Patient Introduction
Ms Ana Saldivar, a 43-year-old (G4P2A2) patient, presents with a mass in her right breast.
History of Present Illness
During a self-examination, the patient initially noticed a tiny nodule in her right breast, which doubled in size during the last two months prior to presentation.
Questions/Patient Introduction
1. Breast cancer is a very common condition that affects women of all ages, races, and socioeconomic backgrounds. Among cancers in women in the United States, how does breast cancer rank in terms of prevalence and mortality?
- 1st, 4th
- 2nd, 3rd
- 2nd, 1st
- 3rd, 2nd
- 1st, 2nd.
Ans. e
Explanation: Among cancers in women in the United States, breast cancer ranks 1st in terms of prevalence and 2nd in terms of cancer mortality (choice e).
2. Ms Saldivar is a 43-year-old who presents with a breast mass. In a woman who is between 20 and 50 years old what is the likelihood that the breast mass is benign?
- 25%
- 50%
- 60%
- 75%
- 90%.
Ans. e
Explanation: According to studies, about 90% of palpable breasts masses in women from 20 to 50 years are benign (choice e).
3. Ms Saldivar is a 43-year-old, G4P2A2 who presents with a breast mass. After further work-up, the mass is biopsied and sent to pathology. Assuming the mass is benign, what is the most likely type of benign breast mass that will be found?
- Intraductal papilloma
- Intraductal carcinoma
- Fibroadenoma
- Fat necrosis
- Abscess.
Ans. c
Explanation: Fibroadenomas and cysts are the most common types of benign breast masses. Fibroadenomas are usually found in women in their 20s, and on examination, they are firm with smooth edges (choice c).129
Cysts are fluid-filled sacs in the breast that may be rubbery in character. Some cysts are hormone-dependent and can become larger depending on the stage of the menstrual cycle.
(Choice a) Intraductal papillomas are growths in the ducts of the breast which resemble warts. They feel like lumps under the nipple and can cause a bloody nipple discharge.
(Choice b) Intraductal carcinomas are a malignant form of breast cancer.
(Choice d) Fat necrosis is a condition that may occur after a bruise or other injury to the chest or breast. After the injury, the fat cells die and become more firm. A scar can result from the injury and show up as an abnormality on mammography.
(Choice e) Breast abscesses are focal locations of infection within the breast. The patient will likely experience pain and redness around the abscess. They often occur in women who are breastfeeding.
4. A medical student is working with a 54-year-old (G4P4) patient who has a lump in her breast. The student says to their attending that “Our patient has a multiparous obstetric history. She should have less risk of developing breast cancer.” Is this statement true? If so, what is the currently accepted explanation for this trend?
- True, a multiparous woman is at less risk because of increased differentiation of breast tissue lobules.
- False, a multiparous female is at a greater risk of developing breast cancer because of increased estrogen exposure.
- True, a multiparous woman is at less risk because of decreased HER2 expression.
- False, a multiparous female has the same risk of developing breast cancer as a nulliparous female.
- True, a multiparous woman is at less risk because breastfeeding reduces cancer incidence.
Ans. a
Explanation: Breast cancer risk has been associated with several different variables. Women who have a higher parity are at a lower risk of developing breast cancer. Current thinking indicates that pregnancies increase the differentiation of the breast lobules which is protective from neoplastic transformation (choice a).
(Choice b) The statement by the medical student is accurate and therefore not false. A multiparous female is at a decreased risk of developing breast cancer.
(Choice c) The statement by the medical student is true, however, pregnancy would not affect the expression of the HER2 gene.
(Choice d) The statement by the medical student is accurate and therefore, not false. A multiparous female is at a decreased risk of developing breast cancer.
(Choice e) The statement by the medical student is accurate and therefore not false; however, in our clinical vignette there is no information about breastfeeding.
Summary/Patient Introduction
Among cancers in women in the United States, breast cancer ranks 1st in terms of prevalence and 2nd in terms of mortality. Despite the fact that the majority of breast masses are benign it is absolutely necessary to work-up a patient with a breast mass for breast cancer.
According to studies, about 90% of palpable breasts masses in women from 20 to 50 years are benign.130
Fibroadenomas and cysts are the most common types of benign breast masses. Other common breast masses include abscesses, fat necrosis, and intraductal papillomas.
Factors that may predispose a woman to breast cancer include nulliparity and obesity. Women who have a higher parity are at a lower risk of developing breast cancer. Current thinking indicates that pregnancies increase the differentiation of the breast lobules which is protective from neoplastic transformation.
Patient History
- Menstrual history: Menarche: 13 years; menstrual cycles: regular, 26-30/5; LMP: one week ago
- Past medical history: Unremarkable
- Current medications: None
- Family history: Family history is significant for a maternal aunt who died of breast cancer at the age of 59; no other cancer-affected relatives are noted
- Social history: Ms Saldivar is employed as a fashion designer. She drinks alcohol only occasionally and in moderation. She does not smoke and reports no history of substance abuse.
Questions/Patient History
1. Which of the following is true regarding screening for breast cancer?
- Women should not be encouraged to perform self-breast exams, as this causes more emotional anxiety than it does benefit
- Women should receive mammograms annually, beginning at age 25
- Women with family history of breast cancer do not need to be screened earlier than women without this history
- Women should receive annual mammograms, beginning at age 40.
