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Breast Pathology 1. Describe the causative factors and potential complications of acute mastitis. Zen Seeker, Stevens and Lowe 421 Infections of the breast are associated with lactation, the organisms (commonly Staph aureus and Strep) gaining access through cracks and fissure in the nipple and areola. The initial infection causes an acute mastitis, with painful tender enlargement of the breast, which generally resolves after treatment with appropriate antibiotics. Without antibiotic therapy, bacterial mastitis is often followed by the development of a breast abscess, which may require surgical drainage Chronic inflammation of the breast is rare, but may develop after incomplete resolution of an acute mastitis. Tuberculous mastitis may occur, but is uncommon in western countries Raylene L S&L 421 Acute mastitis – infection of the breast, usually Staph aureus and strep, which gain access through cracks in the nipple an areola. Causes painful enlargement of the breast and often requires antibiotic treatment, otherwise bacterial mastitis develops and can lead to a breast abscess. Abscesses sometimes require surgical drainage. Chronic inflammation is rare but can occur after incomplete resolution of an acute mastitis. Janelisa Stevens 421 Associated with lactation, acute mastitis is usually caused by S. aureus and Strep. The organisms enter through cracks and fissures in the nipple and areola. If not treated with antibiotics, an abscess will form which may require surgical drainage. 2. Describe the causative factors, pathologic process, and any association with breast cancer of each of the following causes of breast lumps: fat necrosis fibrocystic change fibroadenoma papilloma Zen Seeker, Stevens and Lowe 421-422 fat necrosis Causative factors Following episodes of trauma, localized areas of inflammation of the breast may occur as a result of fat necrosis. pathologic process Trauma causes necrosis of adipose tissue, precipitating an inflammatory and reparative response to the dead fat cells (fig 20.1) any association with breast cancer Organization with fibrous repair takes place, producing a hard, irregular breast lump. The main clinical significance of this condition is that patients may not be able to recall a history of trauma, and these lesions often clinically resemble a breast carcinoma, e.g. the presence of skin tethering. Stevens and Lowe 422 fibrocystic change Causative factors The cause of fibrocystic disease is uncertain. Most believe that it is due to disturbances of cyclical ovarian estrogen and progesterone levels, accompanied by altered responsiveness of breast tissues in women approaching the menopause pathologic process Fibrocystic change is characterized by hyperplasic over-growth of components of the mammary unit, i.e. lobules, ductules and stroma. There is epithelial overgrowth of lobules and ducts, often termed adenosis or epitheliosis, and fibrous overgrowth of specialized hormone-responsive lobule-supporting stroma. Unequal growth of epithelial and stromal elements occurs, giving rise to a range of solid and cystic nodules within the breast, broadly termed fibroadenomatoid hyperplasia or fibroadenosis. This presents as palpable thickening and nodularity of breast tissue, but may also result in the development of single breast lumps any association with breast cancer In a small proportion of cases, it increases the chances of later development of carcinoma of the breast. It must be emphasized that in the majority of cases, patients with fibrocystic disease in the absence of epithelial hyperplasia are not at increased risk from later development of carcinoma of the breast Stevens and Lowe 425 fibroadenoma Causative factors Most frequently seen in women aged 25-35 years as solitary discrete lesions, but histologically identical areas may also be a component of fibrocystic disease. The fibroadenoma is therefore best regarded as a form of hormone-dependent nodular hyperplasia, rather than a true benign tumor pathologic process A benign, localized proliferation of breast ducts and stroma true neoplasm vs. nodular form of hyperplasia any association with breast cancer Tubular adenomas – no associate risk of developing carcinoma Stevens and Lowe 424-425 papilloma Causative factors -? pathologic process Solitary papillomas are most common in middle-aged women and are a common cause of a bloody nipple discharge. any association with breast cancer Multiple papillomas – associated with increased risk of later development of breast carcinoma Raylene L S&L 421-422 Breast lumps from fat necrosis Cause: trauma Pathological process: trauma causes necrosis of adipose