| How is histology of breast? | ➢ The functional unit of the breast is the lobule, which is
supported by a specialized intralobular stroma.
➢ The inner luminal epithelial cells produce milk during
lactation.
➢ The basally located myoepithelial cells have contractile
function to aid in milk ejection and also help support the
basement membrane.
➢ The ducts are conduits for milk to reach the nipple.
➢ The size of the breast is determined primarily by interlobular stroma, which increases during puberty and involutes with age.
➢ Each normal constituent is a source of both benign and
malignant lesions |
| What are origins of breast disorders? | . |
| What are main symptoms of breast diseases? | . |
| What are breast inflammatory processes? | ➢ Rare
➢ May be caused by infections, autoimmune disease, or foreign body–type reactions.
➢ As Inflammatory symptoms may be also caused by some
carcinomas, ths later should always be considered
➢ The only infectious agent to cause breast disease with any frequency is Staphylococcus aureus, which typically gains entry via fissures in nipple skin during the first weeks of
breastfeeding.
➢ May lead to the formation of “lactational abscesses.
➢ Most cases are treated adequately with antibiotics and
continued expression of milk. |
| What are stromal neoplasms? | ➢ FA and PT share driver mutations in the same genes and appear to be part of a spectrum of related neoplasms.
➢ Tumors derived from intralobular stroma are comprised of both stromal cells and epithelial cells :“biphasic”
➢ The neoplastic proliferation of specialized lobular fibroblasts also stimulates reactive proliferation of lobular epithelial cells.
➢ As the intralobular fibroblasts proliferate, they push and distort the epithelial cells so that they form elongated slitlike structures rather than round acini.
➢ in phyllodes tumors the stromal cells tend to outgrow the epithelial cells, resulting in bulbous nodules of proliferating stromal cells that are covered by epithelium
➢ Lesions of interlobular stroma are monophasic (only comprised of mesenchymal cells) and include benign soft tissue tumors found elsewhere in the body, such as hemangiomas and lipomas
➢ The only malignancy derived from interlobular stromal cells of note is angiosarcoma which may arise in the breast after local radiotherapy. |
| Table of stromal neoplasms? | . |
| What are benign epithelial lesions of breast? | ➢ Benign changes are divided into three groups :
1. nonproliferative disease
2. proliferative disease without atypia
3. proliferative disease with atypia
➢ Each one is associated with a different degree of breast cancer risk. |
| What is non-proliferative disease of breast? | ➢ not associated with an increased risk of breast cancer.
➢ consists of three major morphologic changes: cysts, fibrosis, and adenosis.
➢ the lesions contain single layers of epithelial cells = non prolif.
➢ simple cysts : most common nonproliferative breast lesion
➢ lined by a layer of luminal cells that often undergo apocrine metaplasia
➢ The apocrine secretions may calcify and be
detected by mammography.
When cysts rupture, chronic inflammation and fibrosis in response to the spilled debris may producepalpable nodularity of the breast (so-called “fibrocystic changes”) |
| What is proliferative disease w/out atypia? | ➢ associated with a slightly increased risk of breast cancer.
➢ includes epithelial hyperplasia, sclerosing adenosis, complex sclerosing lesion, and papilloma.
➢ Each is associated with varying degrees of epithelial cell
proliferation
➢ in epithelial hyperplasia, increased numbers of both spindled myoepithelial cells and epithelioid luminal cells expand ductal and lobular spaces |
| What is intraductal papilloma? | ➢ Macroscopie :
o Masse polypoide intraluminale
o Parfois uniquement visible à la MO
(distaux)
➢ Histo:
o Papilles embranchées.
o Axes conjonctivo-vasculaires
o Revêtement épithéliale fait d’une
double couche :
Couche luminale épithéliale
Couche externe myoépithéliale |
| What is proliferative disease w/atypia? | ➢ includes monoclonal “precancers” that are associated with a modest increase in the risk of breast cancer in both breasts;
➢ overall, 13% to 17% of women with these lesions develop breast cancer.
➢ includes atypical lobular hyperplasia (ALH) and atypical ductal hyperplasia (ADH).
➢ ALH closely resembles lobular carcinoma in situ (LCIS) and
➢ ADH closely resembles ductal carcinoma in situ (DCIS
➢ The cells in ADH are uniform in appearance and form sharply marginated spaces or rigid bridges |
| What is breast carcinoma? | ➢ Breast carcinoma is the most common malignancy of women
➢ Since the mid-1980s the mortality rate has dropped from 30% to less than 20%.
