describe the causes and predisposing factors for breast cancer
discuss the structural, functional and cellular changes seen with cancer
describe the in situ carcinomas and the invasive breast carcinomas
review the various imaging modalities utilized for the breast cancer patient
discuss the strategies in the diagnostic work-up reviewing biopsy, staging, chemotherapy, surgery, radiation and end of life issues
identify and explain the factors affecting prognosis
Breast cancer is a malignant condition of the ductal or glandular epithelium. The causes for the disease are multifactorial and include genetic, environmental, physical (body habitus) and obstetric elements, but 75% of patients have no risk factors except for gender and age. The disease starts out locally as an aberrant cell in the epithelium, grows and multiplies into a nodule or mass and subsequently results in local extension. When the cancer has not yet invaded it is called carcinoma in situ and when the epithelial membrane is breached it is considered truly malignant and invasive. Each tumor has a specific biology. Sometimes the cells are well differentiated, suggesting a lower grade malignancy, some are intermediate, while others are categorized as high grade and poorly differentiated, suggesting a more aggressive disease. The cells also express individuality by protein and gene expression characterized best by immunohistochemistry.
The disease is complicated by metastatic disease to regional lymph nodes and distant organs. TNM (status of the tumor, nodes, and metastases) classification is commonly used.
The diagnosis may be suspected clinically on finding a new mass in the breast, new nipple or skin retraction, but mammography and MRI are utilized to suggest the diagnosis, and percutaneous biopsy is used to confirm the diagnosis.
The mainstay of treatment is surgery when the tumor is considered localized, usually combined with chemotherapy and radiation therapy. With optimal treatment, 10 year disease free survival ranges from 10-98%, depending on type, grade and staging.
Breast cancer is the second most common cancer in the world after lung cancer. Although it is 100 times more common in women, it affects males as well. It constitutes about 10.9 % of all newly diagnosed cancers each year. Breast cancer is the most frequently diagnosed cancer in women in the United States In 2013 it is estimated that 232,340 new cases of breast cancer will be diagnosed with estimated 39,620 deaths (1) About 64,640 new cases of non invasive carcinoma in situ will be diagnosed (3).
The increase in breast cancer in the 1990s was thought to be due to the detection by screening techniques of in situ disease. Since 2003 there has been a declining incidence due in part to the reduction of postmenopausal hormonal therapy. Approximately 13% of women will develop breast cancer by the age of 90 years.
At 40 years the 5 year risk is .6% with a lifetime risk to age of 90 of 12.4% (2) At 60 years, the 5 year risk is 1.8% and the lifetime risk till the age of 90 years is 9.1% (2).
Death rates from breast cancer have been declining since 1989 thought to be as a result of earlier detection, improved therapies and general increase in awareness. Breast cancer diagnosis is devastating to any woman; however tremendous strides have been made in screening, treatment and follow up of the disease which has made breast cancer a treatable disease.
2) Breast Cancer Risk Assessment Tool. National Institutes of Health. Available at: www.cancer.gov/bcrisktool.
Overview: History of the Disease
Breast cancer is likely to be one of the first known cancers, because of its external manifestations. By history the disease dates back to 1600 BC in ancient Egypt where both recognition of the disease and its treatment begins with cauterization of tumors with an instrument known as “the fire drill.” Although medical practitioners were able to remove these tumors in some cases, they were for the most part unable to stop the disease from taking its course. Writes the ancient Egyptian doctor of breast cancer: “There is no treatment.”
Such was the prevailing wisdom throughout the history of breast cancer. Although cases of breast cancer are documented throughout history, it was not until the 17th century that European doctors linked the tumors in the breast to the lymph glands in the armpit. In the early 18th century, two extremely important figures in the history of breast cancer arose: Jean Louis Petit and Benjamin Bell, who performed the first surgeries removing the lymph nodes, breast tissue and breast muscle in order to remove the cancer from the body and fight its spread.
This pioneering work was continued by the surgeon William Stewart Halsted who began performing complete mastectomies in 1882. His procedure is known as the Halsted radical mastectomy and was popular throughout the 20th century up until the 1970’s and is still common today.
While breast cancer survival rates have gone up somewhat in the last twenty years, the fact remains that this disease is still far too prevalent and resulting in the death of far too many women.
Many great strides have been made in the history of breast cancer treatment but there is still a great amount of work to be done. One in 12 or 13 women will suffer from breast cancer at some time during their lives in the western world. In the United States, these numbers can be even higher. One of the most important aspects of the fight against breast cancer is breast cancer awareness. The more knowledge about the disease and the more done to check for early warning signs, the better is the chance for survival. Continuing research and breakthrough in treatment are a part of the ongoing history of breast cancer.
Overview: Causes and Predisposing Factors
A personal or family history of the disease, (in mothers or father’s family) particularly if acquired before the age of 40, increasingly raises the risk of the disease. Breast cancer is approximately twice as common among first-degree relatives of breast cancer patients as in those women with no family history of the disease. The two most important breast cancer susceptibility genes, BRCA1 and BRCA2, were identified by linkage analyses in the mid-1990s. Since then, rare germ line mutations in several other genes, such as TP53, PTEN, and ATM, have been shown to confer an increased risk of breast cancer. BRCA1 and BRCA2 account for less than 20% of familial clustering of breast cancer. It is likely that most familial breast cancers have polygenic transmission, where multiple genes are involved and difficult to identify.2
It is more common in Caucasian women, than Asian or African American women. The Jewish Ashkenazi population displays a 10 fold higher frequency of 2 founder mutations (185delAG and 5382insC) therefore, screening of such mutations in the above population is indicated.
Reproductive and Endocrine Risk Factors
Gender is the most important risk factor in the development of breast cancer, which occurs 100 times more frequently in women than in men. This is due to endocrine factors that relate to lifetime exposure to estrogen. Estrogen is intimately involved in every aspect of female reproductive physiology including normal sexual development, regulation of menstrual cycles, and pregnancy. The longer the exposure to estrogen, the greater the risk of malignancy. Therefore, the older the patient, the greater the exposure to estrogen and therefore a higher the risk. Additionally, early menarche and late menopause raise the risk by increasing the time of estrogen exposure (> 30 years menstrual time>risk). On the other hand, diets low in fat and high in fiber decrease the levels of estrogen and lower the risk of breast carcinoma.