Ans. d
Explanation: Women should begin getting mammograms at age 40. Mammograms should occur annually (choice d).
(Choice a) Women should be encouraged to perform self-breast examinations, as these examinations can help detect masses, lumps, or changes, at early stages.
(Choice b) Women should begin getting mammograms at age 40, not 25, unless indicated by strong family history.
(Choice c) If women have a strong family history of breast cancer, starting annual screening at an earlier age than 40 may apply.
2. Ms Saldivar presents with a tiny nodule in her breast, identified during a self-breast examination. Which of the following should be on your differential for diagnosing this breast nodule?
- Simple cyst
- Fibroadenoma
- Carcinoma
- Papilloma
- All of the above.
Ans. e
Explanation: Simple cyst, fibroadenoma, carcinoma, papilloma, among others, should all be on your differential diagnosis for a patient who presents with a breast nodule (choice e).
1313. Ms Saldivar is a 43-year-old woman. Which age group is at the highest risk for the development of breast cancer?
- Greater than 80 years of age
- 60–79 years of age
- 45–55 years of age
- 20–35 years of age.
Ans. b
Explanation: The risk of breast cancer increases with increasing age, but decreases after the age of 80. Therefore, the age group in the answer choices with the greatest risk of developing breast cancer would be the age group 60–79 (choice b).
4. Ms Saldivar has a family history of breast cancer in a second degree relative, in her maternal aunt. Patients who have family history of breast cancer in a first degree relative (mother, sister, daughter, etc.) are at how much increased risk for the development of breast cancer?
- 25%
- 50%
- 80%
- No increased risk.
Ans. b
Explanation: Patients who have a first degree relative, meaning sister, daughter, or mother, who have breast cancer, are at a nearly 50% increased risk of also developing breast cancer in their lifetime (choice b).
Summary/Patient History
Women 40 years of age and over should begin having yearly mammograms, and should be encouraged to perform self-breast examinations. Patients with family history of developing breast cancer can start their screening at an earlier age if indicated.
The differential diagnosis a breast nodule should include fibroadenoma, fibrocystic change, simple cyst, papilloma, carcinoma, etc. to name a few. Benign as well as malignant diagnoses should remain on the differential until excluded.
Women with relatives who have had breast cancer are at increased risk for developing this disease. Specifically, women with first degree relatives with breast cancer are at an approximately 50% increased risk for the development of this disease.
The risk of the development of breast cancer increases with age, and decreases after age 80.
Investigations/Pathophysiology
- Physical examination reveals a nonfixed mass in the right lower quadrant (RLQ) of her right breast. No signs of edema or nipple changes are evident. A single palpable, mobile, right axillary lymph node is found. Figures 9.1 to 9.3 show mammography and color Doppler ultrasound findings of a right breast mass. Figure 9.4 illustrates ultrasound guided biopsy of the right breast mass.
- CT scans of the chest and abdomen reveals no masses in the lungs, liver, adrenal glands, kidneys, spleen, or ovaries
- A bone scan is negative
- AP is elevated 210 IU/L (normal from 20 to 140 IU/L)
- Serum calcium is elevated at 12.5 mg/dL, without specific signs or symptoms
- Serum parathyroid hormone (PTH) is slightly lowered.
Fig. 9.2: Color Doppler image of the breast lesion, demonstrating penetrating pattern of the newly formed vessels (neovascularization)
Fig. 9.3: Pulsed Doppler waveform analysis reveals low impedance blood flow signals, suggestive of breast carcinoma
Questions/Investigations
1. 64-year-old, white G2P2 is referred to breast clinic following discovery of a breast mass during a well-woman examination. She has past medical history significant for obesity and estrogen replacement therapy for severe hot flashes. Her family history is remarkable for breast cancer in both her mother and maternal aunt. She had her children at the age of 32 and 35; both were delivered by Cesarean section. Upon physical examination, her blood pressure (BP) is 142/85, heart rate 82 beats per minute (bpm) and temperature 36.5 °C (97.7 °F). A firm, nonmobile breast mass is found in the left, upper outer quadrant of her left breast measuring 2 by 3 cm and a single palpable, rubbery lymph node in the left axilla. If a gene mutation is responsible for her current presentation, which of the following is the least likely scenario?
- Loss of heterozygosity (LOH) mutation of a single gene, leading to decreased ability to repair double strand breaks.
- Mutation leading to reduction of the GTPase activity of a small g-protein, leading to constitutive activation and ultimately, cellular proliferation.
- Amplification or overexpression of a growth factor receptor, leading to inappropriate activation and growth.
- Loss of heterozygosity (LOH) of a single gene, leading to failure to arrest cell cycle and induce apoptosis.
Ans. a
Explanation: Considering the presence of multiple risk factors in this patient, such as obesity, supplemental estrogen treatment and her axillary adenopathy, her breast mass is highly suspicious for malignancy. In addition, her positive family history of a first degree relative (mother) is suggestive of a hereditary factor. The risk factors for the development of breast cancer can be subdivided into two broad categories, hormonal and genetic. Although only approximately 5–10% of breast cancers have a familial or genetic link, the presence of these genes can raise the lifetime risk of suffering from breast carcinoma from 12.5% in the general population to as high 134as 85% depending on the specific mutation, making their detection a high priority among those with a positive family history (choice a).
