Frequent loose bowel movements (4 to 6/day) may occur in normal infants; they are of no concern unless anorexia, vomiting, weight loss, failure to gain weight, or passage of blood also occurs. Breastfed infants tend to have frequent bowel movements, especially if they are not receiving solid food. The significance of diarrhea in a child at any age differs if it is acute (< 2 wk) or chronic (> 2 wk).
Etiology
Acute diarrhea is most likely infectious, especially if onset is sudden or accompanied by vomiting, bloody stools, fever, anorexia, or listlessness. Diagnosis is clinical, and treatment is supportive until the condition resolves spontaneously.
Chronic diarrhea is usually more significant. Causes include gluten-induced enteropathy, cystic fibrosis, sugar malabsorption, and allergic gastroenteropathy. Inflammatory bowel disease and some infections (eg, with Giardia) can also cause chronic diarrhea.
With gluten-induced enteropathy (celiac sprue), the gluten fraction of wheat protein causes intestinal mucosal damage and malabsorption of dietary fats, resulting in malnutrition, anorexia, and bulky, foul-smelling stools. The change in stools starts when wheat and other gluten-containing foods are added.
With cystic fibrosis, pancreatic insufficiency results in trypsin and lipase deficits, causing high fecal losses of protein and fats with consequent malnutrition and growth retardation. The stool is voluminous and often foul-smelling. Children who have cystic fibrosis often have respiratory problems and growth failure.
With sugar malabsorption, intestinal mucosal enzymes, such as lactase, which splits lactose to galactose and glucose, may be congenitally absent or temporarily deficient secondary to GI infection. Improvement after eliminating lactose (or other carbohydrates) from the diet or after substituting a lactose-free formula strongly suggests the diagnosis.
With allergic gastroenteropathy, cow's milk protein may cause diarrhea, often with vomiting and blood in the stools, but intolerance to the carbohydrate fraction of the ingested food should be suspected also. Symptoms often abate promptly when soy formula is substituted for cow's milk and return if cow's milk is reintroduced. Some infants intolerant of cow's milk are also intolerant of soy, so a formula that has had the protein pre-digested and does not contain the offending disaccharide may be needed. Spontaneous improvement usually occurs toward the end of the 1st yr.
Evaluation
History: History focuses on the quality and frequency of stools as well as accompanying signs and symptoms. Reports of vomiting or fever suggest GI infection. An accurate dietary history is critical. Reports of diarrhea beginning with the introduction of wheat cereal suggest celiac disease. Reports of variation in the stool pattern with certain elements of the diet suggest dietary intolerance. The persistent presence of blood in the stool mandates a careful search for more serious infection or GI disorder.
Physical examination: Examination focuses on overall appearance and signs of dehydration, growth parameters, and abdominal findings; poor growth suggests more serious disorders. Pulmonary status is also evaluated in children in whom cystic fibrosis is suspected.
Testing: Tests are ordered if history and examination suggest a chronic condition. Tests include electrolyte levels if there is dehydration; sweat Cl and Na levels for cystic fibrosis; cultures for viruses, bacteria, or parasites when infection appears to be present; and stool pH for disaccharide intolerance. Levels of certain antibodies are associated with celiac disease. Dietary manipulations can be diagnostic as well as therapeutic.
Treatment
Supportive care for acute diarrhea consists primarily of providing adequate oral (or rarely IV) rehydration. Antimotility agents (eg, loperamide: IMODIUM) are generally not recommended for infants and young children.
For chronic diarrhea, adequate nutrition must be maintained, particularly of fat-soluble vitamins. Specific treatments are indicated for certain causes (eg, gluten-free diet for those with celiac disease).
Oct 31, 2010
Breast Disorders
Breast symptoms (eg, pain, lumps, nipple discharge) are common, accounting for > 15 million physician visits/yr. Although > 90% of symptoms have benign causes, breast cancer is always a concern. Because breast cancer is common and may mimic benign disorders, the approach to all breast symptoms and findings is to conclusively exclude cancer.
History includes duration of symptoms; relation of symptoms to menses and pregnancy; presence and type of pain, discharge, and skin changes; use of drugs, including hormone therapy; personal and family history of breast cancer; and date and results of last mammogram.
Breast examination: Principles of examination are similar for physician and patient. Breasts are inspected for asymmetry in shape, nipple inversion, bulging, and dimpling (see Fig. 1: Breast Disorders: Breast Cancer Risks A and B). Although size differential is common, each breast should have a regular contour. An underlying cancer is sometimes detected by having the patient press both hands against the hips or the palms together in front of the forehead (see Fig. 1: Breast Disorders: Breast Cancer Risks C and D). In these positions, the pectoral muscles are contracted, and a subtle dimpling of the skin may appear if a growing tumor has entrapped a Cooper's ligament.
The axillary and supraclavicular lymph nodes are most easily examined with the patient seated or standing (see Fig. 1: Breast Disorders: Breast Cancer Risks E). Supporting the patient's arm during the axillary examination allows the arm to be fully relaxed so that nodes deep within the axilla can be palpated.
The breast is palpated with the patient seated and again with the patient supine, the ipsilateral arm above the head, and a pillow under the ipsilateral shoulder (see Fig. 1: Breast Disorders: Breast Cancer Risks F). The latter position is also used for breast self-examination; the patient examines the breast with her contralateral hand. Having the patient roll to one side, so that the breast on the examined side falls medially, may help differentiate breast and chest wall tenderness because the chest wall can be palpated separately from breast tissue.
The breast should be palpated with the palmar surfaces of the 2nd, 3rd, and 4th fingers, moving systematically in a small circular pattern from the nipple to the outer edges (see Fig. 1: Breast Disorders: Breast Cancer Risks G). Precise location and size (measured with a caliper) of any abnormality should be noted on a drawing of the breast, which becomes part of the patient's record. A written description of the consistency of the abnormality and degree to which it can be distinguished from surrounding breast tissue should also be included. Detection of abnormalities during physical examination largely determines whether a biopsy is needed, even if a subsequent mammogram shows no abnormalities.
