Breast Pathology Carcinoma of the Breast

carcinoma of the breast
breast carcinoma is the most common malignant tumor and the leading cause of death in women,more than 1,000,000cases occurring worldwide.
the incidence is high in north america and northern europe, intermediate in southern european and latin american countries, and low in most asian and african countries (but rising rapidly in recent years with increased in these countries).
75% of women with breast cancer are older than 50,a woman who lives to age 90 has a one in eight chance of developing breast cancer and approximately 50% of the cases are affect the upper outer quadrant of the breast.
risk factors
1-age :: the incidence rises throughout a woman s lifetime, peaking at the age of 75–80 years and then declining slightly thereafter. the average age at diagnosis is 61 for white women, and 46 for african american women. breast cancer is very rare in all groups before the age of 25.
2-age at menarche::women who reach menarche when younger than 11 years of age have a 20% increased risk compared with women who are more than 14 years of age at menarche. late menopause also increases risk.

3-age at first live birth::women who experience a first full-term pregnancy at ages younger than 20 years have half the risk of nulliparous women or women over the age of 35 at their first birth.

4-first-degree relatives with breast cancer ::the risk of breast cancer increases with the number of affected first-degree relatives (mother, sister, or daughter), especially if the cancer occurred at a young age.

5-atypical hyperplasia:: a history of prior breast biopsies, especially if revealing atypical hyperplasia, increases the risk of invasive carcinoma. there is a smaller increase in risk associated with proliferative breast changes without atypia.

6-race/ethnicity:: non-hispanic white women have the highest rates of breast cancer. the risk of developing an invasive carcinoma within the next 20 years at age 50 is 1 in 15 for this group, 1 in 20 for african americans, and 1 in 27 for hispanics, social factors such as decreased access to health care and lower use of mammography may well contribute to these differences, but biologic differences also play an important role.

7-estrogen exposure::postmenopausal hormone replacement therapy increases the risk of breast cancer 1.2- 1.7 fold, and adding progesterone increases the risk further.
oral contraceptives have not been shown strongly to affect breast cancer risk but do decrease the risk of endometrial and ovarian carcinomas. reducing endogenous estrogens by oophorectomy decreases the risk of developing breast cancer by up to 75%. drugs that block estrogenic effects (e.g., tamoxifen) or block the formation of estrogen (e.g., aromatase inhibitors) also decrease the risk of breast cancer.
8-radiation exposure ::radiation to the chest, whether due to cancer therapy, atomic bomb exposure, or nuclear accidents, results in a higher rate of breast cancer. the risk is greatest with exposure at young ages and with high radiation doses.

9-carcinoma of the contralateral breast or endometrium
approximately 1% of women with breast cancer develop a second contralateral breast carcinoma per year.
10-geographic influence :: breast cancer incidence rates in the united states and europe are four to seven times higher than those in other countries. the risk of breast cancer increases in immigrants to the united states with each generation. reproductive history (number and timing of pregnancies), breastfeeding, diet, obesity, physical activity, and environmental factors all probably play a role.

11-breastfeeding::the longer women breastfeed, the greater the reduction in risk, lactation suppresses ovulation and may trigger terminal differentiation of luminal cells, the lower incidence of breast cancer in developing countries largely can be explained by the more frequent and longer nursing of infants.

12-diet:: large studies have failed to find strong correlations between breast cancer risk and dietary intake of any specific type of food. coffee addicts will be pleased to know that caffeine consumption may decrease the risk of breast cancer. on the other hand, moderate or heavy alcohol consumption increases risk.

13-obesity::there is decreased risk in obese women younger than 40 years as a result of the association with anovulatory cycles and lower progesterone levels late in the cycle. in contrast, the risk is increased for postmenopausal obese women, which is attributed to the synthesis of estrogens in fat depots.

14- environmental toxins there is concern that environmental contaminants, such as pesticides, have estrogenic effects on humans. possible links to breast cancer risk are being investigated intensively, but definitive associations have yet to be made.

15-tobacco cigarette smoking has not been clearly associated with breast cancer but is associated with the development of periductal mastitis.