With the single exception of the p53 gene, genes implicated in the pathogenesis of hereditary breast carcinoma are not typically seen in sporadic breast carcinoma. Of the known high-risk breast cancer genes, mutations in the tumor suppressor genes BRCA1 and BRCA2 are responsible for 40–90% of all cases of all cases with the remaining 10% including Li-fraumeni syndrome (germline mutations in p53), Li-fraumeni variant syndrome (germline mutations in CHEK2), LKBI/STK11 (responsible for Peutz-Jeghers syndrome) and ATM (ataxia telangiectasia). Unfortunately, these known genes account for only 25% of all familial breast cancers.
(Choice a) Loss of heterozygosity (LOH) refers to the loss of a functional allele of a pair of genes, the other of which was already inactivated. This mechanism is central in oncogenesis in conditions such retinoblastoma, Li-fraumeni syndrome and inheritance of a mutated BRCA1 or BRCA2 gene, where one tumor suppressor gene of a pair is inactivated from birth; only a single gene must be mutated in these conditions to lead to oncogensis. BRCA1 and BRCA2 code for proteins responsible for repair of double stranded DNA breaks.
(Choice b) This is a description of the RAS family of proto-oncogene. The family includes HRAS, KRAS and NRAS and each plays an important role in cell signaling to the nucleus, ultimately leading to stimulation of mitosis. They are small G proteins that bind to GTP and GDP, sustain mutations that lead to constitutive activation and signaling, and play a role in the development of colon, pancreatic, endometrial and thyroid cancers, but do not play a significant role in breast cancer.
(Choice c) This description is typical of the Human Epidermal Growth Factor Receptor 2 (HER2/neu) and plays a role in the pathogenesis of sporadic cases of breast cancer, but does not play a role in inherited susceptibility to breast cancer.
(Choice d) This mechanism describes the pathogenesis of Li-Fraumeni where one copy of the p53 gene is inactive from conception. Whereas these individuals to tend to develop breast cancer, as well as cancer of the lung and colon, this condition is rare and only accounts for a small percentage of the total number of inherited breast carcinomas.
2. A 42-year-old G0P0 comes into her primary care physician's office for a routine health maintenance examination. She has a past medical history of hypertension and type II diabetes. Her medication regimen includes a thiazide diuretic and lisinopril. Upon physical her blood pressure (BP) is 135/80, heart rate 70 beats per minute (bpm) and temperature 36.0 °C (96.8 °F). A routine mammogram returns showing calcification in the left breast, and a biopsy is recommended. Which of the following combinations of mammogram and biopsy results is most concerning for carcinoma?
- Mammogram shows many small microcalcifications deposited in a linear, branching pattern. Biopsy shows many pleomorphic cells, fibrosis around ducts and evidence of chronic inflammation.
- Clustered, round punctate calcifications are seen on mammo-gram; histology demonstrates cysts lined with “sweat-gland like” apocrine cells containing round nuclei and abundant cytoplasm.
- Large lobulated “popcorn” calcifications are seen on mammogram; histology shows normal epithelium distinctly compressed and distorted by a densely hyalinized and myxoid stroma.
- Mammogram shows larger calcifications with a lucent center. Biopsy shows adipocytes surrounded by bands of fibrosis with scattered, deeply basophilic calcium deposits.
Ans. a
Explanation: Introduced in the 1980s, mammography represents the most widely available and reliable screening test currently available for breast cancer, especially as a means to detect asymptomatic and nonpalpable carcinomas. Often critical to the evaluation of a mammogram is the presence and characteristics of densities and calcifications. For instance, densities can be produced by fibroadenomas, carcinomas and cysts. Calcifications associated with malignancy are typically numerous, small and irregular and clustered. Based on these findings, the Radiologist assigns a score using the American College of Radiology (ACR) Breast Imaging-Reporting and Data System (BI-RADS) system. These scores are based on a scale of 0-7 and indicate the possibility of malignancy as well as the appropriate follow-up treatment.
Findings described in choice a are consistent with ductal carcinoma in situ (DCIS). Typical of DCIS is a malignant clonal population of cells limited by the basement membrane to the ducts and lobules. Histologically, cells are present in sheets, show variability in size, shape and staining, and possess hyperchromatic nuclei. There are often central areas of necrosis giving rise to the calcifications evident on mammography. The linear, branching pattern is the result of the calcifications tracing the ductal pathways. DCIS is classified as proliferative change with atypia and has the worst prognosis of the answer choices listed.
(Choice b) Fibrocystic changes of the breast can sometimes present this way. Cysts are the result of dilation and unfolding of lobules which then coalesce. Calcifications can line the bottoms of these cysts and are termed “milk of calcium” by mammographers. Fibrocystic changes are fundamentally nonproliferative and thus not associated with increased risk of breast cancer.
(Choice c) These large calcifications are characteristic of fibroadenomas; however, these can accompanied by small clustered calcifications similar to those seen in carcinoma. Fibroadenomas are the most benign tumor of the female breast and form from the intralobular breast stroma. The proliferation of this stroma surrounds, compresses and distorts the associated duct epithelium with is histologically normal. Fibroadenomas are categorized as proliferative changes without atypia and confer only a mild increase in the risk of subsequent cancer.
(Choice d) This presentation is consistent with fat necrosis, often presenting as a painless palpably mass or density on mammography. The patient typically has a history of breast trauma, and fat necrosis is more common in obese women with pendulous breasts. The prognosis is excellent with no increased risk for progression to carcinoma; the sole clinical significance being possible confusion with breast cancer.