Protective factors include longer lactation periods and moderate levels of exercise. There is some evidence that circulating levels of estrogen are lower in women who exercise. In addition, they have less body fat.
Birth Control Pills and Hormone Replacement Therapy
The effect of birth control pills is controversial. Theoretically, it should depend on the concentration of estrogen in the pill. The earlier birth control pills had higher levels of estrogen compared to the current oral contraceptive pills and this may relate to the association.
Estrogen in hormone replacement therapy (HRT) in post menopausal women has been linked to increased risk of both breast and endometrial cancer. As such, there has been a move to recommend discontinuation of HRT in post menopausal women.
There appears to be an association between body mass index (BMI) and breast cancer, which may be accounted for by increased estrogen levels in women with a higher BMI. The BMI is a ratio of weight to height. Obesity after menopause is especially important since the ovaries at this time stop producing estrogen, and if estrogen from fat is still present then it increases lifetime exposure.
Overview: Causes and Predisposing Factors Continuted
Alcohol consumption is the best-established dietary factor associated with increased risk for breast cancer and seems to be related to the amount of alcohol consumed. A proposed explanation is that alcohol increases the amount of circulating estrogen.Dietary phytoestrogens are estrogens found in vegetables. They serve as a protective factor since they are much weaker than endogenous estrogen, but compete for estrogen receptors, and thus reduce the effect of the endogenous estrogen theoretically resulting in less cell division.
Data about risk in women from radiation is derived mainly from epidemiologic studies of patients exposed to diagnostic or therapeutic radiation. Low-dose radiation exposure to the breast is carcinogenic and risk increases as a linear function of increasing dose. The risk is particularly high in the developing breast (age <20).
The incidence of breast cancer varies significantly among different countries and is highest in Northern European countries and in the United States, intermediate in Southern America and Southern and Eastern Europe, and lowest in Asia. Japan, Singapore and urban China have seen a rise in rates with the advent of Western-style economy. Breast cancer incidence and mortality vary significantly within the United States. The incidence of breast cancer appears to be highest in white women from Hawaii (128:100,000) followed by those from San Francisco and the Northeast. The lowest incidence is found in Utah (98:100,000) and New Mexico.
The variation of incidence for African-American women is relatively small (94-106:100,000).
The interaction of many different risk factors in the initiation of breast cancer has lead to the creation and use of risk-assessment models. The most frequently used model was designed by Gail in 1970 and incorporates age at menarche, number of breast biopsies, age at first live birth, and the number of first-degree relatives with breast cancer. It is used to predict the risk of developing breast cancer per decade of life. One of the disadvantages of this model is that it doesn’t take into account the age at which a family member was diagnosed and whether the disease occurred in both breasts — early onset and bilateral disease suggesting a BRCA (breast cancer gene) mutation carrier.
Structural Principles and Changes
Breast tissue consists of glandular, fatty and connective tissue. Each breast overlies the pectoral muscle of the chest wall and is tethered to the chest wall with tiny connective tissue fibers called the ligaments of Cooper. Each breast is divided into about 10-20 lobes which are formed by smaller units called lobules. There are about 20-40 lobules per lobe. The lobules are made from small glandular structures called acini. There are 10-100 acini per lobule.
A branching ductal system transports the milk from the acini into the lobular ducts, which converge to a single lactiferous duct, which brings the milk to the nipple.
Structural Principles and Changes: The Terminal Duct Lobular Unit
The understanding of cancer of the breast requires an understanding of the terminal duct lobular unit (TDLU). In order to understand the terminal duct lobular unit the histology of the breast needs to be understood.
The terminal duct lobular unit is the functional unit of the breast and is responsible for the production and transport of milk to the lactiferous duct.
Structurally, it consists of a lobule of the breast with an extralobular terminal duct. A group of acini grouped together with an intralobular duct form a lobule and the lobule empties into an extralobular duct. The TDLU is surrounded by fibrofatty connective tissue.
The TDLU is extremely sensitive to hormonal influences and its appearance varies based on physiologic conditions. It changes within each cycle, enlarges significantly during pregnancy and lactation and finally atrophies in the post menopausal period. Because of its sensitivity to hormonal conditions, it is also subject to aberrances and excesses in the hormonal environment.
From a disease standpoint, the TDLU is the site of origin of ductal carcinoma in situ (DCIS), lobular carcinoma in situ, invasive ductal carcinoma, invasive lobular carcinoma, as well as more benign conditions such as fibroadenoma, fibrocystic disease, cysts, apocine metaplasia, adenosis and epitheliosis.
The diagnosis of disease in the TDLU is usually at a pathological level since, in general, imaging techniques are not sensitive to the histological subtypes.
The 10-20 lobes of the breast are arranged radially around the breast and the single duct that subtends the lobe empties independently on the nipple.
Structural Principles and Changes: Applied Histology Continued
Bands of connective tissue, the suspensory ligaments, extend from the interlobular connective tissue to attach to the dermis.
Malignant Breast Disease
The carcinomas are the most significant lesions of the breast. There are two major types of breast carcinoma that arise from the lobule namely ductal carcinoma and lobular carcinoma. They both arise from the TDLU.
Carcinoma of the breast at this level is divided into the non invasive or “in situ” carcinomas on the one hand and the invasive carcinomas on the other. The “in situ” carcinomas are restricted to the lobule and do not show invasion of the basement membrane while in the invasive group, there is obvious transgression of the basement membrane.
The “in situ” group has variable behavioral patterns and outcomes. These lesions may remain dormant for a lifetime, or may even involute. They do, however, place the woman at increased risk of developing cancer and should therefore be treated with heightened awareness.
The two types of “in situ” carcinomas are called ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS), and they are very different. DCIS is common and occurs in 70-95% of women at autopsy and is commonly associated with microcalcifications on mammography. It arises from ductal epithelium. LCIS is less common, clinically and radiologically more elusive, occurs in 1-5% of biopsies, and is rarely associated with microcalcifications on mammography. Once LCIS is identified, the risk of developing cancer, if untreated, is about 30% within 20 years of diagnosis. It is not considered a precancerous disease, but a marker of increased risk.