tissue causing an inflammatory and fibrous reparative response to the dead cells which produces a hard, irregular lump. Association with breast cancer: clinically resemble a carcinoma, but patient may not recall the trauma. Breast lumps from fibrocystic changes Cause: unknown but thought to be disturbance of cyclical ovarian estrogen and progesterone levels and altered breast tissue responsiveness in women approaching menopause. Pathological process: hyperplastic over growth of parts of the breast (lobules, ductules and stroma) causing a range of solid and cystic nodules within the breast, broadly termed fibroadenomatoid hyperplasia or fibroadenosis. Often a palpable thickening an nodularity of breast tissue but sometimes a single breast lump. Association with breast cancer: increases the chances of later development of carcinoma in a small percentage of cases Breast lumps from fibroadenoma Cause: a hormone dependent nodular hyperplasia rather than a truly benign tumor. Usually seen in women aged 25-35, years old. May be histologically identical to fibrocystic disease. Pathological process: a benign, local proliferation of breast ducts and stroma that appear rubbery , firm and well circumscribed and are often mobile in the breast. Association with breast cancer: no risk Breast lumps from papilloma Cause: unknown Pathological process: delicate supporting stroma covered by a double layer of cuboidal or low columnar epithelial cells that resemble the lining of a duct, most commonly seen in middle aged women presenting with a bloody nipple discharge. Association with breast cancer: no increased risk in single papillomas but increased risk in younger women with multiple papillomas (though much less common). Janelisa Stevens 421-424 • fat necrosis – trauma to the breast causes necrosis of adipose tissue, precipitating an inflammatory and reparative response to the dead fat cells, producing a hard irregular breast lump. If a patient cannot recall the trauma, the lump may be mistaken for carcinoma • fibrocystic change – unknown cause but may be hormone related; characterized by epithelial overgrowth of lobules, and ducts, and fibrous overgrowth of specialized hormone-responsive lobule-supporting stroma. Unequal growth of epithelial and stromal elements leads to palpable thickening and nodularity of breast tissue as well as single breast lumps which must be distinguished from a malignancy. In a small number of cases, it may increase the chance of developing breast cancer. • Fibroadenoma – benign, hormone dependant nodular hyperplasia that is typically 1-4 cm in diameter, firm, rubbery, well-circumscribed, and mobile. The epithelial component forms gland-like structures lined by duct-type epithelium. The stromal component is a loose, cellular fibrous tissue around the epithelial areas. • Papilloma – occur in mammary duct epithelium. Lesions are 1-2 cm, consist of delicate stroma covered by a double layer of cuboidal or low columnar epithelial cells. Solitary papillomas are usually located in the larger lactiferous ducts near the nipple, most common in middle-aged women, commonly cause a bloody discharge from the nipple, and are rarely associated with malignancy. Multiple papillomas are less common, located in smaller ducts deeper in the breasts of younger women, and are associated with an increased risk of later development of breast cancer. 3. Describe the following aspects of female breast cancer: two most common invasive types Paget’s disease characteristic pattern of spread prognosis as related to stage or grade of tumor(don’t memorize numbers, just understand the concepts) prognosis as related to histologic type and hormone receptor status role of oncogenes and BRCA1, BRCA2 genes epidemiological risk factors Zen Seeker, Stevens and Lowe 425 two most common invasive types Invasive lobular carcinomas Invasive ductal carcinomas Stevens and Lowe 424-428 Paget’s disease Paget’s disease of the nipple is a pattern of spread of a ductal carcinoma of the breast. Patients develop reddening and thickening of the skin of the nipple and areola, sometimes followed by ulceration resembling eczema. Histologically the epidermis of the nipple and areola is infiltrated by large pale pleomorphic neolplastic epithelial cells, termed ‘Paget’s cell’ (fig 20.13). Eczematous or inflammatory conditions of the nipple must always be regarded with suspicion, and biopsy should be performed to exclude Paget’s disease. Stevens and Lowe 428 characteristic pattern of spread Carcinoma of the breast spreads in a characteristic fashion Carcinoma of the breast spreads in a characteristic fashion, which explains several of the common clinical manifestations of the