➢ The decrease is attributed to both improved screening, which detects some cancers before they have metastasized, and more effective systemic treatment.
➢ Almost all breast malignancies are adenocarcinomas (>95%).
➢ In the most clinically useful classification system, breast cancers are divided based on the expression of hormone receptors: estrogen and progesterone receptors (ER/PR) and the expression of the human epidermal growth factor receptor 2 (HER2, also known as ERBB2)
➢ They are divided into three major groups:
• ER positive (HER2 negative; 50%–65% of cancers)
• HER2 positive (ER positive or negative; 10%–20% ofcancers)
• Triple negative (ER, PR, and HER2 negative; 10%–20% of cancers) |
| How is classification of breast carcinoma done? | ➢ This system, which is currently used mainly in the context of clinical research, divides breast cancers into four major types:
• Luminal A. The majority are lower-grade ER-positive cancers that are HER2 negative
• Luminal B. The majority are higher-grade ER-positive cancers that may be HER2 positive
• HER2-enriched. The majority overexpress HER2 and do not express ER
• Basal-like. The majority by gene expression profiling resemble basally located myoepithelial cells and are ER-negative, HER2-negative |
| What are risk factors for breast carcinoma? | ➢ Age and Gender : Breast cancer is rare in women younger than age 25, but increases in incidence rapidly after age 30. The incidence in men is only 1% of that in women.
➢ Family History of Breast Cancer : The greatest risk is for
individuals with multiple affected first-degree relatives with
early-onset breast cancer.
➢ Geographic Factors : The risk is significantly higher in the
Americas and Europe than in Asia and Africa
➢ Race/Ethnicity : The highest rate of breast cancer is in women of European descent. Hispanic and African American women tend to develop cancer at a younger age and are more likely to develop aggressive tumors
➢ Reproductive History : Early age of menarche, nulliparity, absence of breastfeeding, and older age at first pregnancy (each increases the exposure of “at-risk” breast epithelial cells to estrogenic stimulation).
➢ Ionizing Radiation : increases the risk of breast cancer if exposure occurs while the breast is still developing.
➢ Other Risk Factors. Postmenopausal obesity, postmenopausal hormone replacement, mammographic density, and alcohol consumption also have been implicated as risk factors. |
| How is pathogenesis of of breast cancer? | ➢ The three major subtypes of breast cancer defined by
differential expression of hormone receptors and HER2 arise
through more-or-less distinct pathways that involve the
stepwise acquisition of driver mutations in the epithelial cells
of the duct/lobular system |
| What are major pathways of development of breast cancer? | ➢ The most common pathway (yellow arrow) leads to ERpositive cancers.
➢ Morphologically recognized precursor lesions include flat epithelial atypia, ADH, and DCIS, all of which share certain genomic events with invasive ER-positive carcinomas, such gains of chromosome 1, losses of chromosome 16, and mutations of PIK3CA (the gene encoding PI3K).
➢ By gene expression profiling, these cancers are classified as "luminal.”
➢ This is the type of cancer that arises most commonly in
individuals with germline BRCA2 mutations
➢ Less common are cancers that overexpress HER2 because of gene amplification (green arrow).
➢ These cancers may be positive or negative for ER and are usually associated with germline TP53 mutations.
➢ A possible precursor lesion is atypical apocrine adenosis, which shares features with apocrine DCIS.
➢ The least common but molecularly most distinctive type of breast cancer is negative for ER and HER2 (“triple negative”; blue arrow). These cancers have loss of BRCA1 and TP53 function and are genomically unstable.
➢ The majority of triple-negative cancers are classified as “basallike” by gene expression profiling. |
| How is morphology of breast cancer? | ➢ The most common location of tumors within the breast is in the upper outer quadrant (50%), followed by the central portion (20%).
➢ About 4% of women with breast cancer have bilateral primary tumors or sequential lesions in the same breast.
➢ Breast cancers are classified morphologically according to whether they have penetrated the basement membrane.
➢ Those that remain within this boundary are termed in situ
carcinomas, and those that have spread beyond it are
designated invasive carcinomas |
| How is morphological classification of breast cancer? | ➢ In this classification, the main forms of breast carcinoma are as
follows:
➢ A. Noninvasive
1. Ductal carcinoma in situ
2. Lobular carcinoma in situ
➢ B. Invasive
1. Invasive ductal carcinoma (includes all carcinomas that are not
of a special type)—70% to 80%
2. Invasive lobular carcinoma— ~10% to 15%
3. Carcinoma with medullary features— ~5%
4. Mucinous carcinoma (colloid carcinoma) — ~5%
5. Tubular carcinoma— ~5%
6. Other types |
| How is breat in situ carcinoma? | ➢ There are two morphologic types of noninvasive breast
carcinoma:
ductal carcinoma in situ (DCIS)
Lobular carcinoma in situ (LCIS).