The two more common invasive carcinomas of the breast are correspondingly called invasive ductal carcinoma and invasive lobular carcinoma and are defined by the transgression of the basement membrane by malignant cells.
The most common site of involvement is the upper outer quadrant since it is the location of “extra” tissue called the axillary tail of Spence. The presence of a larger amount of glandular tissue raises the relative incidence of disease in this quadrant. About 45% of carcinomas arise from this upper outer quadrant. Invasive ductal carcinoma is the most common type of carcinoma.
Malignant Breast Disease: Ductal Carcinoma in Situ (DCIS)
DCIS is a stage zero malignancy of cells confined to the ducts or lobules by the basement membrane. Structurally, the disease is characterized by malignant proliferation of epithelial cells within the ducts and lobules, with intact myoepithelial cells and basement membrane. The cells are able to spread through the ductal system and lobules and therefore, a single clone of cells can spread within the lobular system almost like sludge or debris in a river with intact river banks. DCIS is the most common type of non invasive cancer of the breast.
Histologically, there are five architectural types including comedocarcinoma, solid, cribriform, papillary, and micropapillary. The comedocarcinoma shows the highest grade of behavior, with the most malignant characteristics. There is associated necrosis of the cells giving rise to a cheesy material that can be squeezed like toothpaste out of the ducts. This necrotic debris undergoes dystrophic calcification which manifests as clusters of tubular branching microcalcifications on the mammogram.
Ductal carcinoma in situ (DCIS), also known as intraductal carcinoma is found in approximately 7% of all biopsied specimens. It is considered a premalignant condition and risk of invasive breast cancer is increased nearly five times in women with DCIS. Such risk is primarily ipsilateral as opposed to LCIS which is more likely to be multifocal and bilateral. Multicentricity is seen in 60-90% of patients with LCIS and in 40-80% of patients with DCIS. LCIS occurs bilaterally in 10-20% of DCIS cases and in 50-70% of LCIS cases.
Before mammography DCIS was primarily diagnosed by physical examination as a palpable lesion. In situ breast cancers constituted approximately 2% of all breast cancers in 1980 and LCIS was more common than DCIS by a ratio of 2:1. Screening mammography revealed a 14 fold increase in the incidence of in situ cancer (45%) and DCIS was diagnosed more frequently than LCIS, mostly because small, non specific calcifications associated with DCIS are identifiable, whereas not a characteristic feature of LCIS.
The calcifications seen on mammography arise in the extralobular ducts and hence tend to be small, clustered, and heterogeneous but often rod-shaped.
Biopsy of suspicious areas of calcification confirms the diagnosis.
Treatment in general includes excision of the lesion(s) and radiation therapy is often included. However, the treatment is individualized taking factors such as age, multicentricity, state of health, and family history into account.
Prognosis is excellent with almost a 100% cure rate.
Malignant Breast Disease: DCIS Continued
Malignant Breast Disease: Lobular Carcinoma in Situ (LCIS)
Lobular carcinoma is not truly a carcinoma, but has the risk of developing into a carcinoma. LCIS is considered a marker of increased risk for invasive breast cancer rather a premalignant lesion. Like DCIS, it can be considered a stage zero carcinoma and malignant appearing cells are seen microscopically within the lobules of the breast, with a basement membrane that is intact, i.e. not invaded. The complicating statistic is that about 25% of patients with LCIS will develop invasive cancer in their lifetime, either from the lobules or from the ducts.Lobular carcinoma in situ (LCIS) was first described in 1941 ( Foote and Stewart) and is characterized by three important features:
1) The lesion is a microscopic finding that is not apparent clinically and is usually an incidental finding.
2) The lesion is multicentric in the breast and often bilateral (30%).
3) Both infiltrating ductal and lobular carcinomas may develop in association with LCIS.
Lobular carcinoma in situ arises from the terminal lobular duct units. LCIS is a risk factor for bilateral breast cancer (approximately 1% per year) and therefore, careful clinical follow-up is appropriate for most women.
Treatment is individualized but ranges from increased surveillance with frequent physical exams per year and mammograms once or twice per year. Tamoxifen reduces the risk of breast cancer by approximately 55%.
Bilateral mastectomy is not commonly performed but patients with a strong family history or who have unfavorable genetic mutations sometimes choose this option.
LCIS lacks clinical and mammographic signs and therefore its true incidence is not known. Numerous authors have reviewed breast biopsies in an effort to determine the incidence of LCIS and the results varied from 0.5% (Fajardo) to 3.6% (Haagensen et al) . Incidence is increasing partly because of criteria that contribute to its definition as a pathologic entity and due to mammography which has resulted in increased utilization of biopsy. LCIS is multicentric in 60-80% of cases and bilateral in at least 26% of cases. LCIS is ten times more frequent in white women than in African-American women. The age at diagnosis is most commonly between 44-47 years (vs. 52-58 years for DCIS) and 25-35% of women with LCIS develop invasive carcinoma (65% of invasive carcinomas that develop are infiltrating ductal, i.e. not necessarily lobular, carcinomas).
Malignant Breast Disease: Invasive (Infiltrating) Ductal Carcinoma
Invasive ductal carcinoma is the most common cell type, comprising 70% to 80% of all cases. It most commonly affects women in their mid to late 50’s but affects women of all ages.
Structurally, it is characterized by its desmoplastic nature inferring that it has a tendency to incite a fibrous response. The cells form well developed glands and nests, with individual cells being relatively large with large pleomorphic nuclii. The cells also vary in size and shape. The cells in the ducts may undergo necrosis resulting in the accumulation of a cheesy material often with dystrophic calcifications. This is called a comedo carcinoma and the cheesy material can be extruded from the ducts on pathologic specimens. Multifocality of invasive ductal carcinoma is more frequent when there is a lesion that is larger than 2-2.5cm.
From a clinical and diagnostic perspective, the lesion is hard to palpate because of its fibrous content. The desmoplastic nature also causes fibrosis of the surrounding connective tissue, resulting in a tugging effect on other structures such as the Cooper’s ligament, the skin, or the nipple. Retraction on the ligaments of Cooper presents as peau d’orange – a dimpling of the skin that is reminiscent of the dimpling seen in the skin of an orange. New onset of nipple retraction is also an important warning sign of invasive cancer.
