patho sheet # 5 (breast) - Mohammad Bader

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Fibroadenoma

Fibroadenoma is by far the most common benign neoplasm of the female breast. An absolute or relative increase in estrogen activity is thought to contribute to its development, and indeed similar lesions may appear with fibrocystic changes (fibroadenomatoid changes). Fibroadenomas usually appear in young women; the peak incidence is in the third decade of life.

Morphology

The fibroadenoma occurs as a discrete, usually solitary, freely movable nodule, 1 to 10 cm in diameter. Rarely, multiple tumors are encountered and, equally
rarely, they may exceed 10 cm in diameter (giant fibroadenoma).

Histologically there is a loose fibroblastic stroma containing ductlike, epithelium-lined spaces of various forms and sizes.

Although in some lesions the ductal spaces are open, round to oval, and fairly regular (pericanalicular fibroadenoma), others are compressed by extensive proliferation of the stroma, so that on cross-section they appear as slits or irregular, star-shaped structures (intracanalicular fibroadenoma).

Clinically, fibroadenomas usually present as solitary, discrete, movable masses. They may enlarge late in the menstrual cycle and during pregnancy. After menopause they may regress and calcify.

Cytogenetic studies reveal that the stromal cells are monoclonal and so represent the neoplastic element of these tumors. The basis of ductal proliferation is not clear; perhaps the neoplastic stromal cells secrete growth factors that induce proliferation of epithelial cells. Fibroadenomas almost never become malignant.


Phyllodes Tumor
These tumors are much less common than fibroadenomas and are thought to arise from the periductal stroma and not from preexisting fibroadenomas. They may be small (3-4 cm in diameter), but most grow to large, possibly massive size, distending the breast. On gross section they exhibit leaflike clefts and slits, they have been designated phyllodes (Greek for "leaflike") tumors.

The most ominous change is the appearance of increased stromal cellularity with anaplasia and high mitotic activity, accompanied by rapid increase in size, usually with invasion of adjacent breast tissue by malignant stroma.

Most of these tumors remain localized and are cured by excision; malignant lesions may recur. Only the most malignant, about 15% of cases, metastasize to distant sites.

Intraductal Papilloma
This is a neoplastic papillary growth within a duct. Most lesions are solitary, found within the principal lactiferous ducts.
They present clinically as a result of:
(1) the appearance of serous or bloody nipple discharge
(2)The presence of a small subareolar tumor a few millimeters in diameter
(3)Rarely, nipple retraction.



The tumors are usually solitary and less than 1 cm in diameter, consisting of branching growths within a dilated duct or cyst. Histologically, they are composed of multiple papillae with ??? covered by cuboidal epithelial cells that are frequently double layered, with the outer epithelial layer overlying a myoepithelial layer.

In some cases there are multiple papillomas in several ducts or intraductal papillomatosis. These lesions sometimes become malignant, whereas the solitary papilloma almost always remains benign.

Papillary carcinoma must also be excluded; it often lacks a myoepithelial component and shows either severe cytologic atypia or monotonous ductal epithelium.

Carcinoma

Risk factor:
The risk for this form of neoplasia is significantly higher in North America and northern Europe than in Asia and Africa.

Breast cancer is uncommon in women younger than age 30. Thereafter, the risk increases throughout life, but after menopause the upward slope of the curve almost plateaus.

About 5% to 10% of breast cancers are related to specific inherited mutations. Women are more likely to carry a breast cancer susceptibility gene:
1- If they develop breast cancer before menopause,
2- have bilateral cancer,
3- have other associated cancers (e.g., ovarian cancer),
4- belong to certain ethnic groups.

About half of women with hereditary breast cancer have mutations in gene BRCA1 (on chromosome 17q), and an additional one-third have mutations in BRCA2 (on chromosome l3q). Both of these genes are thought to function in DNA repair (Chapter 6). They act as tumor suppressor genes. However, most carriers will develop breast cancer by the age of 70 years, as compared with only 7% of women who do not carry a mutation.

Less common genetic diseases associated with breast cancer are the Li-Fraumeni syndrome (caused by germ-line mutations in p53), Cowden disease and ataxia telangiectasia.

Hormone replacement therapy posmenopausally is associated with an increased risk of breast cancer. The result are contradictory for oral contraceptive pills that seems not to increase the risk even in women who used them for long periods of time and those who had family history of breast cancer.

Ionizing radiation to the chest before age 30 increases the risk of breast cancer. The low doses of radiation associated with mammographic screening have little, if any, effect on the incidence of breast cancer.