disease. Matastatic disease and recurrence of tumor may be a late event, occurring many years after local treatment of disease. Local spread is into adjacent breast, into overlying skin (skin tethering), and deeply into pectoral muscles (deep fixation of tumor). Lymphatic spread is into local lymphatics in the breast. When lymphatic drainage of the skin is involved, this gives rise to a peau d’orange appearance. Spread to auxiliary lymph nodes and nodes in the internal mammary chain is caused by embolization of tumor to nodes. Vascular spread leads to dissemination of tumor to distant sites. The preferred sites for metastasis are bone (pathological fractures, hypercalcemia, leukoerythoblastic anemia, spinal-cord compression), lung (breathlessness), pleura (effusion and breathlessness), and ovary (Krukenberg tumor, see page 415). Other sites are commonly involved but with less consistency. Stevens and Lowe 428-429 prognosis as related to stage or grade of tumor (don’t memorize numbers, just understand the concepts) Stage of tumor is widely regarded as the most powerful prognostic factor. Several staging systems are in use including the TNM classification (page 88). Although staging systems vary in precise criteria, there are common features: • Large primary tumor size (> 2 cm) or fixation to local tissues is associated with poor prognosis • Spread to nodes is associate with significant reduction in 5-year survival from around 80% to 60% • Vascular spread is associated with a poor prognosis and a 5-year survival of about 10% The link between early stage and good clinical outcome is one of the main reasons for promoting breast-screening programs. Grade of tumor assessed by looking at degree of gland formation, pleomorphism and numbers of mitoses, provides additional prognostic data. Carcinomas can be assigned to three groups, which are related to survival at 10 years: Grade I (85%) Grade II (60%) Grade III (45%) In some recent studies, grade of tumor (when carefully assessed according to objective criteria) is considered to allow more accurate prediction of survival than stage. Stevens and Lowe 429 prognosis as related to histologic type and hormone receptor status Histological type of tumor is another prognostic factor, some specialized types of carcinoma of the breast (tubular, mucoid) being associated with better prognosis than the common ductal and lobular types, as they have a low propensity for metastasis. Hormone receptor status - Prognosis can also be related to Hormone receptor status. Patients with breast tumors that express receptors for estrogen and progesterones have a longer disease-free survival than those that do not. This is a reflection of tumor differentiation and likely response to anti-hormone therapy. Stevens and Lowe 429 role of oncogenes and BRCA1, BRCA2 genes Within each grade and stage of breast cancer there is still some variation in survival rates. Expression of oncogenes is being investigated to see if it explains such variation. In keeping with many other tumors, breast cancer is associated with several oncogene abnormalities, particularly abnormalities of p 53 (see page 94). However, studies show that such factors do not contribute to determining survival. The expression of the neu oncogene (also called ‘HER-2’ or ‘c-erb-B2’) has shown a small contribution to survival in several studies. Stevens and Lowe 429-430 epidemiological risk factors The cause of breast cancer is uncertain, but there are several defined risk factors Epidemiological studies have shown that breast cancer is related to several risk factors, although the cause is uncertain. Geographical. The incidence of disease is five times greater in developed western countries than in less developed areas. Familial breast cancer. There is an increased genetic risk of developing breast cancer in about 5% of all cases (see pink box on page 429) Proliferative breast disease. Epithelial hyperplasia is associated with an approximately two-fold increased risk of development of carcinoma. Atypical hyperplasia is associated with a five-fold increased risk in women with no family history of breast cancer, but the risk increases 11-fold in women with a family history of breast cancer. Early onset of menarche (10 years rather that 15 years) carries a three-fold increased risk. Late birth of first child (35 years rather than 20 years) carries a three-fold increased risk. Late menopause (55 years rather than 45 years) carries a three-fold increased risk. Nulliparous state. Brest cancer is more frequent than in multiparous women Exogenous hormones. Marginal increase in patients on hormone-replacement therapy after menopause. No conclusive association