Testing: Imaging tests are used for screening and for evaluation of breast abnormalities. Annual screening mammography is recommended for women ≥ 50 yr and sometimes for women 40 to 50 yr. Mammography is more effective in older women because with aging, fibroglandular tissue in breasts tends to be replaced with fatty tissue, which can be more easily distinguished from abnormal tissue. Low-dose x-rays of both breasts are taken in 1 (oblique) or 2 views (oblique and craniocaudal). Only about 10% of abnormalities detected result from cancer. Accuracy of mammography depends partly on the techniques used and experience of the mammographer; false-negative results may exceed 15%. Some centers use computer analysis of digitized mammography images to help in diagnosis. Such systems are not recommended for stand-alone diagnosis, but they appear to improve sensitivity for detecting small cancers by radiologists.
Mammography is also used diagnostically to evaluate lumps, pain, and nipple discharge. It can determine size and location of a lesion and provide images of surrounding tissues and lymph nodes. Diagnostic mammography requires more views than screening mammography. For biopsy of a lesion seen on a mammogram but not detectable during physical examination, 2 needles or wires can be inserted via radiologic guidance to localize the lesion. The excised specimen should be x-rayed, and the x-ray compared with the prebiopsy mammogram to determine whether the lesion has been removed. Mammography is repeated when the breast is no longer tender, usually 6 to 12 wk after biopsy, to confirm removal of the lesion.
MRI is thought to be more accurate than clinical breast examination or mammography for screening women with a high (eg, > 15%) risk of breast cancer, such as those with a BRCA gene mutation. It is not considered appropriate for screening women with average or slightly increased risk. Because MRI can accurately determine tumor size, chest wall involvement, and presence of multiple tumors, it is often used in evaluation after breast cancer is diagnosed. Use of MRI to identify axillary node involvement is under study.
History includes duration of symptoms; relation of symptoms to menses and pregnancy; presence and type of pain, discharge, and skin changes; use of drugs, including hormone therapy; personal and family history of breast cancer; and date and results of last mammogram.
Breast examination: Principles of examination are similar for physician and patient. Breasts are inspected for asymmetry in shape, nipple inversion, bulging, and dimpling (see Fig. 1: Breast Disorders: Breast Cancer Risks A and B). Although size differential is common, each breast should have a regular contour. An underlying cancer is sometimes detected by having the patient press both hands against the hips or the palms together in front of the forehead (see Fig. 1: Breast Disorders: Breast Cancer Risks C and D). In these positions, the pectoral muscles are contracted, and a subtle dimpling of the skin may appear if a growing tumor has entrapped a Cooper's ligament.
The axillary and supraclavicular lymph nodes are most easily examined with the patient seated or standing (see Fig. 1: Breast Disorders: Breast Cancer Risks E). Supporting the patient's arm during the axillary examination allows the arm to be fully relaxed so that nodes deep within the axilla can be palpated.
The breast is palpated with the patient seated and again with the patient supine, the ipsilateral arm above the head, and a pillow under the ipsilateral shoulder (see Fig. 1: Breast Disorders: Breast Cancer Risks F). The latter position is also used for breast self-examination; the patient examines the breast with her contralateral hand. Having the patient roll to one side, so that the breast on the examined side falls medially, may help differentiate breast and chest wall tenderness because the chest wall can be palpated separately from breast tissue.
The breast should be palpated with the palmar surfaces of the 2nd, 3rd, and 4th fingers, moving systematically in a small circular pattern from the nipple to the outer edges (see Fig. 1: Breast Disorders: Breast Cancer Risks G). Precise location and size (measured with a caliper) of any abnormality should be noted on a drawing of the breast, which becomes part of the patient's record. A written description of the consistency of the abnormality and degree to which it can be distinguished from surrounding breast tissue should also be included. Detection of abnormalities during physical examination largely determines whether a biopsy is needed, even if a subsequent mammogram shows no abnormalities.
Testing: Imaging tests are used for screening and for evaluation of breast abnormalities. Annual screening mammography is recommended for women ≥ 50 yr and sometimes for women 40 to 50 yr. Mammography is more effective in older women because with aging, fibroglandular tissue in breasts tends to be replaced with fatty tissue, which can be more easily distinguished from abnormal tissue. Low-dose x-rays of both breasts are taken in 1 (oblique) or 2 views (oblique and craniocaudal). Only about 10% of abnormalities detected result from cancer. Accuracy of mammography depends partly on the techniques used and experience of the mammographer; false-negative results may exceed 15%. Some centers use computer analysis of digitized mammography images to help in diagnosis. Such systems are not recommended for stand-alone diagnosis, but they appear to improve sensitivity for detecting small cancers by radiologists.
Mammography is also used diagnostically to evaluate lumps, pain, and nipple discharge. It can determine size and location of a lesion and provide images of surrounding tissues and lymph nodes. Diagnostic mammography requires more views than screening mammography. For biopsy of a lesion seen on a mammogram but not detectable during physical examination, 2 needles or wires can be inserted via radiologic guidance to localize the lesion. The excised specimen should be x-rayed, and the x-ray compared with the prebiopsy mammogram to determine whether the lesion has been removed. Mammography is repeated when the breast is no longer tender, usually 6 to 12 wk after biopsy, to confirm removal of the lesion.
MRI is thought to be more accurate than clinical breast examination or mammography for screening women with a high (eg, > 15%) risk of breast cancer, such as those with a BRCA gene mutation. It is not considered appropriate for screening women with average or slightly increased risk. Because MRI can accurately determine tumor size, chest wall involvement, and presence of multiple tumors, it is often used in evaluation after breast cancer is diagnosed. Use of MRI to identify axillary node involvement is under study.