Obesity is a recognized risk factor in postmenopausal women

Pathogenesis:

Genetic Changes:
In addition to those producing the well-established familial syndromes, genetic changes have also been implicated in the genesis of sporadic breast cancer. Mutations affecting proto-oncogenes and tumor suppressor genes contribute to the oncogenesis.

Among the best characterized is overexpression of the HER2/NEU proto-oncogene, which has been found to be amplified in up to 30% of invasive breast cancers and its overexpression is associated with a poor prognosis.

Hormonal Influences:

Endogenous estrogen excess, or more accurately, hormonal imbalance, clearly has a significant role.

Estrogens stimulate the production of growth factors by normal breast epithelial cells such as transforming growth factor α, platelet-derived growth factor, and fibroblast growth factor elaborated by human breast cancer cells, to create an autocrine mechanism of tumor development.

Environmental Variables:

Geographic, irradiation and exogenous estrogens, etc

Morphology:


Cancer of the breast affects the left breast slightly more often than the right. About 4% of women with breast cancer have bilateral primary tumors or sequential lesions in the same breast. The locations of the tumors within the breast are:

Upper outer quadrant
50%
Central portion
20%

Lower outer quadrant
10%

Upper inner quadrant
10%

Lower inner quadrant 10%


Breast cancers are classified into those that have not penetrated the limiting basement membrane (noninvasive) and those that have (invasive). The chief forms of carcinoma of the breast are classified as follows:
A. Noninvasive
1. Ductal carcinoma in situ (DCIS; intraductal carcinoma)
2. Lobular carcinoma in situ (LCIS)
B. Invasive (infiltrating)
1. Invasive ductal carcinoma ("not otherwise specified")
2. Invasive lobular carcinoma
3. Medullary carcinoma
4. Colloid carcinoma (mucinous carcinoma)
5. Tubular carcinoma
6. Other types

Of these, invasive ductal carcinoma is by far the most common. Because it usually has an abundant fibrous stroma, it is also referred to as scirrhous carcinoma.
Noninvasive (in Situ) Carcinoma (including Paget Disease): both are confined by a basement membrane and do not invade into stroma or lymphovascular channels.
DCIS has a wide variety of histologic appearances and include solid, comedo, cribriform, papillary, micropapillary, and clinging types. Necrosis may be present in any of these types. Nuclear appearance ranges from bland and monotonous (low nuclear grade) to pleomorphic (high nuclear grade). The comedo subtype is distinctive and is characterized by cells with high-grade nuclei with extensive central necrosis
Calcifications are frequently associated with DCIS. The incidence of DCIS markedly increases from less than 5% of breast cancers in unscreened populations up to 40% of those screened by mammography, primarily because of the detection of calcifications.
The prognosis for DCIS is excellent, with over 97% long-term survival after simple mastectomy. Some women develop distant metastases without local recurrence; such cases usually have high-nuclear-grade DCIS and probably had undetected small areas of invasion. At least one-third of women with small areas of untreated low-nuclear-grade DCIS will eventually develop invasive carcinoma. When invasive cancer does develop, it is usually in the same breast and quadrant as the earlier DCIS.
Paget disease of the nipple is caused by the extension of DCIS up to the lactiferous ducts and into the contiguous skin of the nipple. The malignant cells disrupt the normal epidermal barrier. The clinical appearance is usually of a unilateral crusting exudate over the nipple and areolar skin. In about half of cases, an underlying invasive carcinoma will also be present. Prognosis is based on the underlying carcinoma and is not worsened by the presence of Paget disease.
LCIS: like the low-nuclear-grade DCIS and unlike high-nuclear-grade DCIS, has a uniform appearance. The cells are monomorphic with bland, round nuclei and occur in loosely cohesive clusters in ducts and lobules.Intracellular mucin vacuoles (signet ring cells) are common. LCIS is virtually always an incidental finding, and, unlike DCIS, it does not form masses and is only rarely associated with calcifications. Therefore, the incidence of LCIS is almost unchanged in mammographically screened populations.
Approximately one-third of women with LCIS will eventually develop invasive carcinoma. Unlike DCIS, subsequent invasive carcinomas arise in either breast at significant frequency. About one-third of these cancers will be of lobular type but most are of no special type.
Invasive ductal carcinoma (of no specific type or not otherwise specified)
70% to 80% of cancers fall into this group. This type of cancer is usually associated with DCIS, but rarely LCIS is present. Most ductal carcinomas produce a desmoplastic response, which replaces normal breast fat (resulting in a mammographic density) and forms a hard, palpable mass. The microscopic appearance is heterogeneous, ranging from tumors with well-developed tubule formation and low-grade nuclei to tumors consisting of sheets of anaplastic cells.
About 2/3 express estrogen and progesterone receptors and 1/3 express HER2/NEU.
Inflammatory carcinoma is defined by the clinical presentation of an enlarged, swollen, erythematous breast, usually without a palpable mass. The underlying carcinoma is generally poorly differentiated and blocks numerous dermal lymphatic spaces by carcinoma results in the clinical appearance and the prognosis is extremely poor.
Invasive lobular carcinoma two-thirds of the cases are associated with adjacent LCIS. The cells invade individually into stroma and are often aligned in strands or chains. Lobular carcinomas, more frequently than ductal carcinomas, metastasize to cerebrospinal fluid, serosal surfaces, gastrointestinal tract, ovary and uterus, and bone marrow. Lobular carcinomas are also more frequently multicentric and bilateral (10% to 20%). Almost all of these carcinomas express hormone receptors, but HER2/NEU overexpression is very rare or absent. These tumors comprise fewer than 20% of all breast carcinomas.
Medullary carcinoma is a rare subtype of carcinoma constituting fewer than 1% of cases. These cancers consist of sheets of anaplastic cells with pushing borders. There is invariably a pronounced lymphoplasmacytic infiltrate. DCIS is usually absent. Occur with increased frequency in women with BRCA1 mutations. These carcinomas lack hormone receptors and do not overexpress HER2/NEU.
Colloid (mucinous) carcinoma is also a rare subtype. The tumor cells produce abundant quantities of extracellular mucin they often present as well-circumscribed masses and can be mistaken for fibroadenomas, express hormone receptors, and rare examples may overexpress HER2/NEU.
Tubular carcinomas rarely present as palpable masses but account for 10% of invasive carcinomas smaller than 1 cm found with mammographic screening. Microscopically, the carcinomas consist of well-formed tubules with low-grade nuclei. Lymph node metastases are rare, and prognosis is excellent. Virtually all tubular carcinomas express hormone receptors, but overexpression of HER2/NEU is unusual.
Spread of Breast Cancer
Spread eventually occurs through lymphatic and hematogenous channels. Lymph node metastases are present in about 40% of cancers presenting as palpable masses but in fewer than 15% of cases found by mammography screening. Outer quadrant and centrally located lesions typically spread first to the axillary nodes.