with use of oral contraceptives. Dietary factors. Increased risk of development of breast cancer has been linked to obesity in the pre-menopausal period and also to a high alcohol intake. Raylene L S&L 425 Two most common invasive types of breast cancer: Invasive lobular carcinoma Or Invasive ductal carcinoma ex: Paget’s disease – reddening and thickening of the skin of the nipple and areola sometimes with ulceration resembling eczema. Eczematous or inflammatory conditions of the nipple must always be regarded with suspicion and biopsied to exclude Paget’s. Pattern of spread of carcinoma of the breast : Is characteristic and explains several common clinical manifestations of the disease. Local – spread is into adjacent breast, into overlying skin (skin tethering) and deeply into pectoral muscles (deep fixation of tumor) Lymphatic – spread is into local lymphatics and appears like the skin of an orange ( peau d’orange). Spread to axillary lymph nodes and internal mammary nodal chain is caused by embolization of tumor. Vascular – spread leads to metastasis of tumor to distant sites, often bone, lung, pleura, and ovary. Other sites can be involved but are less common. Prognosis by stage: [within each stage and grade there is still some variation (~) in survival rates] Large ~= poor Spread to nodes ~= 5 years in about 60-80% Vascular ~= 5 years in about 10% Grade based on 10 year survival (thought to be more accurate prediction than stage): Grade I (85%) Grade II (60%) Grade III (45%) Histological prognosis: Some specialized types of carcinomas (tubular and mucoid) have a lower propensity for metastasis than ductal and lobular types. Hormone receptor status prognosis: Tumors that express receptors for estrogen and progesterone have a longer disease free survival rate than those that do not because of tumor differentiation likely from anti-hormone therapy. Oncogenes: Do not seem to explain survival variations, although the neu oncogen (HER2) has shown a small contribution in some studies. BRCA1 and BRCA2 genes: A fully penetrant dominant genetic predisposition to breast cancer. Risk factors include: Early onset of disease Bilateral breast cancers Patients with both ovarian and breast cancer Several affected members in the family Families where there are breast, ovarian, endometrial and colon cancers or sarcomas in both males and females. Epidemiological risk factors S&L 429 Cause is uncertain. Geographical – 5 times greater in western countries Familial – 5% greater risk in families with affected members. Proliferative breast disease – 2-11% greater risk depending upon: Early onset of menarche (10 yrs. vs. 15 yrs.) Late birth of first child (35 yrs. vs. 20 yrs.) Late menopause (55 yrs. vs. 45 yrs.) Nulliparaous vs. multiparaous Exogenous hormones [HTR and ? oral contraceptives) Dietary factors (pre menopausal obesity; high alcohol intake) Janelisa Stevens 427-430 • Two most common invasive types are invasive ductal carcinomas (most common) and invasive lobular carcinomas (2nd most common) • Paget’s disease is a pattern of spread of a ductal carcinoma. The skin of the nipple and areola reddens and thickens, and sometimes ulcerates to look like eczema. Histologically, the epidermis is infiltrated by large pale pleomorphic neoplastic cells called Paget’s cells. • characteristic pattern of spread o local spread is into adjacent breast, into overlying skin (skin tethering) and deeply into pectoral muscles (deep fixation of tumor) o lymphatic spread is into local lymphatics of the breast giving rise to peau d’orange appearance. Spread to other nodes is by embolization of tumor to nodes. o Vascular spread leads to dissemination of tumor to distant sites. Common sites for metastasis are bone, lung, pleura, and ovary. • prognosis as related to stage or grade of tumor (don’t memorize numbers, just understand the concepts) – the stage is widely regarded as the most powerful prognostic factor. Detection at an early stage is linked to good clinical outcome. The grade of tumor, of which there are 3, is assessed by looking at degree of gland formation, pleomorphism and number of mitoses. Grade I has the highest percentage of survival at 10 years. • prognosis as related to histologic type and hormone receptor status – Some histological types, like tubular and mucoid, are associated with a better prognosis than the ductal and lobular types, because they don’t tend to metastasize. Patients with tumors that express receptors for estrogen and progesterones have a longer disease-free survival than those that do not because they respond to anti-hormone therapy. • role of oncogenes and BRCA1, BRCA2 genes – expression of oncogenes is being investigated