Breast Cancer (5)
Treatment
Hormone therapy includes tamoxifen and aromatase inhibitors. Tamoxifen competitively binds estrogen receptors. Aromatase inhibitors (anastrozole, exemestane, letrozole) block peripheral production of estrogen in postmenopausal women. Benefit of hormone therapy is greatest when tumors have estrogen and progesterone receptors, nearly as good when they have only estrogen receptors, minimal when they have only progesterone receptors, and absent when they have neither receptor. In patients with ER+ tumors, particularly low-risk tumors, hormone therapy may be used instead of chemotherapy. Aromatase inhibitors have recently been proven more effective than tamoxifen and are becoming the preferred treatment for early-stage breast cancer in receptor-positive postmenopausal patients. Adjuvant tamoxifen for 5 yr reduces annual odds of death by about 25% in premenopausal and postmenopausal women regardless of axillary lymph node involvement; treatment for 2 yr is not as effective, but treatment for > 5 yr has no advantage and may increase the likelihood that any recurrent cancer is tamoxifen-resistant. Letrozole may be used for postmenopausal women who have completed 5 yr of daily tamoxifen.
Tamoxifen can induce or exacerbate menopausal symptoms but reduces incidence of contralateral breast cancer and lowers serum cholesterol. Tamoxifen improves bone density in postmenopausal women, and there is some evidence of fracture reduction. Tamoxifen may reduce cardiovascular mortality risk. However, it significantly increases risk of developing endometrial cancer; reported incidence is 1% in postmenopausal women after 5 yr of use. Thus, if such women have spotting or bleeding, they must be evaluated for endometrial cancer. Nonetheless, the improved survival for women with breast cancer far outweighs increased risk of death due to endometrial cancer. Unlike tamoxifen, aromatase inhibitors do not cause menopausal symptoms, but they may increase risk of osteoporosis.
Metastatic disease: Any indication of metastases should prompt immediate evaluation. Treatment of metastases increases median survival by only 3 to 6 mo, although relatively toxic therapies (eg, chemotherapy) may palliate symptoms and improve quality of life; the decision to undergo treatment is highly personal.
Choice of therapy depends on the hormone-receptor status of the tumor, length of the disease-free interval (from diagnosis to manifestation of metastases), number of metastatic sites and organs affected, and patient's menopausal status. Most patients with symptomatic metastatic disease are treated with systemic hormone therapy or chemotherapy. Radiation therapy alone may be used to treat isolated, symptomatic bone lesions or local skin recurrences not amenable to surgical resection. Radiation therapy is the most effective treatment for brain metastases, occasionally achieving long-term control. Patients with multiple metastatic sites outside the CNS should initially be given systemic therapy. There is no proof that treatment of asymptomatic metastases substantially increases survival, and it may reduce quality of life.
Hormone therapy is preferred over chemotherapy for patients with ER+ tumors, a disease-free interval of > 2 yr, or disease that is not life threatening. Tamoxifen is often used first in premenopausal women. Ovarian ablation by surgery, radiation therapy, or use of a luteinizing-releasing hormone agonist (eg, buserelin, goserelin, leuprolide) is a reasonable alternative. Some experts combine ovarian ablation with tamoxifen therapy. If the cancer initially responds to hormone therapy but progresses months or years later, additional forms of hormone therapy may be used sequentially until no further response is seen. Aromatase inhibitors are being increasingly used as primary hormone therapy in postmenopausal women.
The most effective cytotoxic drugs for treatment of metastatic breast cancer are capecitabine, doxorubicin, gemcitabine, the taxanes paclitaxel and docetaxel, and vinorelbine. Response rate to a combination of drugs is higher than that to a single drug, but survival is not improved and toxicity is increased. Thus, some oncologists use single drugs sequentially.
For tumors with amplification of HER2/neu, the humanized monoclonal antibody trastuzumab is effective in treating and controlling visceral metastatic sites. It is used alone or with hormone therapy or chemotherapy.
About 10% of patients with bone metastases eventually develop hypercalcemia, which can be treated with IV bisphosphonates (eg, pamidronate).
Hormone therapy includes tamoxifen and aromatase inhibitors. Tamoxifen competitively binds estrogen receptors. Aromatase inhibitors (anastrozole, exemestane, letrozole) block peripheral production of estrogen in postmenopausal women. Benefit of hormone therapy is greatest when tumors have estrogen and progesterone receptors, nearly as good when they have only estrogen receptors, minimal when they have only progesterone receptors, and absent when they have neither receptor. In patients with ER+ tumors, particularly low-risk tumors, hormone therapy may be used instead of chemotherapy. Aromatase inhibitors have recently been proven more effective than tamoxifen and are becoming the preferred treatment for early-stage breast cancer in receptor-positive postmenopausal patients. Adjuvant tamoxifen for 5 yr reduces annual odds of death by about 25% in premenopausal and postmenopausal women regardless of axillary lymph node involvement; treatment for 2 yr is not as effective, but treatment for > 5 yr has no advantage and may increase the likelihood that any recurrent cancer is tamoxifen-resistant. Letrozole may be used for postmenopausal women who have completed 5 yr of daily tamoxifen.
Tamoxifen can induce or exacerbate menopausal symptoms but reduces incidence of contralateral breast cancer and lowers serum cholesterol. Tamoxifen improves bone density in postmenopausal women, and there is some evidence of fracture reduction. Tamoxifen may reduce cardiovascular mortality risk. However, it significantly increases risk of developing endometrial cancer; reported incidence is 1% in postmenopausal women after 5 yr of use. Thus, if such women have spotting or bleeding, they must be evaluated for endometrial cancer. Nonetheless, the improved survival for women with breast cancer far outweighs increased risk of death due to endometrial cancer. Unlike tamoxifen, aromatase inhibitors do not cause menopausal symptoms, but they may increase risk of osteoporosis.
Metastatic disease: Any indication of metastases should prompt immediate evaluation. Treatment of metastases increases median survival by only 3 to 6 mo, although relatively toxic therapies (eg, chemotherapy) may palliate symptoms and improve quality of life; the decision to undergo treatment is highly personal.