➢ The terms ductal and lobular are misleading, as both types of CIS are thought to arise from cells in the terminal duct that give rise to lobules.
➢ LCIS usually expands involved lobules, whereas DCIS distorts lobules into ductlike spaces.
➢ By definition, both “respect” the basement membrane and do not invade into stroma or lymphovascular channels |
| How is DCIS? | ➢ DCIS has a wide variety of histologic appearances, including solid, comedo, cribriform, papillary, micropapillary, and "clinging” types.
➢ Nuclear appearances range from bland and monotonous (low nuclear grade) to pleomorphic (high nuclear grade).
➢ The distinctive comedo subtype is characterized by extensive central necrosis, which produces toothpastelike necrotic tissue that extrudes from transected ducts on application of gentle pressure.
➢ Calcifications frequently are associated with DCIS
➢ constitutes only 5% of breast cancers in unscreened populations but up to 30% in screened populations, largely because of the ability of mammography to detect calcifications.
➢ Current treatment strategies for DCIS use surgery and
irradiation to eradicate the lesion.
➢ Treatment with anti-estrogenic agents such as tamoxifen also is used to decrease the risk of recurrence of ER-positive DCIS.
➢ The prognosis is excellent, with greater than 97% long-term survival.
➢ If untreated, DCIS progresses to invasive cancer in roughly one-third of cases, usually in the same breast and quadrant as the earlier DCIS |
| How is paget disease of the nipple? | ➢ caused by the extension of DCIS up the lactiferous ducts and into the contiguous skin of the nipple, producing a unilateral crusting exudate over the nipple and areolar skin.
➢ Unlike Paget disease of the vulva, Paget disease of the nipple stems from in situ extension of an underlying carcinoma.
➢ The prognosis of the carcinoma of origin is affected by the presence of Paget disease and is determined by other factors. |
| How is LCIS? | ➢ Uniform appearance.
➢ The cells are monomorphic, have bland, round nuclei, and are found in loosely cohesive clusters within the lobules
➢ LCIS is virtually always an incidental finding because, unlike DCIS, it is only rarely associated with calcifications.
➢ Approximately one-third of women with LCIS eventually
develop invasive carcinoma.
➢ Unlike DCIS, invasive carcinomas following a diagnosis of LCIS may arise in either breast : 2/3 in the same breast and 1/3 in the contralateral breast.
➢ LCIS is both a marker of an increased risk of carcinoma in both breasts and a direct precursor of some cancers.
➢ Current treatment options include close clinical and radiologic follow-up, chemoprevention with tamoxifen or, less commonly, bilateral prophylactic mastectomy |
| What is invasive ductal carcinoma? | ➢ All carcinomas that cannot be subclassified into one of the specialized types ILC/Ca with medullary
features/mucinous/tubular/inflammatory
➢ A majority (70%–80%) of cancers falls into this group.
➢ usually is associated with DCIS.
➢ The microscopic appearance varies, ranging from tumors with well-developed tubules and low-grade nuclei to tumors consisting of sheets of anaplastic cells.
➢ Most invasive ductal carcinomas produce a desmoplastic response, which replaces normal breast fat (resulting in a mammographic density; and eventually leads to the appearance of a hard, palpable irregular mass.
➢ About 50% to 65% of ductal carcinomas are ER positive, 20% are HER2 positive, and 15% are negative for both ER and HER2. |
| What is invasive lobular carcinoma? | ➢ Consists of infiltrating cells that are morphologically similar to the tumor cells seen in LCIS;
➢ two-thirds of the cases are associated with LCIS
➢ 10% to 15% of all breast carcinomas.
➢ The cells invade stroma individually and often are aligned in “single-file”
➢ Although most manifest as palpable masses or mammographic densities, a significant subgroup invade without producing a desmoplastic response;
➢ May be clinically occult and difficult to detect by imaging
➢ The pattern of metastasis of lobular carcinoma is unique among breast cancers, as they frequently spread to cerebrospinal fluid, serosal surfaces, gastrointestinal tract, ovary, uterus, and bone marrow.