breast cancer pathogenesis
the major risk factors for the development of breast cancer are hormonal and genetic therefore breast carcinomas can be divided into:
sporadic cases, probably related to hormonal exposure.
hereditary cases, associated with germline mutations.
hereditary breast cancer
the inheritance of a susceptibility gene or genes is the primary cause of approximately 12% of breast cancers.
the probability of a hereditary etiology increases in the cases of:
1-multiple affected first-degree relatives.
2-individuals are affected before menopause and/or have multiple cancers.
3-there are family members with other specific cancers.
4-mutations in brca1 and brca2 account for the majority of cancers attributable to hereditary causes.
5-mutations in brca1 located on chromosome 17q21also markedly increase the risk of developing ovarian carcinoma, which occurs in as many as 20-40% of carriers.
the finding of a positive test for the mutation can lead to an distressing decision on the part of the affected individual, the main choices being close follow-up and prophylactic mastectomy.
breast carcinomas are commonly poorly differentiated and triple negative (basal-like), and have p53 mutations
6-brca2 located on chromosome 13q12.3confers a smaller risk for ovarian carcinoma (10- 20%) but is associated more frequently with male breast cancer.
7-p53 is the most commonly mutated gene in sporadic breast cancers

sporadic breast cancer
the major risk factors for sporadic breast cancer are related to hormone exposure and these are: gender, age at menarche and menopause, reproductive history, breastfeeding, and exogenous estrogens.
hormones increase the risk of carcinoma by the following mechanisms:
1 - hormonal exposure increases the number of breast epithelial cells by stimulating breast growth during puberty, menstrual cycles, and pregnancy.
2 - exposure also drives cycles of proliferation that place cells at risk for dna damage.
3-once premalignant or malignant cells are present, hormones can stimulate their growth, as well as the growth of normal epithelial and stromal cells that may aid and assist tumor development.
diagnosis of breast carcinoma

1- history
2-examination
3-investigation:
a-radiological (mammography, ultrasound)
b-lab
1- fna.
2-true cut biopsy.
3-incisional biopsy.
4-excisinal biopsy.
5-immunohistochemistry
6-gencs


classification of breast carcinoma
greater than 95% of breast malignancies are adenocarcinomas, which are divided into
1 - carcinoma in situ
ductal carcinoma in situ
lobular carcinoma in situ


2 - invasive carcinoma
no-special-type carcinoma (ductal)
lobular carcinoma
tubular/cribriform carcinoma
mucinous (colloid) carcinoma
medullary carcinoma
papillary carcinoma
metaplastic carcinoma


ductal carcinoma in situ (dcis)
dcis consists of a malignant population of cells limited to ducts and lobules by the basement membrane. the myoepithelial cells are preserved.
most are detected as a result of calcifications less commonly, as a mammographic density or a vaguely palpable mass. rarely, dcis produces a nipple discharge or is detected as an incidental finding upon biopsy for another lesion.
morphology:: many morphologic variants of dcis exist, such as comedocarcinoma , solid ,cribriform ,papillary,micropapillary. some cases of dcis have a single growth pattern, but the majority show a mixture of patterns .
comedocarcinoma is characterized by the presence of solid sheets of pleomorphic cells with “high-grade” hyperchromatic nuclei and lacking connective tissue support. necrosis is always present and constitutes an important diagnostic sign, whether in the form of a large central focus or of individual tumor cells.coarse calcification often supervenes in these necrotic areas.
noncomedo dcis consists of a monomorphic population of cells with nuclear grades ranging from low to high. several morphologic variants can be seen. in cribriform dcis, intraepithelial spaces are evenly distributed and regular in shape (cookie cutter–like).
solid dcis completely fills the involved spaces .
papillary dcis grows into spaces along fibrovascular cores that typically lack the normal myoepithelial cell layer .
micropapillary dcis is recognized by shows elongated epithelial projections projecting into the glandular lumen these lack connective tissue support, may have a space at the base, and often show a bulbous expansion at the tip.
all women with dcis were treated with mastectomy, usually followed by radiation.if untreated, women with small, low-grade dcis develop invasive cancer at a rate of about 1% per year.
lobular carcinoma in situ (lcis)
lcis is always an incidental biopsy finding, since it is not associated with calcifications nor produce mammographic densities. lcis is more common in young women, with 80-90% of cases occurring before menopause. it is multicentric in approximately 70% of cases and bilateral in approximately 30–40%.
lcis consist of dyscohesive cells with oval or round nuclei and small nucleoli, the cells lack the cell adhesion protein e-cadherin, resulting in the cells appearing rounded without attachment to adjacent cells.

women with lcis develop invasive carcinomas at a frequency similar to that of women with untreated dcis, treatment choices include bilateral prophylactic mastectomy, or, close clinical follow-up and mammographic screening.