Choice of therapy depends on the hormone-receptor status of the tumor, length of the disease-free interval (from diagnosis to manifestation of metastases), number of metastatic sites and organs affected, and patient's menopausal status. Most patients with symptomatic metastatic disease are treated with systemic hormone therapy or chemotherapy. Radiation therapy alone may be used to treat isolated, symptomatic bone lesions or local skin recurrences not amenable to surgical resection. Radiation therapy is the most effective treatment for brain metastases, occasionally achieving long-term control. Patients with multiple metastatic sites outside the CNS should initially be given systemic therapy. There is no proof that treatment of asymptomatic metastases substantially increases survival, and it may reduce quality of life.
Hormone therapy is preferred over chemotherapy for patients with ER+ tumors, a disease-free interval of > 2 yr, or disease that is not life threatening. Tamoxifen is often used first in premenopausal women. Ovarian ablation by surgery, radiation therapy, or use of a luteinizing-releasing hormone agonist (eg, buserelin, goserelin, leuprolide) is a reasonable alternative. Some experts combine ovarian ablation with tamoxifen therapy. If the cancer initially responds to hormone therapy but progresses months or years later, additional forms of hormone therapy may be used sequentially until no further response is seen. Aromatase inhibitors are being increasingly used as primary hormone therapy in postmenopausal women.
The most effective cytotoxic drugs for treatment of metastatic breast cancer are capecitabine, doxorubicin, gemcitabine, the taxanes paclitaxel and docetaxel, and vinorelbine. Response rate to a combination of drugs is higher than that to a single drug, but survival is not improved and toxicity is increased. Thus, some oncologists use single drugs sequentially.
For tumors with amplification of HER2/neu, the humanized monoclonal antibody trastuzumab is effective in treating and controlling visceral metastatic sites. It is used alone or with hormone therapy or chemotherapy.
About 10% of patients with bone metastases eventually develop hypercalcemia, which can be treated with IV bisphosphonates (eg, pamidronate).
Breast Cancer (4)
Treatment
For most patients, primary treatment is surgery, often with radiation therapy. Chemotherapy, hormone therapy, or both may also be used, depending on tumor and patient characteristics. For inflammatory or advanced breast cancer, primary treatment is systemic therapy, which, for inflammatory breast cancer, is followed by surgery and radiation therapy; surgery is usually not helpful for advanced cancer. Paget's disease of the nipple is treated as for other forms of breast cancer, although a very few patients can be treated successfully with local excision only.
Surgery: Most patients with DCIS are cured by simple mastectomy. However, more patients are being treated with wide excision alone, especially when the lesion is < 2.5 cm and histologic characteristics are favorable, or with wide excision plus radiation therapy when size and histologic characteristics are less favorable.
For patients with invasive cancer, survival rates do not differ significantly whether modified radical mastectomy (simple mastectomy plus lymph node dissection) or breast-conserving surgery (lumpectomy, wide excision, partial mastectomy, or quadrantectomy) plus radiation therapy is used. Thus, patient preference can guide choice of treatment within limits. The main advantage of breast-conserving surgery plus radiation therapy is cosmetic. In 15% of patients treated with breast-conserving surgery and radiation therapy, cosmetic results are excellent. However, need for total removal of the tumor with a tumor-free margin overrides cosmetic considerations. With both types of surgery, a lymph node dissection or node sampling should be done. Routine use of extensive procedures is not justified because the main value of lymph node removal is diagnostic, not therapeutic. However, results of frozen section analysis may change the extent of surgery needed. Some surgeons get prior agreement for more invasive surgery in case nodes are positive; others wake the patient and do a 2nd procedure if needed.
Some physicians use preoperative chemotherapy to shrink the tumor before removing it and applying radiation therapy; thus some patients who might otherwise have required mastectomy can have breast-conserving surgery. Early data suggest that this approach does not affect survival. Radiation therapy after mastectomy significantly reduces incidence of local recurrence on the chest wall and in regional lymph nodes and may improve overall survival in patients with primary tumors > 5 cm or with involvement of ≥ 4 axillary nodes. Adverse effects of radiation therapy are usually transient and mild.
Procedures for reconstruction include submuscular or subcutaneous (less common) placement of a silicone or saline implant, use of a tissue expander with delayed placement of the implant, muscle flap transfer using the latissimus dorsi or the lower rectus abdominis, and creation of a free flap by anastomosing the gluteus maximus to the internal mammary vessels. Free flap transfer is being increasingly used for DCIS.
After axillary dissection or radiation therapy, lymphatic drainage of the ipsilateral arm can be impaired, sometimes resulting in significant swelling due to lymphedema; magnitude of the effect is roughly proportional to the number of nodes removed. Venipuncture, BP measurement, and IV infusions are avoided on the affected side. A specially trained therapist must treat lymphedema. Special massage techniques once or twice daily may help drain fluid from congested areas toward functioning lymph basins; low-stretch bandaging is applied immediately after manual drainage, and patients should exercise daily as prescribed. After the lymphedema resolves, typically in 1 to 4 wk, patients continue daily exercise and overnight bandaging of the affected limb indefinitely.
Adjuvant systemic therapy: Patients with LCIS are treated with daily oral tamoxifen. If tamoxifen is unsuitable or refused, bilateral mastectomy may be considered.
For patients with invasive cancer, chemotherapy or hormone therapy is usually begun soon after surgery and continued for months or years; these therapies delay or prevent recurrence in almost all patients and prolong survival in some. However, some experts believe that these therapies are not necessary for tumors < 1 cm (particularly in postmenopausal patients) if lymph nodes are not involved because the prognosis is already excellent. Some experts begin adjuvant systemic therapy before surgery if tumors are > 5 cm.