3. A woman presents to breast clinic with a 3 month history of a possible inflammatory breast disorder. Following further discussion, history taking and physical examination, the physician suspects a diagnosis of mammary duct ectasia but is considering an excisional biopsy to exclude other causes. Which of the following combinations of history and histological findings is most consistent with the diagnosis of mammary duct ectasia?136
- A 54-year-old G3P3 with unilateral, multicolored, sticky nipple discharge and periareolar mass. Histology shows dilation of ducts and inspissation of breast secretions with periductal inflammation.
- A 46-year-old G2P2 with a strong 35 pack-year history of smoking with unilateral, painful, subareolar mass and nipple inversion. Histology shows keratinizing squamous metaplasia of the nipple ducts forming keratin plugs in the ductal system, surrounded by chronic inflammation.
- A 34-year-old G1P1 with type I diabetes with a single hard palpable mass. Histology shows collagenized stroma surrounded by atrophic ducts and lobule. Histology shows a lymphocytic infiltrate surrounding the epithelium and small blood vessels.
- A 32-year-old G2P2 who recently delivered a 40-week-old infant with unilateral breast pain and erythema. Histology shows infiltration by neutrophils and small areas of necrosis.
Ans. a
Explanation: While inflammatory breast disease is relatively uncommon, it is an important part of the differential to consider when suspecting inflammatory breast cancer. Women typically present with an erythematous swollen, painful breast, but the etiologies of each condition are distinct. Inflammatory breast cancer itself mimics inflammation due to tumor emboli that obstruct breast vasculature. Mammary duct ectasia, of which this is a typical presentation, appears in the fifth or six decade of life. The patient is usually multiparous, presents with a palpable periareolar mass and often has thick, whitish secretions. Histologically this condition is characterized by dilated ducts filled with inflammatory cells, thick breast secretions and surround by a chronic, granulomatous inflammatory reaction (choice a).
(Choice b) Although not associated with a specific condition, age or demographic, more than 90% of females that develop periductal mastitis have a significant smoking history. The salient feature of this disorder is a keratinized, squamous metaplasia of the normal ductal epithelium, and it is possible that this secondary irritation by toxic substances within tobacco smoke. Histologically periductal mastitis is associated with plugs of shed keratin that clog the ductal system leading to an intense and chronic inflammation.
(Choice c) Lymphocytic mastopathy is a rare condition most common in women with autoimmune disease, such as type I diabetes or autoimmune thyroid disease. It is characterized by extremely hard breast lesions that can be single or multiple. Microscopically the lesions are highly collagenized and rest on a thickened basement membrane, usually surrounded by lymphocytic infiltrates.
(Choice d) This presentation is typical periductal mastitis, seen among recently delivered, child-bearing aged females in their first month of breastfeeding. Due to repetitive episodes wetting and subsequent drying of the nipple in the process of breast feeding, cracks and fissures develop and serve as entryways for staphylococal or streptococcal bacteria. Although biopsy is never performed for this particular condition, if it were, it would be characterized by general inflammation and possibly focal areas of necrosis.
4. A 70-year-old woman presents to the ER with a 4 month history of intermittent abdominal pain and constipation, now having severe abdominal cramps. Her past medical history is significant for hypertension and hypothyroidism. Her 137blood pressure is well controlled with hydrochlorothiazide (HCTZ), and she is also on levothyroxine 50 mcg/day. Three-months-ago, she underwent a skin sparing mastectomy for invasive breast carcinoma, and a surgical pathology report of the resected mass showed dyscohesive infiltrating tumor cells arranged in loose clusters. An abdominal CT scan shows small bowel obstruction with possible thickened terminal ileum, and she is scheduled for laparotomy. Following a limited small bowel resection, samples are sent for surgical pathology for histology and staining. If immunohistochemistry is performed on these samples, which of the following is most likely?
- Absence of ER, PR and HER2/neu expression, a “Triple Negative” carcinoma
- HER2/neu overexpression
- Decreased expression of E-cadherin
- Increased expression of E-cadherin.
Ans. c
Explanation: The key to this clinic vignette is identification of the characteristic findings of invasive lobular carcinoma. The patient's surgical history is consistent with a diagnosed invasive carcinoma, and her pathology report is suggestive of cells lacking adhesiveness to adjacent cells, a histological hallmark of lobular carcinoma (choice c). Mucin-positive signet-ring cells are also commonly found with this type of carcinoma. In addition to histology, the pattern of metastasis to the bowel is revealing. While most breast carcinomas metastasize along lymphatics to lymph nodes, in particular those of the axilla, lobular carcinomas tend to metastasize to the peritoneum and retroperitoneum, the leptomeninges, the gastrointestinal tract, the ovaries and the uterus. Moreover, in some cases, metastasized lobular carcinoma may be confused with signet ring carcinoma of the GI tract; this is due to a common molecular etiology, as both are characterized by a loss of E-cadherin, a cell adhesion molecule and tumor suppressor gene.