➢ Almost all lobular carcinomas express hormone receptors, whereas HER2 overexpression is rare |
| What are carcinomas w/medullary features? | ➢ special type of triple-negative cancer comprising about 5% of all breast cancers. These carcinomas typically grow as rounded masses
➢ that can be difficult to distinguish from benign tumors on imaging
➢ They consist of sheets of large anaplastic cells associated with pronounced lymphocytic infiltrates composed predominantly of T cells
➢ The presence of lymphocytes is associated with a favorable prognosis, at least in part due to a better response to chemotherapy compared to poorly differentiated carcinomas without lymphoid infiltrates.
➢ This type is seen frequently in women with germline BRCA1 mutations, but most women with these carcinomas are not carriers. |
| What is mucinous carcinoma? | ➢ is an ER-positive/HER2- negative tumor that produces
abundant amounts of extracellular mucin.
➢ The tumors usually are soft and gelatinous because of the
presence of mucin pools that create an expansile circumscribed mass |
| What is tubular carcinoma? | ➢ type of ER-positive/HER2- negative cancer
➢ almost always detected on mammography as a small irregular mass.
➢ The tumor cells are arranged in wellformed tubules and have low-grade nuclei.
➢ Lymph node metastases are rare, and the prognosis is excellent. |
| What is inflammatory carcinoma? | ➢ is defined by its clinical presentation, rather than a specific morphology.
➢ Patients present with a swollen erythematous breast without a palpable mass.
➢ The underlying invasive carcinoma is generally poorly
differentiated and diffusely infiltrates and obstructs dermal
lymphatic spaces, causing the “inflamed” appearance; true inflammation is absent.
➢ Many of these tumors metastasize to distant sites;
➢ the overall 5-year survival is less than 50%, and understandably even lower in those with metastatic disease at diagnosis.
➢ About half express ER and 40% to 60% overexpress HER2. |
| How is grading of breast carcinoma? | ➢ All types of invasive breast carcinoma are assigned a grade from 1 (low-grade) to 3 (high-grade) based on :
1. nuclear pleomorphism,
2. tubule formation,
3. Proliferation.
➢ Low-grade nuclei are similar in appearance to the nuclei of normal cells.
➢ High-grade nuclei are enlarged and have irregular nuclear contours resulting from abnormal DNA content and structure
➢ Most low-grade carcinomas form well-defined tubules and may be difficult to distinguish from benign lesions, whereas highgrade carcinomas lose this capacity and invade as solid sheets or single cells.
➢ Proliferation is evaluated by counting mitotic figures.
➢ The majority of HER2-positive and triple-negative carcinomas are highly proliferative
➢ whereas ER-positive cancers show a wide range of proliferation |
| How is staging of breast carcinoma? | ➢ measure of the extent of tumor at the time of diagnosis and is important for all biologic types of carcinoma.
➢ It is based on features of the primary tumor (T), involvement of regional lymph nodes (N), and the presence of distant metastases (M)
➢ The AJCC/UICC staging system, classifies tumors as T1, T2, and T3 based on the tumor size, whereas T4 tumors have ulceration of the skin, involvement of the deep muscles of the chest wall, or are clinically diagnosed as inflammatory carcinoma.
➢ The majority of cancers first metastasize to regional nodes, and nodal involvement is a very strong prognostic factor
➢ Lymphatic drainage goes to one or two sentinel lymph nodes in the axilla in most patients.
➢ If these nodes are not involved, the remaining axillary nodes are usually free of carcinoma.
➢ Sentinel node biopsy has become the standard for assessing nodal involvement, replacing more extensive lymph node dissections, which are associated with significant morbidity.
➢ Distant metastases (M) are only detected in 5% of newly diagnosed women.
➢ Stage 0 is CIS, which is associated with survival rates greater than 95%. |
| What are breast-implant associated anaplastic large cell lymphoma? | ➢ Morphology and immunophenotype similar to those of ALK-negative ALCL
➢ Arises around a breast implant
➢ Usually confined by a fibrous capsule.
➢ The average patient age at diagnosis is 52 years
➢ The median time from implant placement to clinical presentation is 8–9 years
➢ Most patients present with unilateral effusion around the implant
➢ One third of patients present with a mass, and about 20% develop regional lymphadenopathy,
➢ Approximately 5% of cases are bilateral.
➢ Surgery is the cornerstone of therapy, with complete excision of capsule and implant leading to a 5-year overall survival rate of 100% in patients with effusion only |