From an imaging perspective, invasive ductal carcinoma is very dense on mammography and between 70-90% are associated with calcifications, usually shaped as linear casts of the ducts, but are sometimes granular. There are usually more than five in number. Calcification is dystrophic in nature, commonly associated with necrosis. Those patients who do not show calcifications pathologically usually show malignancies of lower grade (low nuclear grade and low grade growth pattern).
An associated ductal carcinoma in-situ is frequently present and comedo necrosis may occur in both invasive areas and areas of intraductal carcinoma.
Invasive ductal carcinoma carries the poorest prognosis among various ductal types. Nuclear and histological grade have shown to be effective predictors of prognosis. In general, the prognosis for the most common histological form which is called invasive ductal carcinoma, not otherwise specified (“IDC NOS”) is intermediate. The mucinous, papillary, cribriform, and tubular forms have better survival than the rarer types such as the sarcomatoid and inflammatory carcinomas.
Treatment, in general, depends on the size but surgery remains the mainstay of therapy. In general, when the lesion is less than 4cm, the mass is excised and the axillary lymph nodes are sampled. Grading and staging after surgery allows the decision for further adjuvant (post surgical) treatment that may include chemotherapy, radiation therapy, and hormonal therapy.
When the mass is larger than 4cm, modified or full mastectomy is performed and lymph nodes are sampled and treatment is tailored to the patient’s individual situation.
Malignant Breast Disease: Invasive Lobular Carcinoma
Invasive lobular carcinoma is less common than invasive ductal carcinoma, common cell type.
Infiltrating lobular carcinoma is present in 5%-10% of breast cancers. It is characterized by its bilaterality in up to 20% of patients and may be multicentric as well.
Structurally, it is poorly circumscribed and like invasive ductal carcinoma may be associated with some fibrosis, but is not as desmoplastic. It has a typical microscopic appearance characterized by small uniform cells organized in strands with one or two layers of cells organized in a single-file (“Indian file”). It may encircle the ducts and often preserves the architecture of the ducts. It typically grows around ducts and lobules. Lobular carcinomas are frequently multifocal and multicentric and they have a similar prognosis to infiltrating ductal carcinomas. They metastasize to unusual sites such as the meninges and serosal surfaces in the GI tract and the retroperitoneum.
Clinically, it may present as poorly defined areas of thickening of the breast and these may be hard to detect clinically. Therefore, the patients themselves may not be able to palpate these masses on self examination and they, therefore, may be larger than IDC when presenting. (Harminder)
Unlike DCIS, LCIS is not associated with a mass or obvious finding on mammography and the diagnosis is usually made by the pathologist as an incidental finding on a biopsy specimen.
Mammographically, the lesion if present, is often ill-defined, vague, with calcifications only seen in about 2%. (Hilleren). In addition when observed, it usually underestimates the extent of the disease. As a result of the low sensitivity of mammography, ultrasound and more increasingly MRI are being used when clinical suspicion is raised. MRI has increased sensitivity to the lesions and is essential for preoperative planning to define extent and to define multicentricty and bilaterality. Lobular carcinoma in situ coexists with invasive lobular carcinoma in most cases (70%-80%).
Treatment, in general, depends on the size, but surgery remains the mainstay of therapy. Breast conserving surgery followed by radiation therapy is recommended for early stages I or II. Although there is a higher incidence of bilaterality, mirror image biopsy, or prophylactic mastectomy is not generally recommended.
Malignant Breast Disease: Other Less Common Invasive Carcinomas – Inflammatory Carcinoma
Inflammatory carcinoma is a malignant condition of the breast, accounting for 1-4% of breast cancer cases, characterized by poorly differentiated, invasive ductal carcinoma with tumor invasion into dermal lymphatics, with a universally poor prognosis.
Clinically, the breast appears inflamed, red, swollen, and painful, with peau d’orange manifestations in the skin and nipple retraction. A mass is not always apparent.
Mammographically, the breast is less compressible and dense with skin and trabecular thickening.
Biopsy should include a section of the skin to reveal the presence of the malignancy in the dermal lymphatics in order to make the diagnosis. Despite the name, inflammatory cells are not usually present.
Staging of the tumor is based on the size and extent of metastases.
In general, inflammatory breast carcinoma is first treated with chemotherapy before surgery is contemplated and if surgery is performed, then radiation therapy follows. If the tumor is receptor positive, hormonal therapy is added.
Other Less Common Invasive Carcinomas – Inflammatory Carcinoma: Medullary Carcinoma
Medullary carcinoma is a rare cancer of the breast arising from the stromal cells and represents less than 5% of invasive breast cancers (Meyer). It is characterized structurally by its large size at detection, soft texture, and mobility since it appears to have no significant associated desmoplasia and has less invasive properties and less commonly metastasizes. The center of large tumors may be hemorrhagic or necrotic. Pathologically, the cells are large, lack glandular morphology and there may be a lymphocytic infiltrate. They all appear to be poorly differentiated, DCIS is usually not seen, and lymphatic and vascular invasion is not seen.
Clinically, medullary carcinoma presents at a slightly younger age (45-55) as a palpable mass, sometimes with a history of explosive growth, commonly in the upper, outer quadrant. Rarely, it has been documented in men; it is associated with BRCA-1 mutations in many cases.
It has benign appearing features on imaging studies often mimicking benign disease. The mammographic features of medullary carcinoma include the presence of a well-defined mass, sometimes lobulated, absent calcifications, often with a complete or incomplete halo. On ultrasound, they are usually large, well-defined, oval, round or lobulated, hypoechoic with through transmission. They have similar appearance to fibroadenomas.
Some studies suggest a more favorable prognosis, yet others suggest that the prognosis is the same as other breast malignancies. Overall at 10 years there appears to be no difference in recurrence rates between patients with medullary carcinomas and other subtypes of invasive breast cancer.
Other less common tumors include the mucinous or colloid carcinoma which is characterized by its slow growing, soft, well-circumscribed nature that presents as a circumscribed mass in older women. It tends to have a more favorable prognosis.