Relative reduction in risk of recurrence and death associated with chemotherapy or hormone therapy is the same regardless of the clinical-pathologic stage of the cancer. Thus, absolute benefit is greater for patients with a greater risk of recurrence or death (ie, a 20% reduction reduces a 10% recurrence rate to 8% but a 50% rate to 40%). Adjuvant chemotherapy reduces annual odds of death on average by 25 to 35% for premenopausal patients; for postmenopausal patients, the reduction is about 1⁄2 of that (9 to 19%), and the absolute benefit in 10-yr survival is much smaller. Postmenopausal patients with ER– tumors benefit the most from adjuvant chemotherapy (see Table 3: Breast Disorders: Preferred Breast Cancer Adjuvant Systemic Therapy).
Combination chemotherapy regimens (eg, cyclophosphamide, methotrexate, plus 5-fluorouracil; doxorubicin plus cyclophosphamide) are more effective than a single drug. Regimens given for 4 to 6 mo are preferred; they are as effective as regimens given for 6 to 24 mo. Acute adverse effects depend on the regimen but usually include nausea, vomiting, mucositis, fatigue, alopecia, myelosuppression, and thrombocytopenia. Long-term adverse effects are infrequent with most regimens; death due to infection or bleeding is rare (< 0.2%). Whether increasing dose density (giving treatments more frequently) or adding a taxane (eg, docetaxel, paclitaxel) improves response or survival is uncertain.
High-dose chemotherapy plus bone marrow or stem cell transplantation offers no therapeutic advantage over standard therapy and should not be used.
For most patients, primary treatment is surgery, often with radiation therapy. Chemotherapy, hormone therapy, or both may also be used, depending on tumor and patient characteristics. For inflammatory or advanced breast cancer, primary treatment is systemic therapy, which, for inflammatory breast cancer, is followed by surgery and radiation therapy; surgery is usually not helpful for advanced cancer. Paget's disease of the nipple is treated as for other forms of breast cancer, although a very few patients can be treated successfully with local excision only.
Surgery: Most patients with DCIS are cured by simple mastectomy. However, more patients are being treated with wide excision alone, especially when the lesion is < 2.5 cm and histologic characteristics are favorable, or with wide excision plus radiation therapy when size and histologic characteristics are less favorable.
For patients with invasive cancer, survival rates do not differ significantly whether modified radical mastectomy (simple mastectomy plus lymph node dissection) or breast-conserving surgery (lumpectomy, wide excision, partial mastectomy, or quadrantectomy) plus radiation therapy is used. Thus, patient preference can guide choice of treatment within limits. The main advantage of breast-conserving surgery plus radiation therapy is cosmetic. In 15% of patients treated with breast-conserving surgery and radiation therapy, cosmetic results are excellent. However, need for total removal of the tumor with a tumor-free margin overrides cosmetic considerations. With both types of surgery, a lymph node dissection or node sampling should be done. Routine use of extensive procedures is not justified because the main value of lymph node removal is diagnostic, not therapeutic. However, results of frozen section analysis may change the extent of surgery needed. Some surgeons get prior agreement for more invasive surgery in case nodes are positive; others wake the patient and do a 2nd procedure if needed.
Some physicians use preoperative chemotherapy to shrink the tumor before removing it and applying radiation therapy; thus some patients who might otherwise have required mastectomy can have breast-conserving surgery. Early data suggest that this approach does not affect survival. Radiation therapy after mastectomy significantly reduces incidence of local recurrence on the chest wall and in regional lymph nodes and may improve overall survival in patients with primary tumors > 5 cm or with involvement of ≥ 4 axillary nodes. Adverse effects of radiation therapy are usually transient and mild.
Procedures for reconstruction include submuscular or subcutaneous (less common) placement of a silicone or saline implant, use of a tissue expander with delayed placement of the implant, muscle flap transfer using the latissimus dorsi or the lower rectus abdominis, and creation of a free flap by anastomosing the gluteus maximus to the internal mammary vessels. Free flap transfer is being increasingly used for DCIS.
After axillary dissection or radiation therapy, lymphatic drainage of the ipsilateral arm can be impaired, sometimes resulting in significant swelling due to lymphedema; magnitude of the effect is roughly proportional to the number of nodes removed. Venipuncture, BP measurement, and IV infusions are avoided on the affected side. A specially trained therapist must treat lymphedema. Special massage techniques once or twice daily may help drain fluid from congested areas toward functioning lymph basins; low-stretch bandaging is applied immediately after manual drainage, and patients should exercise daily as prescribed. After the lymphedema resolves, typically in 1 to 4 wk, patients continue daily exercise and overnight bandaging of the affected limb indefinitely.
Adjuvant systemic therapy: Patients with LCIS are treated with daily oral tamoxifen. If tamoxifen is unsuitable or refused, bilateral mastectomy may be considered.
For patients with invasive cancer, chemotherapy or hormone therapy is usually begun soon after surgery and continued for months or years; these therapies delay or prevent recurrence in almost all patients and prolong survival in some. However, some experts believe that these therapies are not necessary for tumors < 1 cm (particularly in postmenopausal patients) if lymph nodes are not involved because the prognosis is already excellent. Some experts begin adjuvant systemic therapy before surgery if tumors are > 5 cm.
Relative reduction in risk of recurrence and death associated with chemotherapy or hormone therapy is the same regardless of the clinical-pathologic stage of the cancer. Thus, absolute benefit is greater for patients with a greater risk of recurrence or death (ie, a 20% reduction reduces a 10% recurrence rate to 8% but a 50% rate to 40%). Adjuvant chemotherapy reduces annual odds of death on average by 25 to 35% for premenopausal patients; for postmenopausal patients, the reduction is about 1⁄2 of that (9 to 19%), and the absolute benefit in 10-yr survival is much smaller. Postmenopausal patients with ER– tumors benefit the most from adjuvant chemotherapy (see Table 3: Breast Disorders: Preferred Breast Cancer Adjuvant Systemic Therapy).
