer treatment is
    A) 2% to 5%.
    B) 20% to 36%.
    C) 30% to 45%.
    D) 70% to 86%.

    LYMPHEDEMA

    Lymphedema occurs when the volume of interstitial lymph exceeds the capability of the lymphatic transporting system. It is a frequent complication of surgical interventions and radiation therapy administered for the treatment of breast cancer, an association that was documented as early as 1898. When radical mastectomies were the primary surgical treatment option for breast cancers, 80% of women developed lymphedema. Today, the prevalence of lymphedema two years following breast cancer treatment is 20% to 36%, increasing to 30% to 45% after 15 years [32,135,144,145].

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    33 . According to the International Society of Lymphology staging system, stage III lymphedema is characterized by
    A) elephantiasis.
    B) reversible edema and some pitting.
    C) impaired lymph flow but no evidence of swelling.
    D) irreversible swelling and no pitting due to the presence of fibrotic tissue.

    LYMPHEDEMA

    The International Society of Lymphology uses a staging system to help guide treatment decisions and prognosis for lymphedema. The established stages are [48,50,51,146,151]:

    • Stage 0: Lymph flow is impaired, although there is no clinical evidence of swelling.

    • Stage I: Limb elevation may reduce the (reversible) edema, the tissues are soft, and some pitting may be evident.

    • Stage II: Elevating the affected limb has no impact on swelling (irreversible). Fibrotic tissue may prohibit pitting. It is probable that the lymphedema will persist for 12 months or longer. This stage may present with a positive Stemmer sign (i.e., an inability to lift the skin of the dorsum of the fingers or toes).

    • Stage III: Skin thickens, with chronic inflammation and lymph stasis that culminates in elephantiasis. This infrequently seen stage is formidable, usually resulting from lymphedema that was neglected and not treated in a timely manner. Fibrotic skin changes are evident, with cysts and hyperkeratosis.

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    34 . Manual lymphatic drainage is a mainstay of lymphedema treatment. This massage therapy technique begins with the
    A) trunk, slowly working outward to the extremities.
    B) neck, quickly progressing to include the shoulder and affected arm.
    C) lower forearm, gradually working upwards to the axilla and shoulder.
    D) the axilla and shoulder, gradually working downwards to the forearm.

    LYMPHEDEMA

    The initial goal is to maintain the integrity of the skin and underlying structures, reducing the fluid volume in the affected arm until a plateau is reached. Manual lymphatic drainage is a massage therapy designed to gently propel fluid forward, allowing superficial lymph vessels to fill and larger conduits to open, thereby promoting drainage of lymph back into the circulation. This generally requires treatment sessions five days per week for two to four weeks. Therapy begins with the lower forearm, gradually working upwards to the axilla and shoulder. Compression bandages may be worn overnight, but are removed prior to therapy [151].

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    35 . Breast-conserving surgery followed by radiation therapy has become the standard of care for all of the following, EXCEPT:
    A) Stage I breast cancer
    B) Stage II breast cancer
    C) Stage III (locally advanced) breast cancer
    D) Stage IV breast cancer

    RADIATION THERAPY

    Having successfully undergone surgery, the next step for many patients is radiation therapy. Radiation therapy with whole breast irradiation has been the mainstay of breast cancer treatment for nearly 100 years. But in a manner similar to surgery, radiation treatment has evolved to focus more on breast conservation [128]. Morbidity and mortality rates have decreased as a result of earlier detection, allowing for less invasive procedures and increased control of microscopic disease. Breast-conserving surgery followed by radiation therapy has become the standard of care for stage I, stage II, and locally advanced stage III breast cancers [129,135,153].

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    36 . Which of the following is an absolute contraindication to radiation therapy for patients with breast cancer?
    A) Childbearing age
    B) Multi-centric tumors
    C) Repeated positive margins
    D) Tumor measuring 2 cm or less

    RADIATION THERAPY

    While the majority of women are able to make decisions that reflect their personal preferences, others are ineligible due to absolute or relative contraindications relating to existing health issues. Absolute contraindications to radiation therapy include [114,135]:

    • Pregnancy: Women during their third trimester can undergo breast-conserving surgery, but radiation therapy is delayed until after delivery. After receiving radiation, women should be advised to wait two years before conceiving.

    • Multi-centric tumors in more than one quadrant of the breast (i.e., unable to be removed with a single excision)

    • Prior malignancy requiring radiation to the chest, as additional radiation therapy could result in toxic cumulative doses

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    37 . Radiation-induced moist desquamation is usually the result of doses of
    A) 10 to 30 Gy.
    B) 45 to 60 Gy.
    C) 50 to 65 Gy.
    D) 60 to 75 Gy.

    RADIATION THERAPY

    Radiation dermatitis can vary widely in severity. Pruritus occurs after about three weeks of treatment of 30 Gy. In some cases, sebaceous glands are damaged, resulting in less perspiration. Dry desquamation results from damaged stem cells in the epidermis. This can progress to moist desquamation as it invades the dermis, usually with doses of 45 to 60 Gy. Chemotherapy and friction in skin folds can exacerbate these symptoms. In severe cases, patients may require a break in radiation therapy until symptoms subside [164]. Extreme moist desquamation seldom occurs, but it can be a cause of tissue necrosis.

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    38 . Tamoxifen acts to
    A) increase DNA synthesis.
    B) potentiate the effects of progesterone.
    C) inhibit the systemic effects of estrogen.
    D) decrease the synthesis of adrenal and thyroid hormones.

    ENDOCRINE THERAPY

    Tamoxifen is a nonsteroidal SERM that competitively binds to estrogen receptors on tumor cells and other tissue targets, decreasing DNA synthesis and inhibiting the systemic effects of estrogen. Tamoxifen causes cells to remain in the G0 and G1 phases of the cell cycle. Because it prevents malignant cells from dividing but does not cause cell death, it is considered cytostatic rather than cytocidal [168].

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    39 . Which of the following chemotherapeutic agents used in the treatment of breast cancer is categorized as an anthracycline?
    A) Doxorubicin
    B) Gemcitabine
    C) 5-fluorouracil
    D) Cyclophosphamide

    CHEMOTHERAPY

    Anthracyclines prescribed to treat breast cancer are doxorubicin, liposomal doxorubicin (Doxil), and epirubicin (Ellence). Anthracyclines (antitumor antibiotics) are used frequently in combination regimens, definitely with a taxane as first-line treatment for metastatic breast disease. Anthracyclines are cell cycle non-specific, binding with DNA and interrupting the synthesis of DNA and RNA [103,129,185,205].

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    40 . Which of the following is a breast cancer risk factor unique to men?
    A) Mastitis
    B) Infertility
    C) Orchiectomy
    D) All of the above

    MALE BREAST CANCER

    Male breast cancer has not been extensively studied, and research is difficult because of the small numbers of men with the disease. Reviews of the literature have been helpful in identifying risk factors, clinical and pathologic characteristics, and the role of genetics [241,242,244]. Studies have shown that male breast cancer differs from female breast cancer in many ways. For example, some risk factors unique to men include [243,244]:

    • Undescended testes

    • Orchiectomy

    • Infertility

    • Gynecomastia

    • Mastitis

    • Breast trauma

    • Klinefelter syndrome

    • Radiation to the chest wall

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