invasive (infiltrating) carcinoma
clinically
invasive carcinoma almost always presents as a palpable mass that may be fixed to the chest wall or cause dimpling of the skin. palpable tumors are associated with axillary lymph node metastases in over 50% of patients, retraction of the nipple may develop. lymphatics may become so involved as to block the local area of skin drainage and cause lymphedema and thickening of the skin. in such cases, tethering of the skin to the breast by cooper ligaments mimics the appearance of an orange peel, an appearance referred to as peau d orange.
the term inflammatory carcinoma is reserved for tumors that present with a swollen, erythematous breast, this gross appearance is caused by extensive invasion and obstruction of dermal lymphatics by tumor cells.
paget disease of the nipple
paget disease is the name given to a crusted lesion of the nipple caused by breast carcinoma, its a rare manifestation of breast cancer and account 1- 4% of cases. it is accompanied in nearly all instances by an underlying dcis of breast carcinoma, with or without associated stromal invasion.
clinically a unilateral erythematous eruption with a scale crust. pruritus is common, and the lesion may be mistaken for eczema.
microscopically large clear cells with atypical nuclei are seen within the epidermis, usually concentrated along the basal layer,the cells can be isolated or in clusters, and sometimes they form small glandular structures.
a palpable mass is present in 50- 60% of women with paget disease, the carcinomas are usually poorly differentiated, er negative, and overexpress her2/neu.
rarely, breast cancer presents as an axillary nodal metastasis or distant metastasis before cancer is detected in the breast.

invasive ductal carcinoma, no special type (nst)
invasive carcinomas of no special type include the majority of carcinomas (70 - 80%).
morphology.
grossly
most tumors are firm to hard and have an irregular border, when cut they typically produce a resistant gritty sensation, and shows a yellowish-gray cut surface,with trabeculae radiating through the surrounding parenchyma into the fat.
microscopically
well-differentiated carcinomas show prominent tubule formation, small round nuclei, and rare mitotic figures
moderately differentiated carcinomas may have tubules, but solid clusters or single infiltrating cells are also present. these tumors have a greater degree of nuclear pleomorphism and contain mitotic figures.
poorly differentiated carcinomas often invade as nests or solid sheets of cells with enlarged irregular nuclei. a high proliferation rate and areas of tumor necrosis are common.
invasive lobular carcinoma
invasive lobular carcinomas usually present as a palpable mass or a mammographic density with irregular borders.
lobular carcinomas have been reported to have a greater incidence of bilaterality.
the actual fraction of women who develop invasive carcinomas in the contralateral breast is only 5-10%.
morphology
microscopically
the histologic hallmark is the presence of dyscohesive infiltrating tumor cells, often arranged in single file or in loose clusters or sheets, tubule formation is absent.signet-ring cells containing an intracytoplasmic mucin dropinglet are common. desmoplasia may be minimal or absent.
lobular carcinomas have a different pattern of metastasis than other breast cancers. metastasis tends to occur to the peritoneum and retroperitoneum, the leptomeninges (carcinoma meningitis), the gastrointestinal tract, and the ovaries and uterus.

immunohistochemistry
estrogen and progesterone receptors (er, pr).
these are nuclear hormone receptors, and represent an important predictor of response to hormonal therapy, 80 % of carcinomas that are er and pr positive respond to hormonal manipulation, whereas only about 40% of those with either er or pr alone respond. er-positive cancers are less likely to respond to chemotherapy. conversely, cancers that fail to express either er or pr have a less than 10% likelihood of responding to hormonal therapy but are more likely to respond to chemotherapy.
her2/neu.
her2/neu is a transmembrane receptor, its overexpression is associated with poorer survival, but its main importance is as a predictor of response to certain drugs like (herceptin).
genetic study:

recently developed techniques that examine the dna, rna, and proteins of carcinomas have provided new molecular classifications of breast cancers.
gene expression profiling has identified four major patterns of gene expression in the ductal carcinoma group: luminal a, luminal b, basal-like, and her2 positive.
these molecular classes correlate with prognosis and response to therapy, and thus have taken on clinical importance.

1-luminal a (40- 55% of nst cancers): this is the largest group and consists of cancers that are er positive and her2/neu negative. the majority are well- or moderately differentiated, and most occur in postmenopausal women, these cancers are generally slow growing and respond well to hormonal treatments.

2-luminal b
3-basal-like
4-her2 positive

use of immunohistochemistry as surrogate marker for the molecular subtypes of breast cancer

molecular subtype
immunoprofile luminal a luminal b her2/neu basal-like
er, pr er and/or pr+ er and/or pr+ er–, pr– er–, pr–
her2 and others her2–
low ki-67 (<14%) her2+ or her2–
ki-67 =14% her2+ her2–
ck5/6 and/or egfr+


prognostic and predictive factors
the outcome for women with breast cancer varies widely. many women have a normal life expectancy, whereas others have only a 10% chance of being alive in 5 years.
the major prognostic factors are as follows:
1. invasive carcinoma versus in situ disease.
2. distant metastases.
3. lymph node metastases
4. tumor size.
5. locally advanced disease.
6. inflammatory carcinoma.


minor prognostic and predictive factors
• histologic subtype.
• histologic grade.
• estrogen and progesterone receptors.
• her2/neu.
• lymphovascular invasion.
• proliferative rate.
• dna content.
• response to neoadjuvant therapy.