Combination chemotherapy regimens (eg, cyclophosphamide, methotrexate, plus 5-fluorouracil; doxorubicin plus cyclophosphamide) are more effective than a single drug. Regimens given for 4 to 6 mo are preferred; they are as effective as regimens given for 6 to 24 mo. Acute adverse effects depend on the regimen but usually include nausea, vomiting, mucositis, fatigue, alopecia, myelosuppression, and thrombocytopenia. Long-term adverse effects are infrequent with most regimens; death due to infection or bleeding is rare (< 0.2%). Whether increasing dose density (giving treatments more frequently) or adding a taxane (eg, docetaxel, paclitaxel) improves response or survival is uncertain.
High-dose chemotherapy plus bone marrow or stem cell transplantation offers no therapeutic advantage over standard therapy and should not be used.
Breast Cancer (3)
Diagnosis
Testing is required to differentiate benign lesions from cancer. Because early detection and treatment of breast cancer improves prognosis, this differentiation must be conclusive before evaluation is terminated.
If advanced cancer is suspected based on physical examination, biopsy should be done first; otherwise, the approach is as for breast lumps. A prebiopsy bilateral mammogram may help delineate other areas that should be biopsied and provides a baseline for future reference. However, mammogram results should not alter the decision to perform a biopsy. Biopsy can be needle or incisional biopsy or, if the tumor is small, excisional biopsy. Any skin with the biopsy specimen should be examined because it may show cancer cells in dermal lymphatic vessels. Routinely, stereotactic biopsy (needle biopsy during mammography) or ultrasound-guided biopsy is being used to improve accuracy.
Evaluation after cancer diagnosis: Part of a positive biopsy specimen should be analyzed for estrogen and progesterone receptors and for HER2 protein. WBCs should be tested for BRCA1 and BRCA2 genes when family history includes multiple cases of early-onset breast cancer, when ovarian cancer develops in patients with a family history of breast or ovarian cancer, when breast and ovarian cancer occur in the same patient, when patients have Ashkenazi Jewish heritage, or when family history includes a single case of male breast cancer.
Chest x-ray, CBC, and liver function tests should be done to check for metastatic disease. Generally, measuring serum carcinoembryonic antigen (CEA), cancer antigen (CA) 15-3, CA 27-29, or a combination is not recommended because results have no effect on treatment or outcome. Bone scanning should be done if patients have tumors > 2 cm, musculoskeletal pain, lymphadenopathy, or elevated serum alkaline phosphatase or Ca levels. Abdominal CT is done if patients have abnormal liver function results, hepatomegaly, or locally advanced cancer with or without axillary lymph node involvement.
Grading and staging follow the TNM classification (see Table 2: Breast Disorders: Staging and Survival of Breast Cancer). Staging is refined during surgery, when regional lymph nodes can be evaluated.
Screening: Screening includes mammography, clinical breast examination (CBE) by health care practitioners, and monthly breast self-examination (BSE).
Mammography, done annually, reduces mortality rate by 25 to 35% in women ≥ 50 yr. However, there is considerable disagreement about screening for women 40 to 50 yr; recommendations include annual mammography (American Cancer Society), mammography every 1 to 2 yr (National Cancer Institute), and no periodic mammography (American College of Physicians).
CBE is usually part of routine annual care for women > 35; it can detect 7 to 10% of cancers that cannot be seen on a mammogram. In the US, CBE augments rather than replaces screening mammography. However, in some countries where mammography is considered too expensive, CBE is the sole screen; reports on its effectiveness in this role vary.
BSE has not been shown to reduce mortality rate but is widely practiced. Because a negative BSE may tempt some women to forego mammography or CBE, the need for these procedures is reinforced when BSE is taught.
Prognosis
Long-term prognosis depends on extent of lymph node involvement, number of axillary lymph nodes involved, size of primary tumor, tumor grade, stage, presence of estrogen and progesterone receptors, patient age, and presence of HER2 protein.
Nodal status correlates with disease-free and overall survival better than other prognostic factors. For node-negative patients, 10-yr disease-free survival rate is > 70%, and overall survival rate is > 80%. For node-positive patients, rates are about 25% and 40%, respectively.
Larger tumors are more likely to be node-positive and also confer a worse prognosis independent of nodal status. Patients with poorly differentiated tumors have a worse prognosis.
Patients with ER+ tumors have a somewhat better prognosis and are more likely to benefit from hormone therapy. Patients with progesterone receptors on a tumor may also have a better prognosis.
When the HER2 gene is amplified, HER2 is overexpressed, increasing cell growth and reproduction and often resulting in more aggressive tumor cells. Overexpression of HER2 may be associated with high histologic grade, ER– tumors, greater proliferation, larger tumor size, and thus a poor prognosis.
For any given stage, patients with the BRCA1 gene appear to have a worse prognosis than those with sporadic tumors, perhaps because they have a higher proportion of high-grade, hormone receptor-negative cancers. Patients with the BRCA2 gene probably have the same prognosis as those without the genes if the tumors have similar characteristics. With either gene, risk of a 2nd cancer in remaining breast tissue is increased (to perhaps as high as 40%).
Testing is required to differentiate benign lesions from cancer. Because early detection and treatment of breast cancer improves prognosis, this differentiation must be conclusive before evaluation is terminated.
If advanced cancer is suspected based on physical examination, biopsy should be done first; otherwise, the approach is as for breast lumps. A prebiopsy bilateral mammogram may help delineate other areas that should be biopsied and provides a baseline for future reference. However, mammogram results should not alter the decision to perform a biopsy. Biopsy can be needle or incisional biopsy or, if the tumor is small, excisional biopsy. Any skin with the biopsy specimen should be examined because it may show cancer cells in dermal lymphatic vessels. Routinely, stereotactic biopsy (needle biopsy during mammography) or ultrasound-guided biopsy is being used to improve accuracy.