Tubular carcinomas present in women who are younger (mid 40’s) and are characterized histologically by well formed tubules of malignant cells, often multicentric (10-50%), and sometimes bilateral (10-40%). It has uniformly excellent prognosis.
Other Less Common Invasive Carcinomas – Inflammatory Carcinoma: Paget’s Disease of the Nipple
Paget’s disease of the nipple is a malignant disorder of the nipple areolar complex of the breast, with invasion of cells characterized as adenocarcinomatous and accounting for 2-3% of breast carcinomas. The causative factors are multifactorial and they are often associated with DCIS.
Paget’s disease typically presents as erythema and scaling of the nipple skin that progresses to crusting, skin erosion and ulceration, if left untreated. Symptoms may include pruritus, tingling, hypersensitivity, burning or pain. Many diseases must be included when differentiating Paget’s disease from other conditions that lead to erythema and scaling of the skin. The differential diagnosis therefore includes: eczema, contact dermatitis, post radiation dermatitis, and Paget’s disease. Bilateral changes are most consistent with eczema and contact dermatitis. Less common diseases in the differential diagnoses include nipple adenoma and a variety of skin cancers (melanoma, Merkel cell carcinoma, basal cell carcinoma and squamous cell carcinoma).
The diagnosis is obtained in a variety of ways including scrape cytology, shave biopsy, 2mm punch biopsy, wedge incisional biopsy or nipple excision.
Conventional imaging is usually unable to detect the underlying neoplasia though recently the utility of MRI to distinguish between superficial disease and deep disease has been utilized Echevarria).
Since Paget’s disease presents earlier it tends to have a more favorable prognosis. However, prognosis depends on the presence of a breast mass. When present, the prognosis worsens with a survival rate of 40% at 5 years and about 30% at 10 years. In the absence of a mass, survival at 5 years is 90-94% and at 10 years it is 82-90%.
Paget’s disease is diagnosed pathologically more frequently than it is clinically. Its clinical incidence ranges from 0.5% to 2.8% (mean 1.3%) whereas its pathological incidence is approximately 4%.
Treatment of Paget’s disease varies depending on the presence of underlying breast carcinoma or DCIS. Mammographic evaluation looking for evidence of breast cancer is therefore part of the routine evaluation of patients with Paget’s disease (bilateral mammograms). If available, preoperative MRI of the breast can identify occult disease. When possible, breast conserving surgical intervention should be considered. The combination of radiation to breast conserving surgery has been shown to decrease recurrence rates. For patients undergoing mastectomy or breast preservation, the decision of evaluation and treatment of axillary nodes should be reserved for invasive breast cancers.
Other Less Common Invasive Carcinomas – Inflammatory Carcinoma: Cystosarcoma Phyllodes (Phyllodes Tumor)
Phyllodes is a rare type of breast disease, more commonly benign, but may be malignant, (10-15%) usually presenting in women with an average age of 70, structurally characterized by features of stromal origin rather than epithelial origin and histology that is reminiscent of a fibroadenoma but with a cellular stroma and epithelial lined branching clefts. The benign disease can be locally recurrent after resection, which is another characteristic feature of the disease. Its name originates from the Greek words “sarcoma” meaning fleshy, and “phyllo” meaning a leaf, but because it is more commonly a benign tumor, the term Phyllodes tumor is favored over the more malignant sounding name of “sarcoma”.
Clinically, it presents as a large, well-circumscribed, rapidly enlarging mass in an elderly patient.
On mammography, it is a well-circumscribed, solid mass, usually in the 5cm range and resembles a fibroadenoma. However, fibroadenoma presents in young, premenopausal patients and the phyllodes tumor is seen in post menopausal, elderly patients. On ultrasound, the tumor is seen as well circumscribed and may have cystic spaces in the matrix.
The treatment includes wide local excision with a margin of at least 2cm on lesions <5cm, and a 5cm margin on lesions >5cm. Nodal resection is reserved for those patients where nodes are large enough to raise clinical suspicion. Chemotherapy and radiation therapy are not used in the treatment of phyllodes tumors. Hormonal intervention also has no role.
Malignant Breast Disease: Summary
Malignant Breast Disease: Clinical Approach
The approach to the patient with suspected breast cancer should always follow solid clinical principles that include a directed history and thorough directed clinical examination. These are followed by investigation with imaging and documentation by biopsy. Once the diagnosis is established, grading and staging of the disease is necessary with the initial goal of establishing whether surgery is indicated.
Malignant Breast Disease: History Related to the Primary Site
The most common symptom associated with breast cancer is a lump or alteration in the shape of breast. The breast cancer by itself may be painless unless there is a superimposed infection or bony lesion. There may be a change in the nipple in the form of nipple retraction or nipple discharge. The inflammatory breast cancer may present with pain and redness.
Questions in the clinical history that are relevant include:
how long the patient has noted the mass
how big the mass is
where it is located
whether it feels hard or soft
Its relationship to the menstrual cycle and the presence of associated symptoms such as pain, nipple retraction, nipple discharge, itching, or skin change are relevant questions.
Directed history, probing the possibility of metastatic disease includes symptoms of back pain, bone pain, breathing difficulties, local neurological symptoms, or jaundice. Weight loss, malaise, weakness and fever reflect systemic manifestations of cancer.
The overall risk of the patient is probed by finding out the genetic links of the patient. The incidence is four times higher in patients who have a mother or sister with the disease. The risk is also much higher in patients who have family members with a history of both breast and ovarian cancer. The risk is higher in Jewish Ashkenazi women but lower in African American, Japanese, and Taiwanese women. The patients who have ataxia telangiectasia have a four times increased risk. Inherited breast cancer though, only makes up a quarter of all breast cancer cases.
Other diseases that have increased risk include patients with a previous history of breast disease that include breast carcinoma, DCIS, LCIS, complex fibroadenoma, radial scar, sclerosing adenosis, ovarian carcinoma, or endometrial carcinoma.
It is important to ask questions that relate to both lifetime exposure to estrogen, as well as hormonal therapy that incorporates estrogen. The onset of menarche and menopause, obstetric history, and duration of breastfeeding have relevance to the disease. Directed questioning on the use of estrogen containing oral contraception and hormone replacement therapy both raise the risk.