(Choice a) The “basal-like” carcinomas are defined by their absence of ER, PR and HER2/neu expression (triple negative expression) but do express markers typical of myoepithelial cells (basal keratins, P-cadherin, p63, laminin), progenitor cells and stem cells (cytokeratins 5 and 6). This group includes subsets of invasive ductal carcinomas of no special type (NST), medullary carcinomas and carcinomas with a central fibrotic focus. Lobular carcinomas may lack hormone receptors but may overexpress HER2/neu and thus do not belong to this group.
(Choice b) The HER2 positive carcinomas include carcinomas that overexpress the Human Epidermal Growth Factor Receptor 2 (HER2/neu). In 90% of cases, HER2/neu overexpression is due to amplification of a segment of DNA on chromosome 17 containing the HER2/neu sequence. These cancers include subsets of invasive ductal carcinomas of no special type (these lack estrogen receptor expression, i.e., are ER negative) that often metastasize to the brain. Lobular carcinomas very rarely overexpress HER2/neu.
(Choice c) Decreased expression of E-cadherin is responsible for the distinctive round morphology without attachment to neighboring cells characteristic to lobular carcinoma. It also may be responsible for the unique pattern of metastatic spread seen in this type of carcinoma.
(Choice d) Increased expression of E-cadherin is seen in medullary carcinomas and, along with overexpression of other adhesion molecules such as intercellular adhesion molecule, may be responsible for the solid, syncytial pattern of growth 138with pushing borders seen in these carcinomas. The overexpression of adhesion molecules may limit the metastatic potential of medullary carcinoma.
Summary/Investigations
Given that breast cancer is the most frequently diagnosed cancer among women in the United States and the second leading cause of cancer death, an understanding of the pathogenesis of breast cancer is critical to well-woman care. Documenting family history is important as hereditary predispositions toward development of breast cancer are responsible for a small but significant percentage of cases. Figures 9.5 and 9.6 demonstrate gross anatomy of breast cancer and recorded quadrant incidence of female breast cancer, respectively.
Breast mammography remains the most widely used means of screen for breast cancer, and an understanding of the salient mammographic features and their relationship to underlying pathology is central to determining the next step in management.
Figs 9.5A and B: Pathological example of an infiltrating breast cancer(Courtesy: Harsh Mohan. The Female Genital Tract. In: Textbook of Pathology, 6th edn. New Delhi, India: Jaypee Brothers Medical Publishers; 2010. Fig. 25.27)
Fig. 9.6: Recorded quadrant incidence of female breast cancer. Note the upper outer quadrant (UOQ) is the most frequent site of incidence of breast cancer(Courtesy: Harsh Mohan. The Female Genital Tract. In: Textbook of Pathology, 6th edn. New Delhi, India: Jaypee Brothers Medical Publishers; 2010. Fig. 25.5)
A basic knowledge of inflammatory breast disorders is useful for differentiating inflammatory reactions from true carcinoma.
Finally, as we progress in our understanding of the genetics of different types of breast cancer, the mapping of certain tumor markers will play a larger role in tailoring individual treatment as well as determining prognosis.
Management
- Modified right radical mastectomy to remove the tumor, including axillary lymph node dissection was performed
- Of the 14 lymph nodes removed, one was completely replaced by tumor cells, and three others showed microscopic involvement.
Questions/Management
1. A 42-year-old G5P5 patient comes to the office after noticing a breast mass while performing a breast self-examination. She is in good health, has normal menstrual cycles and multiple relatives with breast cancer. Physical examination reveals a 2 inch (5 cm) breast mass and a solid fixed axillary lymph node. Mammography shows calcifications and a mastectomy is performed. The lump is poorly demarcated and is invading into the chest wall. What is the staging of this patient based on this scenario?
- Stage 1
- Stage 2
- Stage 3
- Stage 4.
Explanation: Stage 3, the cancer is larger than 2 inches (larger than 5 cm) in diameter or has invaded the chest wall or surrounding skin. Lymph nodes are enlarged, but there is no sign of cancer in distant organs (choice c).
(Choice a) Stage 1 consists of a small lump, less than 3/4 of an inch in diameter, which has invaded the breast beyond the ducts or lobules but has not spread to the lymph nodes or other body areas.
(Choice b) Stage 2 has a lump between 3/4 (2 cm) and 2 inches (5 cm), without signs of distant metastasis. This stage may have enlarged lymph nodes.
(Choice d) At stage 4, the cancer is detectable in other organs and is considered incurable.
2. A 45-year-old patient presents to the office for her annual mammogram. She has no history of prior breast disease and has large breasts. Upon inspection her breasts are asymmetric with skin dimpling of the left breast. Further evaluation reveals a 3 inch (7.6 cm) lump. Fine needle aspiration reveals malignant-looking cells. Upon testing, the cells do not have estrogen or progesterone receptors. Scans reveal evidence of metastasis in multiple organs. What is the treatment modality best fit for this patient?
- Hormone blocking therapy
- Chemotherapy
- Radiation therapy
- Surgery.
Ans. b
Explanation: Chemotherapy uses medications to destroy cancer cells. When used on metastatic cancers, it attempts to try to control the cancer and decrease any symptoms the cancer is causing. When used after surgery, it is called adjuvant systemic chemotherapy and the goal is to decrease recurrence. When given before surgery to women with large tumors it is called neoadjuvant chemotherapy and the goal is to shrink the tumor size for better removal (choice b).
(Choice a) Her tumor is estrogen receptor and progesterone receptor negative. Hormone blocking therapy is only effective against cancers that are sensitive to hormones. On a receptor positive tumor, hormone therapy can be used to prevent recurrence or to shrink and control cancers.