Evaluation after cancer diagnosis: Part of a positive biopsy specimen should be analyzed for estrogen and progesterone receptors and for HER2 protein. WBCs should be tested for BRCA1 and BRCA2 genes when family history includes multiple cases of early-onset breast cancer, when ovarian cancer develops in patients with a family history of breast or ovarian cancer, when breast and ovarian cancer occur in the same patient, when patients have Ashkenazi Jewish heritage, or when family history includes a single case of male breast cancer.
Chest x-ray, CBC, and liver function tests should be done to check for metastatic disease. Generally, measuring serum carcinoembryonic antigen (CEA), cancer antigen (CA) 15-3, CA 27-29, or a combination is not recommended because results have no effect on treatment or outcome. Bone scanning should be done if patients have tumors > 2 cm, musculoskeletal pain, lymphadenopathy, or elevated serum alkaline phosphatase or Ca levels. Abdominal CT is done if patients have abnormal liver function results, hepatomegaly, or locally advanced cancer with or without axillary lymph node involvement.
Grading and staging follow the TNM classification (see Table 2: Breast Disorders: Staging and Survival of Breast Cancer). Staging is refined during surgery, when regional lymph nodes can be evaluated.
Screening: Screening includes mammography, clinical breast examination (CBE) by health care practitioners, and monthly breast self-examination (BSE).
Mammography, done annually, reduces mortality rate by 25 to 35% in women ≥ 50 yr. However, there is considerable disagreement about screening for women 40 to 50 yr; recommendations include annual mammography (American Cancer Society), mammography every 1 to 2 yr (National Cancer Institute), and no periodic mammography (American College of Physicians).
CBE is usually part of routine annual care for women > 35; it can detect 7 to 10% of cancers that cannot be seen on a mammogram. In the US, CBE augments rather than replaces screening mammography. However, in some countries where mammography is considered too expensive, CBE is the sole screen; reports on its effectiveness in this role vary.
BSE has not been shown to reduce mortality rate but is widely practiced. Because a negative BSE may tempt some women to forego mammography or CBE, the need for these procedures is reinforced when BSE is taught.
Prognosis
Long-term prognosis depends on extent of lymph node involvement, number of axillary lymph nodes involved, size of primary tumor, tumor grade, stage, presence of estrogen and progesterone receptors, patient age, and presence of HER2 protein.
Nodal status correlates with disease-free and overall survival better than other prognostic factors. For node-negative patients, 10-yr disease-free survival rate is > 70%, and overall survival rate is > 80%. For node-positive patients, rates are about 25% and 40%, respectively.
Larger tumors are more likely to be node-positive and also confer a worse prognosis independent of nodal status. Patients with poorly differentiated tumors have a worse prognosis.
Patients with ER+ tumors have a somewhat better prognosis and are more likely to benefit from hormone therapy. Patients with progesterone receptors on a tumor may also have a better prognosis.
When the HER2 gene is amplified, HER2 is overexpressed, increasing cell growth and reproduction and often resulting in more aggressive tumor cells. Overexpression of HER2 may be associated with high histologic grade, ER– tumors, greater proliferation, larger tumor size, and thus a poor prognosis.
For any given stage, patients with the BRCA1 gene appear to have a worse prognosis than those with sporadic tumors, perhaps because they have a higher proportion of high-grade, hormone receptor-negative cancers. Patients with the BRCA2 gene probably have the same prognosis as those without the genes if the tumors have similar characteristics. With either gene, risk of a 2nd cancer in remaining breast tissue is increased (to perhaps as high as 40%).
Breast Cancer (2)
Pathology
Most breast cancers are epithelial tumors that develop from cells lining ducts or lobules; less common are nonepithelial cancers of the supporting stroma (angiosarcoma, primary stromal sarcomas, phyllodes tumor). Cancers are divided into carcinoma in situ and invasive cancer.
Carcinoma in situ is proliferation of cancer cells within ducts or lobules and without invasion of stromal tissue. Usually, ductal carcinoma in situ (DCIS) is detected only by mammography and is localized to one area; it may become invasive. Lobular carcinoma in situ (LCIS) is a nonpalpable lesion usually discovered via biopsy; it is rarely visualized with mammography. LCIS is not malignant, but its presence indicates increased risk of subsequent invasive carcinoma in either breast; about 1 to 2% of patients with LCIS develop cancer annually.
Invasive carcinoma is primarily adenocarcinoma. About 80% is the infiltrating ductal type; most of the remainder is infiltrating lobular. Rare forms include medullary, mucinous, and tubular carcinomas.
Paget's disease of the nipple (not to be confused with the metabolic bone disease also called Paget's disease) is a form of ductal carcinoma in situ that extends into the overlying skin of the nipple and areola, manifesting with an inflammatory skin lesion. Characteristic malignant cells called Paget cells are present in the epidermis. The cancer may be in situ or invasive.
Breast cancer invades locally and spreads initially through the regional lymph nodes, bloodstream, or both. Metastatic breast cancer may affect almost any organ in the body—most commonly, lungs, liver, bone, brain, and skin. Most skin metastases occur in the region of the breast surgery; scalp metastases also are common. Metastatic breast cancer frequently appears years or decades after initial diagnosis and treatment.
Estrogen and progesterone receptors, present in some breast cancers, are nuclear hormone receptors that promote DNA replication and cell division when they are bound to the appropriate hormones. Thus, drugs that block these receptors may be useful in treating tumors with the receptors. About 2⁄3 of postmenopausal patients have an estrogen-receptor positive (ER+) tumor. Incidence of ER+ tumors is lower among premenopausal patients. Another cellular receptor is human epidermal growth factor receptor 2 (HER2) protein; its presence correlates with a poorer prognosis at any given stage of cancer.
Symptoms and Signs
Most breast cancers are discovered as a lump by the patient or during routine physical examination or mammography. Less commonly, the presenting symptom is breast pain or enlargement or a nondescript thickening in the breast. Paget's disease of the nipple presents with skin changes, including erythema, crusting, scaling, and discharge; these usually appear so benign that the patient ignores them, delaying diagnosis for a year or more. About 50% of patients with Paget's disease of the nipple have a palpable mass at presentation. A few patients with breast cancer present with signs of metastatic disease (eg, pathologic fracture, pulmonary dysfunction).