The exam for a patient who has suspected breast cancer should include an exam of both breasts. The directed clinical exam explores the size of the mass, its texture, mobility, and symmetry. Evaluation of the nipple and overlying skin looking for tethering, inversion, and peau d’orange follows. Nodal assessment in the subpectoral region, axilla, and supraclavicuar area is the next step.
Systemic evaluation for metastases should include evaluation of the sclera for jaundice, neurological exam for focal motor or sensory deficit, the lungs for pleural effusion, and the spine for focal back pain.
Lab tests are not very helpful in breast cancer. A high calcium level may be seen in bony metastatic disease. Low blood count may be seen due to bone marrow involvement
Imaging forms the epicenter of breast cancer management.
Malignant Breast Disease: Imaging Strategies
All women are recommended to undergo breast cancer screening in the form of an annual mammogram once they are above 40 years of age. After treatment for breast cancer women should continue to undergo an annual mammogram except for the women who have undergone bilateral mastectomies. The most important imaging is mammography, however, ultrasound may be requested in women with dense breasts or cystic lesions. Magnetic Resonance Imaging (MRI) may be recommended in women with high risk features such as history of breast cancer in the past, family history or presence of mutations that confers high risk of breast cancer.
Imaging Strategies: Mammography
Mammography is an x-ray technique designed to detect cancers at an earlier stage than physical examination. Earlier detection translates into earlier stage cancer and, hence, improved long-term prognosis. Most cancers detected by mammography are non-palpable and are ductal carcinoma in situ, which is highly curable.
Indications: Current screening guidelines are based on a patient’s individual risk. For the average woman, annual mammography starting at age 40 years is recommended. If the patient is high-risk (i.e. has a first degree relative diagnosed with breast cancer), she should begin screening a decade prior to the relative’s age at diagnosis or 40 years, whichever is soonest. Women who are known carriers of the BRCA-1/BRCA-2 mutations often begin screening in their 30’s as they have an 80% lifetime risk of developing breast cancer (10-12% lifetime risk for average patients). Nearly 40% of women treated with mantle radiation for Hodgkin’s disease prior to the age of 25 years will develop breast cancer by age 45, so these women begin annual screening mammography in their 30’s as well.
Diagnostic mammograms are indicated if a patient has a specific problem, such as pain, lump, thickening, or nipple discharge. This examination is performed on symptomatic patients over the age of 30 years and is usually combined with an ultrasound targeted to the area of concern.
Contraindications: The benefits of any imaging test should always outweigh the risks. In general, there are no true contraindications to mammography. However, mammography is not performed on women who are in the first trimester of pregnancy (unless there is substantial clinical suspicion for breast cancer) or who have an active mastitis. As patients must be able to sit or stand upright, bedridden patients cannot undergo the examination.
Advantages: In multiple randomized screening studies, mammography has been shown to reduce breast cancer mortality by up to 30%. This mortality reduction even applies to women in their 40’s, and more recent studies suggest that these women may benefit even more with reductions up to 45%.
Disadvantages: For the rare patient, the breast compression associated with mammography is extremely painful and cannot be tolerated. If this is the case, the patient is asked to take Motrin or ibuprofen an hour prior to her appointment and to schedule the study during the first week of the menstrual cycle (if applicable).
Patient Preparation: Patients are requested not to wear antiperspirants or powders on the day of the study as the metals in these compounds can appear similar to microcalcifications. Deodorants usually do not interfere with the images. Patients are also asked to bring all of their prior outside mammograms with them to their appointment as the radiologist will need these as they interpret the current study.
Technique: The patient is asked to undress from the waist up and put on a gown. The technologist takes the patient into a mammography room and reviews the patient information sheet for accuracy and completeness. Each breast is then positioned for the craniocaudad (CC) and mediolateral oblique (MLO) views. The patient waits until the technologist determines that the images are of good quality. She then can leave the center. The radiologist will interpret the screening study later that day. If the patient has a symptom, she will wait at the center until the radiologist reviews the films, as there may be a need for additional mammographic views or possibly even an ultrasound.
Results: Recall for additional imaging from a screening examination ranges from 3-12% depending upon the center. The positive predictive value of biopsy for most centers ranges between 20-40%.
The false negative rate of mammography is approximately 5-15%, depending upon the experience of the interpreting radiologist. Double reading (i.e. two radiologists interpret every screening study) and/or the use of computer-aided detection (CAD) can help reduce the false negative rates by up to 40-60%.
Conclusions: Mammography is a safe, effective tool for the early detection of breast cancer and reduces mortality from breast cancer by up to 30%.
Imaging Strategies: Ultrasound
Ultrasound uses sound waves to image the breast. This modality is predominantly designed to differentiate a cystic mass from a solid mass. In addition, ultrasound can be used to guide percutaneous procedures, such as fine needle aspiration, core needle biopsy, or percutaneous excision.
Indications: Ultrasound is indicated to:
1) Evaluate a palpable abnormality on physical exam (focal pain, lump, thickening)
2) Evaluate a mammographic finding (focal mammographic lesion)
3) Evaluate focal pain persistent for greater than 3 months
4) To guide a percutaneous procedure such as a core biopsy or fine needle aspiration (FNA).
Although there are a few studies using ultrasound to screen for breast cancer, this is not widely embraced as the modality is highly operator dependent. In addition, there are no large randomized studies showing that screening ultrasound reduces mortality from breast cancer.
Contraindications: There are no known contraindications to breast ultrasound.
Advantages: Ultrasound is a safe technology with no known side effects. It does not require breast compression. Although usually performed with the patient supine or supine oblique, it can be performed in the upright position in wheelchair bound patients. It offers a means to better characterize palpable and mammographic findings and provides a mechanism to biopsy lesions percutaneously.
Disadvantages: Ultrasound is highly operator dependent. Despite standard planes to image abnormalities, the detection of an abnormality depends on the skill of the operator. Although there are features on ultrasound which favor benign disease from malignancy, ultrasound cannot reliably differentiate solid lesions, and therefore, biopsy is often necessary.
Patient Preparation: There is no particular preparation for this examination, except that we do ask patients to bring all previous breast imaging studies with them to their appointment.