(Choice c) Radiation therapy uses high powered beams of energy to kill cancer cells. This can be done by external beam radiation or by placing radioactive material inside the body (brachytherapy). External beam radiation is commonly used after lumpectomy for early stage breast cancer.
(Choice d) Surgery is typically performed only prior to metastasis. Surgery may remove the lump only or the entire breast, with or without lymph node removal.
3. A 58-year-old G4P4 woman comes to the office for breast tenderness. She is in good health and is not taking any medications. Her family history is negative for breast cancer. On breast examination, she has a palpable, nonpainful mass on her right breast, and a hard fixed axillary lymph node. She chooses to have a mastectomy. Upon pathologic examination the mass appears malignant. The following are signs of malignancy except:
- Anaplasia
- Poor demarcation
- Hyperplasia
- High nucleus to cytoplasm ratio.
Explanation: Hyperplasia is not a sign of malignancy. Hyperplasia occurs as an inflammatory change. It may over time lead to cancer, but is not in itself a sign of cancer (choice c).
(Choice a) Anaplasia is a lack of differentiation. A tissue that is correctly dividing and replicating will maintain its natural architecture. Cells that are replicating and reproducing without control will have a lack of differentiation.
(Choice b) A poorly demarcated tumor is a sign that the cancerous cells have invaded the basement membrane. This increases the likelihood that the cancer is malignant and metastatic. Once cancer cells penetrate the basement membrane they are able to travel to distant sites in the body.
(Choice d) High nucleus to cytoplasm ratio is a sign that a cell is mitotically active. Cancer is the unregulated replication of cells, leading to a higher than normal number of cells in mitosis at any given time. This increases the nucleus to cytoplasm ratio.
4. A 45-year-old woman presents with a breast mass she noticed three months ago. She has a strong family history of breast cancer. On examination there is a painful lump on her outer upper quadrant. The lump feels rounded, smooth and is mobile. What is the next step in management?
- Mammography
- Fine needle aspiration
- Excisional biopsy
- Annual physical examination.
Ans. a
Explanation: Mammography is the appropriate next step. Even though there are no suspicious findings during the physical examination, mammography is recommended to evaluate breast changes. A breast cancer lump is typically fixed and nonpainful (choice a).
(Choice b) The findings described in this patient are consistent with fibrocystic breast changes. Fine needle aspiration is not warranted until after mammography is performed.
(Choice c) The findings described in this patient are consistent with fibrocystic breast changes. An excisional biopsy is usually performed when there are findings consistent with breast cancer, not in this benign condition.
(Choice d) Even though there are no pathological physical findings, it is still recommended to evaluate the patient by mammography to exclude the possibility of breast cancer. A breast cancer lump is typically fixed and nonpainful.
Summary/Management
Fibrocystic breast changes are characterized by lumpy breasts, where the lumps are painful and mobile. This differentiates them from breast cancer that is typically fixed and painless. It is recommended to evaluate breast changes by mammography, even if the clinician suspects fibrocystic changes.
Pathological findings that may indicate a malignant tumor include a lack of differentiation, a high nucleus to cytoplasmic ratio, and a tumor with poor differentiation. Cancer cells are replications without differentiation and so the less architecture and differentiation, the more likely it is an advanced cancer.142
Stage 0 is confined to the duct or lobule of the breast. They are thought of as precancerous and have not yet invaded the surrounding breast tissue.
Stage 1 consists of a small lump, less than 3/4 of an inch (2 cm) in diameter, which has invaded the breast beyond the ducts or lobules but has not spread to the lymph nodes or other body areas.
Stage 2 has a lump between 3/4 and 2 inches (2–5 cm), without signs of distant metastasis. This stage may have enlarged lymph nodes.
Stage 3, the cancer is larger than 2 inches (5 cm) in diameter or has invaded the chest wall or surrounding skin. Lymph nodes are enlarged, but there is no sign of cancer in distant organs.
At stage 4, the cancer is detectable in other organs and is considered incurable.
Therapy used on patients depends upon their staging and the qualities of the tumor. Hormone blocking therapy is effective against cancers that are receptor positive to prevent recurrence or to shrink and control cancers. Chemotherapy used on metastatic cancers is to control the cancer and decrease any symptoms the cancer is causing. When used after surgery, it is called adjuvant systemic chemotherapy and the goal is to decrease recurrence. When given before surgery to women with large tumors it is called neoadjuvant chemotherapy and the goal is to shrink the tumor size for better removal. External beam radiation is commonly used after lumpectomy for early stage breast cancer. Surgery is typically performed only prior to distant metastasis. Surgery may remove the lump only or the entire breast, with or without lymph node removal.
Follow-up
Questions/Follow-up (Table 9.1)
1. Five years after initial treatment for breast cancer your patient wants to know if there is any significant chance of relapse. Beyond the basic chance of reoccurrence, what factor about your patient's particular case would make late relapse of particular concern?
- Multiple positive lymph nodes
- ER positive tumors
- Ductal carcinoma in situ
- Lobular carcinoma in situ.
Explanation: Estrogen receptor (ER) positive tumors have a greater risk for late reoccurrence than non-ER positive tumors. According to one major study one-third of reoccurrences in hormone receptor positive tumors and two-thirds of deaths occurred after five years. The number of lymph nodes involved is the most important prognostic factor for survival after primary disease and reoccurrence. And there is a low-risk of reoccurrence and mortality if the pathology is caught while still in situ (choice b).