Those in the inner quadrants often involve the lymph node along the internal mammary arteries. Favored locations are the lungs, skeleton, liver, and adrenals. Metastases may appear many years after apparent therapeutic control of the primary lesion, sometimes 15 years later.

Clinical Course
Breast cancer is often discovered by the woman or her physician as a deceptively discrete, solitary, painless, and movable mass. At this time, the carcinoma is typically 2 to 3 cm in size, and involvement of the regional lymph nodes is already present in about half of patients. With mammographic screening, carcinomas are frequently detected before they become palpable. The average invasive carcinoma found by screening is around 1 cm in size, and only 15% of these have nodal metastases.

Prognosis is influenced by the following variables :
1. The size of the primary carcinoma. Invasive carcinomas smaller than 1 cm have an excellent prognosis in the absence of lymph node metastases and may not require systemic therapy.
2. Lymph node involvement and the number of lymph nodes involved by metastases. With no axillary node involvement, the 5-year survival rate is close to 90%.
3. Distant metastases. Patients who develop hematogenous spread are rarely curable, although chemotherapy may prolong survival.
4. The grade of the carcinoma. tubule formation, nuclear grade, and mitotic rate.
5. The histologic type of carcinoma. All specialized types of breast carcinoma have a somewhat better prognosis than carcinomas of no special type ("ductal carcinomas").
6. The presence or absence of estrogen or progesterone receptors. The presence of hormone receptors confers a slightly better prognosis. However, the reason for determining their presence is to predict the response to therapy. The highest rate of response (∼80%) in women whose tumors have both estrogen and progesterone receptors.
7. The proliferative rate of the cancer. High proliferative rates are associated with a poorer prognosis.
8. Aneuploidy. Carcinomas with an abnormal DNA content (aneuploidy) have a slightly worse prognosis
9. Overexpression of HER2/NEU: is associated with a poorer prognosis. However, the importance of evaluating HER2/NEU is to predict response to a monoclonal antibody ("Herceptin") to the gene product.


Mohammad Bader