Technique: Usually, the patient is asked to lie down on a stretcher. With their arm above their head and in a supine or supine oblique position, the technologist or radiologist places gel on the skin and scans the patient with a linear 12-17MHz transducer in the radial and antiradial planes. Images are usually acquired in both planes if an abnormality is identified and only in one plane if the study is normal. If there is a palpable abnormality, the patient is asked to put their finger on the spot prior to scanning.
Results: Ultrasound has a high specificity for the diagnosis of simple cysts.
Conclusions: Ultrasound is a safe modality to evaluate a palpable abnormality or a suspicious mammographic finding. It can reliably differentiate cysts from solid masses.
Imaging Strategies: MRI of the Breast
Magnetic resonance imaging (MRI) of the breast uses a high-field magnet to image the breast. Multiplanar imaging with different sequences prior to and following contrast administration permits evaluation of the breast tissue. Interpretation of MRI studies entails a combination of lesion morphology and enhancement pattern. Lesions that demonstrate early rapid uptake of contrast with a plateau or delayed washout over time are most suspicious for malignancy and warrant biopsy. Gradual uptake of the contrast over time favors a benign process.
Indications: Current indications for this study are as follows:
1) To determine the integrity of silicone breast implants.
2) To determine disease extent in a newly diagnosed breast cancer patient, particularly younger patients with dense tissue.
3) To identify the breast primary in patients with positive axillary lymph nodes and negative physical exams.
4) To differentiate scar from recurrence in selected patients previously treated for breast cancer.
5) To further characterize an incompletely evaluated suspicious mammographic finding.
6) To monitor response to neoadjuvant chemotherapy in patients with locally advanced breast cancer.
7) To screen high-risk women, particularly BRCA-1 and BRCA-2 known carriers.
Contraindications: The standard contraindications to MR imaging apply. In addition, as intravenous gadolinium is given for almost all studies, an allergy to gadolinium would preclude this examination. Relative contraindications include pregnant women as the safety of gadolinium to the fetus is unknown.
Advantages: MR imaging of the breast is a highly sensitive test with sensitivities approaching 100% for the detection of invasive carcinoma.
Disadvantages: The specificity is variable depending upon the specific sequences employed and the experience of the interpreting radiologist. In addition, the imaging sequences are not standardized across sites in the United States.
MRI of the Breast: Method
Patient Preparation: Patients must be screened for contraindications to MR imaging. Premenopausal patients and cycling postmenopausal patients should be imaged between days 5-15 of the menstrual cycle in order to control for hormonal fluctuations.
Technique: The patient lies prone on the scanner with her breasts pendent and in mild compression in the dedicated breast coil. An intravenous line is placed through which contrast will be administered. Every center utilizes different sequences for imaging the breasts. In general, most centers acquire images in the sagittal and/or axial plane prior to and following contrast administration. During the contrast injection, dynamic imaging is performed such that images of the entire breast volume are acquired every 1-2 minutes for up to 8-10 minutes following the start of the injection. Using CAD software (Confirma or DynaCad), the enhancement curves can be generated. The entire study usually takes approximately 30 minutes to perform. The radiologist then interprets the images by looking at the lesion morphology and its enhancement pattern.
Results: MR imaging of the breasts is a highly sensitive test with sensitivities approaching 100% for the detection of invasive carcinoma. Its sensitivity for ductal carcinoma in situ ranges between 10-90% depending upon the center and its sequences. Specificity for this study ranges between 75-90%, once again depending on the specific sequences employed. The false negative rate of MRI is unknown.
Conclusions: MR imaging of the breast serves as a useful adjunct to other breast imaging modalities and for screening high-risk women, particularly known carriers of BRCA-1 and BRCA-2. MRI-guided percutaneous core needle biopsy is now available at most centers permitting minimally invasive diagnosis of suspiciously enhancing lesions detected only on MR imaging.
Imaging Strategies: Positron Emission Tomography (PET)
Positron Emission Tomography or PET is not usually recommended for the work up of breast carcinoma. It is limited by the size of the tumor and tumors less than 1cm may not be identified. While it is sensitive and able to detect invasive ductal carcinoma, it is not sensitive to in situ carcinomas and less sensitive to lobular carcinoma.
Malignant Breast Disease: Reporting the Findings on Imaging Studies
Breast Imaging Reporting and Data System (BI-RADS) is a standardized method of reporting mammography studies allowing for a quality assurance mechanism, consistency and clarity of the reports. It was developed by the American College of Radiology as a standard for rating the likelihood of cancer by setting up levels of suspicion. BI-RADS system takes into account presence of a discrete nodule, calcifications, and architectural distortion of focal asymmetric densities. The radiologist scores the findings from 1-6 providing the referring physician with a standardized report on the likelihood of cancer in their patient.
|0||Incomplete||The mammogram or ultrasound does not provide enough information to make a clear diagnosis; follow-up imaging is necessary|
|1||Negative||routine screening recommended|
|2||Benign||Definite benign findings present; routine screening recommended|
|3||Probably Benign||Findings that have a high likelihood of being benign, six-month short interval follow-up, then every 6-12 months for 1-2 years|
|4||Suspicious Abnormality||Not characteristic of breast cancer, biopsy should be considered|
|5||Highly Suspicious of Malignancy||Lesion that has a high probability of being malignant, biopsy needed|
|6||Known Biopsy Proven Malignancy||Lesions known to be malignant that are being imaged prior to definitive treatment; assure that treatment is completed|
Reporting the Findings on Imaging Studies: Biopsy
Once an abnormality is detected in the breast by palpation or imaging studies, the gold standard for diagnosis is histopathological exam of a biopsy specimen. The optimal method to do biopsy is decided upon size, depth and nature of abnormality. Cystic lesion may be aspirated under ultrasound guidance. Fine needle aspiration may be done which may help in diagnosis. Core biopsy is an excellent method; the lesion may be studied in greater detail as well as staining is possible for hormone receptors. It may be done by stereotactic guidance or needle localization. Rarely when a lesion is not accessible incisional biopsy may be needed.
Histopathological examination of breast biopsy of the suspicious lesions remains the gold standard of diagnosis. This is most commonly performed using imaging guidance. In the event that usual techniques are indeterminate or fail then surgical biopsy is performed.
The image guided techniques include ultrasound, stereotactic (X-ray using specially designed mammography equipment), and MRI.