(Choice a) Number of lymph nodes with metastasis is the most important prognostic factor.
(Choices c and d) Carcinoma in situ has a lower reoccurrence and mortality.
2. The general schedule for mammography after initial treatment for breast cancer is every six months for one year and then annually after that. Part of any report is a section on BI-RADS which is the standardized form of reporting and management recommendations for mammography. On a follow-up mammography one of your breast cancer patients has a radiologic finding of Breast imaging reporting and data system 0 (BI-RADS 0). What is the most accurate description of this finding?
- Incomplete or inconclusive
- Negative, benign, or probably benign
- Suggestive of malignancy
- Proven malignancy.
Ans. a
Explanation: BI-RADS is the assessment categories used in reporting mammography interpretation. It provides a grading system that is standardized to enable multiple physicians to understand the radiographic results.
- 0-Corresponds to an inconclusive reading or more commonly an incomplete reading that is awaiting a final review by the radiology staff (choice a).
- 1-Negative, continue screening as recommended by age and PMH.
- 2-Benign conditions like adenomas, cysts, or unconcerning parenchymal irregularities. Note in record to prevent unnecessary work-up and continue screening as before.
- 3-Probably benign, less than 2% malignancy risk but with some atypical findings, follow at six months for one year then annually until up grade or down grade cause a change in management.
- 4-Suspicious of malignancy, consider biopsy. Broken down into categories 4A-4C. 4A is consistent with 2–9% risk, 4B is consistent with 10–49% risk, 4C is consistent with 50–94% risk.
- 5-Greater than 94% risk of malignancy, classic malignant findings like retractions or varying and multiple calcifications.
- 6-Category 5 findings in a patient with a PMH of malignancy proven by tissue sample.(Choice b) BI-RADS categories 1-3.(Choice c) BI-RADS categories 4-5.(Choice d) BI-RADS category 6.
3. Oncology and Women's Health are fields of medicine that depend on the details of each case and guidelines are algorithmic instead of linear. That being said there are a few definitive guidelines for all patients with breast cancer according 144to their age. Other than post treatment mammography what recommendations are appropriate for all post treatment patient populations who were diagnosed with breast cancer?
- Ultrasound
- Breast MRI
- PET scan
- Tumor markers
- CBC
- LFT
- None of the above.
Ans. g
Explanation: Mammography is the only routine screening that has consistently been proven to increase positive outcome for all post treatment patients with breast cancer as measured by mortality and morbidity. The other general guidelines that consistently increase morbidity or mortality in the general patient population are a low fat diet, increased physical activity, and minimal alcohol intake. There is a role for each of the other answer choices in the treatment of cancer but none are appropriate for all patients under current guidelines (choice g).
(Choice a) Ultrasound is the screening exam of choice for women under 30 and/or pregnant patients. It is also used in further work-up of an abnormal mammogram.
(Choice b) Breast MRI can be a more sensitive than US but the cost and relative availability makes it a poor choice for most patients.
(Choice c) PET scanning can be an appropriate test for staging breast cancer in patients with Stage 2 and significant LN involvement or higher.
(Choice d) Tumor makers are appropriate modalities to follow the reoccurrence or response to treatment of some breast cancer patients.
(Choice e and f) CBC and LFT are most commonly used to follow effects of treatment not to screen for breast cancer.
4. One of your patients who is a breast cancer survivor wants to know how a reoccurrence will be initially diagnosed if there is one. Of all the exams, imaging, and patient recommendations, what is the most likely route of initial detection of reoccurrence?
- Mammogram
- Breast self-examination
- Office breast examination
- Tumor markers.
Ans. b
Explanation: The most common source of initial detection of reoccurrence of breast cancer is the self-breast examination. Guidelines for BSE are not universal but most sources recommend monthly BSE for cancer survivors (choice b).
(Choice a) Mammograms are an important part of cancer follow-up, and increase survival. However, they are not the most common source of initial detection.
(Choice c) Office breast examinations are an important part of the follow-up but this is not the correct answer.
(Choice d) Tumor markers are an important part of the follow-up in some patients, but this is not the correct answer.
Summary/Follow-up
Estrogen receptor (ER) positive tumors have a greater risk for late reoccurrence than non-ER positive tumors. According to one major study, one-third of reoccurrences in hormone receptor positive tumors and two-thirds of deaths occurred after five 145years. The number of lymph nodes involved is the most important prognostic factor for survival after primary disease and reoccurrence. And there is a low-risk of reoccurrence and mortality if the pathology is caught while still in situ.
BI-RADS is the standard form of reporting and recommendation for management for mammography reporting. The categories range from BI-RADS 0 to 6.
- 0-Corresponds to an inconclusive reading or more commonly an incomplete reading that is awaiting a final review by the radiology staff.
- 1-Negative, continue screening as recommended by age and PMH.
- 2-Benign conditions like adenomas, cysts, or unconcerning parenchymal irregularities. Note in record to prevent unnecessary work-up and continue screening as before.
- 3-Probably benign, less than 2% malignancy risk but with some atypical findings, follow at six months for one year then annually until up grade or down grade cause a change in management.