to see if it explains why there is variation in survival rates within each grade and stage of breast cancer. Within families that have a strong history of breast cancer, many have an abnormality in the BRCA1 gene which is also associated with ovarian and prostate cancer. Another familial breast cancer syndrome is associated with the BRCA2 gene. • epidemiological risk factors o geographical – incidence of disease is 5x higher in western developed countries o familial breast CA – there is an increased genetic risk of developing breast CA in about 5% of all cases o proliferative breast disease – epithelial hyperplasia is associated with an approximate 2-fold increased risk. Atypical hyperplasia has 5-fold increase if no family history, but increase is 11-fold if history is present o early onset of menarche – 3-fold risk if at 10 years versus 15 years o late birth of first child – 3-fold risk if at 35 years versus 20 years o late menopause – 3-fold risk if at 55 years versus 45 years o nulliparous state – breast CA more frequent than in multiparous women o exogenous hormones – marginal increase in patients on HRT after menopause; no conclusive association with BCP o dietary factors – increased risk linked to obesity in the pre-menopausal period and also to high ETOH intake 4. Briefly describe the following examples of male breast disease: adenocarcinoma of the breast gynecomastia Zen Seeker, Stevens and Lowe 431 adenocarcinoma of the breast Carcinoma of the breast in men is uncommon Adenocarcinoma of the breast in men accounts for only 1% of all cases of breast cancer. Lesions fall into the same spectrum as those seen in the female breast cancer, with the exception of lobular carcinoma in situ (as the male breast contains no lobular tissue). Paget’s disease (see page 428) may also be seen in the male, and any rash of the nipple should be viewed with the same suspicion as in the female. The prognosis of carcinoma of the male breast is similar to that for females. Invasion of the chest wall is seen more often in males, possibly because of the small size of the breast, and so lesions are more often locally advanced at diagnosis. Squamous carcinoma of the nipple may also be seen in men, but it is a very uncommon tumor. Stevens and Lowe 431 Gynecomastia Gynecomastia of male breast is most commonly idiopathic, but may be a sign of underlying endocrine disturbance The male breast is normally rudimentary and inactive, consisting of fibroadipose tissue containing atrophic mammary ducts. Enlargement of the male breast, which is termed gynecomastia, may be unilateral (70% of cases) or bilateral. In most cases it is idiopathic. Other causes include: Klinefelter’s syndrome (page 69). Estrogen excess (cirrhosis, puberty, adrenal tumor, exogenous estrogens). Gonadotrphin excess (testicular tumor). Prolactin excess (hypothalamic or pituitary disease). Drug-related (spironolactone (steroid derivative used as a diuretic primarily in the treatment of hypertension), chlorpromazine, digitalis). There is enlargement of the breast as a firm, raised, rubbery mass behind the nipple (fig 20.16) Raylene L S&L 431 Male breast cancer Adenocarcinoma - accounts for only 1% of all cases of breast cancer. Lesions characteristic of female breast cancer except lobular carcinoma in situ since male breast does not have lobular tissue. Paget’s disease also seen in the male, view rash of the nipple with same suspicion. Prognosis is similar to females. Invasion of the chest wall seen more often in males than females probably because of the small size of the breast, consequently lesions are more often locally advanced at diagnosis. Squamous carcinoma of the nipple may also be seen in men but is very uncommon. Gynecomastia – (enlargement of the breast) – usually the male breast is rudimentary and inactive with fibroadipose tissue and atrophic mammary ducts. Enlargement may be unilateral (70%) or bilateral but usually idiopathic. May be caused by Klinefelter’s, or excess estrogen from cirrhosis, puberty, adrenal tumor or exogenous estrogens. Janelisa Stevens 431 • adenocarcinoma of the breast – accounts for 1% of all breast CA. Lesions are same as in females, except there is no lobular carcinoma, and Paget’s may also occur. Prognosis is similar except that invasion of chest wall is seen more often in males, perhaps because they have less breast tissue. • Gynecomastia – may be unilateral or bilateral. It is most often idiopathic but may be caused by Klinefelter’s, estrogen excess (from cirrhosis, in puberty, adrenal tumor, exogenous estrogens), gonadotropin excess (from testicular tumor), prolactin excess (as in hypothalamic or pituitary disease), or be drug related.