Ultrasound is the most commonly performed because it allows real time visualization of the needle and the lesion and avoids radiation. Stereotactic guidance is used when calcifications are present since it is more sensitive than ultrasound to identify this important aspect of the lesion. MRI is performed when the lesion cannot be seen by ultrasound or mammography. Surgery is performed when the above techniques fail.
Percutaneous breast biopsy is usually performed as an outpatient using imaging guidance, commonly by ultrasound, but mammography and MRI are also utilized.
The aim of the procedure is to obtain sufficient tissue to diagnose malignancy and to characterize the tissue relating to its specific histopathological type, grade and hormonal receptor status.
Based on the BI-RADS system the lesions for biopsy are most commonly those designated as BI-RADS score 4 or 5. There will be some uncommon situations where a biopsy for a category 3 lesion is indicated, (e.g. inability to obtain mammographic follow up, anxiety about the lesion, planned pregnancy, planned breast cosmetic surgery) but the goal is to avoid biopsy of benign disease.
Since many lesions identified by mammography are impalpable and are seen only by mammography or ultrasound, image guided biopsy is utilized. Ultrasound guided procedures are most widely used since they are real time inferring that the needle can be observed as it is advanced into the lesion. Ultrasound also avoids radiation and is relatively inexpensive. However, when microcalcifications are present or when the lesion cannot be seen by ultrasound, then stereotactic biopsy is employed. MRI guided procedures are used when the the lesion can only be seen by MRI.
There are no absolute contraindications and only relative contraindications. Obviously, if the lesion cannot be definitely seen it cannot be biopsied. In patients who cannot come off anticoagulation, there is a relative contraindication to the procedure but this circumstance is rarely encountered.
The risks of the procedure are low and the need to diagnose the disease, evaluate the type, and grade the tumor are essential to treatment planning.
There are no disadvantages other than the innate concerns of radiation in the case of stereotactic method, and the risk of bleeding, infection and low seeding the tumor.
The procedure, the technique, and the risks and benefits need to be explained to the patient in a quiet and confident manner and informed consent is necessary.
Aspirin prophylaxis should be stopped a week before the procedure and any other anticoagulation should be discontinued to enable the INR (international normalized ratio) to be below 1.5. The patient does not have to be NPO (nothing by mouth).
There are a variety of needles and cutting devices that are used. Cytological aspirates are no longer used by radiologists, who use only core technique. The cutting needles which are used for obtaining a core are usually 14 gauge. More recently, uses of the vacuum assisted devices (VAD) are being utilized, since they are able to obtain larger samples of tissue. The 9 French cutting needle increases the yield of invasive carcinoma in a DCIS environment, because of the larger sample size. In general, these are used for the stereoscopic and MRI guided procedures.
All of the procedures require sterile technique and local anesthesia. Whichever technique is used the principles include:
- Find the shortest distance to the lesion and transgress the least amount of tissue
- Biopsy it
- Mark the biopsy site with a clip
- Prove that the appropriate tissue was acquired by specimen X-ray for microcalcifications, or post procedure mammogram to prove that the lesion has disappeared
Reporting the Findings on Imaging Studies: Fine Needle Aspiration and Core Biopsy
Fine Needle Aspiration
Fine needle aspiration (FNA) using a 21 gauge needle is the least invasive and most commonly used needle and has a sensitivity of 50-95%% and a specificity of 95-100%. As stated, radiologists do not use this technique due to the limited amount of information that it provides.
The technique uses a slow back and forth motion in the lesion while observing the needle in real time, until some material is seen in the bottom of the barrel of the syringe.
The aspirate is transferred onto glass slides and is spread by a second glass slide in order to ensure that the material is thinly distributed. This is best done by an attending cytopathology technologist. Staining techniques are individualized by the preference of specific pathology laboratories.
Core biopsy specimens may be obtained in a variety of ways. A 14 gauge trucut needle using a spring loaded firing device facilitates needle penetration of hard fibrous elements in the tumor which may otherwise be difficult to penetrate. The volume of tissue is larger than the aspirate and the architecture of the tumor can be appreciated. Once the specimen is obtained the material is transferred to formalin. If the lesion was known to contain calcifications then specimen radiographs are obtained to ensure accuracy of sampling.
A pressure dressing is usually applied for 24 hours after the procedure to prevent or limit bleeding.
Vacuum Assisted Device (VAD)
The VAD is usually an 11 gauge percutaneous system that is vacuum driven used in stereotactic biopsies and in MRI. It is particularly helpful in the DCIS environment where a small pocket of invasive carcinoma may be present. In this instance the larger the sample the more likely one is able to identify invasive disease.
On occasion it is used to excise benign lesions that are less than 15mm in size. The purpose is to avoid surgery for benign disease.
The fine needle procedures appear to be adequate if the only question is the presence or absence of malignancy. It requires cytopathologists, who are experienced in the technique. It proves to be inadequate for treatment planning since detailed information of the architecture grade and histologic type is needed and that can only be provided by core specimens. The Tru Cut needle which is a well known core biopsy needle has a sensitivity that ranges between 64%-84%, and the 14 gauge biopsy cut has a sensitivity of 88-98%. Both have specificity of 100%.
The complications of the procedure include bleeding and infection. Hematomas have become more frequent as the sizes of the needles have increased. The MRI guided procedures are particularly prone to hematoma because while the patient is in the scanner the ability to identify bleeding or to compress bleeding if it is present is restricted, since the patient is out of reach and observation while in the gantry.
Biopsy of an equivocal finding in the breast is an essential and key step in the diagnosis and management of breast carcinoma. The histopathological type, grade, and hormone receptor status are necessary before embarking on a treatment program. Ultrasound and core biopsy technique are favored in most cases, while stereotactic biopsy is favored when microcalcifications are present, or the lesion cannot be seen by ultrasound. MRI guided procedures are utilized when it is the only modality able to visualize suspicious areas. Needles have become larger so that current sized needles range from 9 gauge to 14 gauge, though some institutions use 18 gauge for the cores and 21 gauge for cytology. Surgical excisional biopsy is used for lesions that reveal equivocal pathological findings such as atypical intraductal hyperplasia, or in breasts that are less than 25mm when compressed.