- 4-Suspicious of malignancy, consider biopsy. Broken down into categories 4A-4C. 4A is consistent with 2–9% risk, 4B is consistent with 10–49% risk, 4C is consistent with 50–94% risk.
- 5-Greater than 94% risk of malignancy, classic malignant findings like retractions or varying and multiple calcifications.
- 6-Category 5 findings in a patient with a PMH of malignancy proven by tissue sample.
Mammography is the only routine screening that has consistently been proven to increase positive outcome for all patients as measured by mortality and morbidity. The other general guidelines that consistently increase morbidity or mortality in the general patient population are a low fat diet, increased physical activity, and minimal alcohol intake. US is the screening examination of choice for women under 30 and/or pregnant patients. It is also used in further work-up of an abnormal mammogram. Breast MRI can be a more sensitive than US but the cost and relative availability makes it a poor choice for most patients. PET scanning can be an appropriate test for staging breast cancer in patients with Stage 2 and significant LN involvement or higher. Tumor makers are appropriate modalities to follow the reoccurrence or response to treatment of some breast cancer patients. CBC and LFT are most commonly used to follow effects of treatment.
The most common source of initial detection of reoccurrence of breast cancer is the breast self-examination (BSE). Guidelines for BSE are not universal but most sources recommend monthly BSE for cancer survivors.
Learning Objectives
Clinical Presentation: Breast Mass
Patient History/History of Present Illness
- Know the incidence and prevalence of breast cancer.
- List the most common benign breast masses.
- List the risk factors for breast cancer.
- Discuss diagnostic approach to a woman with chief complaint of breast mass.
- List clinical and physical findings that may suggest benign and/or malignant breast lesions.
- Select women who are at high-risk for breast cancer based on age, family history or the presence of other pre-existing risk factors, signs and symptoms for mammography and/or genetic screening.
Investigations and Pathophysiology
- Know the identity and function of the most common genes responsible for a hereditary predisposition for breast cancer.
- Know how the basic mammographic features associated with breast cancer correlates with the underlying histology.
- Know the principle characteristics of inflammatory breast disorders.
- Know the chief tumor markers using in identification and classification of breast carcinoma.
Diagnosis and Management
- Describe the clinical staging of breast cancer.
- Be able to describe when therapeutic options are appropriate for a given patient.
- Describe pathological findings that increase the likelihood that a cancer is malignant.
Follow-up
- Know the follow-up recommendations for breast cancer patients.
- Know how reoccurrence of breast cancer is commonly detected.
- Understand the BI-RADS classification system.
- Know the risk of reoccurrence associated with ER positive tumors.
- Counsel/educate patients on the role of breast self-examination, mammography and ultrasound.
Bibliography
- Eberl MM, Fox CH, Edge SB, Carter CA, Mahoney MC. BI-RADS classification for management of abnormal mammograms. J Am Board Fam Med. 2006;19(2):161–4.
- Elmore JG, Barton MB, Moceri VM, Polk S, Arena PJ, Fletcher SW. Ten-year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med. 1998;338(16):1089.
- Hayes, MD, DF. An overview of breast cancer. In: Up-To-Date, Gralow JR (Ed), Up-To-Date, Waltham, MA, 2012.
- Ikeda D, Mammogram Interpretation. Breast Imaging—The Requisites, 2nd edn. Mosby: St Louis, 2011, Chapter 2.
- Katz VL. Breast Diseases: Diagnosis and Treatment of Benign and Malignant Disease. In: Katz VL, LENTZ GM, Lobo RA, Gershenson DM (Eds). Comprehensive Gynecology. 5th edn. Mosby Elsevier; Philadelphia, Pa: 2007, Chapter 15.
- Mettler, Fred A, MD Consult LLC. Essentials of Radiology. 2nd edn. Chapter 4 – Breast. MD Consult, St Louis, Mo.: 2005.
- Morrow M. The evaluation of common breast problems. Am Fam Physician. 2000;61(8):2371.
- P Ghezzi, S Magnanini, M Rinaldini, et al. Impact of Follow-up Testing on Survival and Health-Related Quality of Life in Breast Cancer Patients. JAMA. 1994;271(20):1587.
- P Rosen, S Groshen, D Kinne. Prognosis in T2N0M0 stage I breast carcinoma: a 20-year follow-up study. J Clin Oncol. 1991;9(9):1650.
- Robbins, Stanley L, Vinay, Kumar and Ramzi S. Cotran. Robbins and Cotran Pathologic Basis of Disease. 8th edn. Chapter 23, The Breast. Saunders/Elsevier, Philadelphia, PA: 2010. Print.
- Russo J, Rivera R, Russo IH. Influence of age and parity on the development of the human breast. Breast Cancer Res Treat. 1992;23(3):211.
- Schorge JO, Schaffer JI, Pietz J, Halvorson LM, Hoffman BL, Bradshaw KD, Cunningham FG. Chapter 12. Breast Disease. In: Schorge JO, Schaffer JI, Pietz J, Halvorson LM, Hoffman BL, Bradshaw KD, Cunningham FG (Eds). Williams Gynecology. McGraw-Hill; New York: 2008.
- Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61(4):212.
- W Eljabu, G Finch, J Nottingham, N Vaingankar. Metastatic Deposits of Breast Lobular Carcinoma to Small Bowel and Rectum. Int J Breast Ca 2011. doi:10.4061/2011/413949.