A common finding during physical examination is a dominant mass—a lump distinctly different from the surrounding breast tissue. Diffuse fibrotic changes in a quadrant of the breast, usually the upper outer quadrant, are more characteristic of benign disorders; a slightly firmer thickening in one breast but not the other may be a sign of cancer. More advanced breast cancers are characterized by fixation of the lump to the chest wall or to overlying skin, by satellite nodules or ulcers in the skin, or by exaggeration of the usual skin markings resulting from lymphedema (so-called peau d'orange). Matted or fixed axillary lymph nodes suggest tumor spread, as does supraclavicular or infraclavicular lymphadenopathy. Inflammatory breast cancer is characterized by diffuse inflammation and enlargement of the breast, often without a lump, and has a particularly aggressive course.
Most breast cancers are epithelial tumors that develop from cells lining ducts or lobules; less common are nonepithelial cancers of the supporting stroma (angiosarcoma, primary stromal sarcomas, phyllodes tumor). Cancers are divided into carcinoma in situ and invasive cancer.
Carcinoma in situ is proliferation of cancer cells within ducts or lobules and without invasion of stromal tissue. Usually, ductal carcinoma in situ (DCIS) is detected only by mammography and is localized to one area; it may become invasive. Lobular carcinoma in situ (LCIS) is a nonpalpable lesion usually discovered via biopsy; it is rarely visualized with mammography. LCIS is not malignant, but its presence indicates increased risk of subsequent invasive carcinoma in either breast; about 1 to 2% of patients with LCIS develop cancer annually.
Invasive carcinoma is primarily adenocarcinoma. About 80% is the infiltrating ductal type; most of the remainder is infiltrating lobular. Rare forms include medullary, mucinous, and tubular carcinomas.
Paget's disease of the nipple (not to be confused with the metabolic bone disease also called Paget's disease) is a form of ductal carcinoma in situ that extends into the overlying skin of the nipple and areola, manifesting with an inflammatory skin lesion. Characteristic malignant cells called Paget cells are present in the epidermis. The cancer may be in situ or invasive.
Breast cancer invades locally and spreads initially through the regional lymph nodes, bloodstream, or both. Metastatic breast cancer may affect almost any organ in the body—most commonly, lungs, liver, bone, brain, and skin. Most skin metastases occur in the region of the breast surgery; scalp metastases also are common. Metastatic breast cancer frequently appears years or decades after initial diagnosis and treatment.
Estrogen and progesterone receptors, present in some breast cancers, are nuclear hormone receptors that promote DNA replication and cell division when they are bound to the appropriate hormones. Thus, drugs that block these receptors may be useful in treating tumors with the receptors. About 2⁄3 of postmenopausal patients have an estrogen-receptor positive (ER+) tumor. Incidence of ER+ tumors is lower among premenopausal patients. Another cellular receptor is human epidermal growth factor receptor 2 (HER2) protein; its presence correlates with a poorer prognosis at any given stage of cancer.
Symptoms and Signs
Most breast cancers are discovered as a lump by the patient or during routine physical examination or mammography. Less commonly, the presenting symptom is breast pain or enlargement or a nondescript thickening in the breast. Paget's disease of the nipple presents with skin changes, including erythema, crusting, scaling, and discharge; these usually appear so benign that the patient ignores them, delaying diagnosis for a year or more. About 50% of patients with Paget's disease of the nipple have a palpable mass at presentation. A few patients with breast cancer present with signs of metastatic disease (eg, pathologic fracture, pulmonary dysfunction).
A common finding during physical examination is a dominant mass—a lump distinctly different from the surrounding breast tissue. Diffuse fibrotic changes in a quadrant of the breast, usually the upper outer quadrant, are more characteristic of benign disorders; a slightly firmer thickening in one breast but not the other may be a sign of cancer. More advanced breast cancers are characterized by fixation of the lump to the chest wall or to overlying skin, by satellite nodules or ulcers in the skin, or by exaggeration of the usual skin markings resulting from lymphedema (so-called peau d'orange). Matted or fixed axillary lymph nodes suggest tumor spread, as does supraclavicular or infraclavicular lymphadenopathy. Inflammatory breast cancer is characterized by diffuse inflammation and enlargement of the breast, often without a lump, and has a particularly aggressive course.
Breast Cancer---1
Breast cancer most often involves glandular breast cells in the ducts or lobules. Most patients present with an asymptomatic lump discovered during examination or screening mammography. Diagnosis is confirmed by biopsy. Treatment usually includes surgical excision, often with radiation therapy and adjuvant systemic therapy.
About 203,000 new cases were identified in 2003. It is the 2nd leading cause of cancer death in women (after lung cancer), with about 40,000 deaths in 2003. Male breast cancer accounts for < 1% of total cases; manifestations, diagnosis, and management are the same, although men tend to present later.
Risk Factors
In the US, cumulative risk of developing breast cancer is 12% (1 in 8) by age 95, and risk of dying of it is about 4%. Much of the risk is incurred after age 60 (see Table 1: Breast Disorders: Breast Cancer Risks). These statistics can be misleading because cumulative risk of developing the cancer in any 20-yr period is considerably lower.
Family history of breast cancer in a 1st-degree relative (mother, sister, daughter) doubles or triples risk of developing the cancer, but history in more distant relatives increases risk only slightly. When ≥ 2 1st-degree relatives have breast cancer, risk may be 5 to 6 times higher. About 5% of women with breast cancer carry a mutation in one of the 2 known breast cancer genes, BRCA1 or BRCA2. If relatives of such a woman also carry the gene, they have a 50 to 85% lifetime risk of developing breast cancer. Women with BRCA1 mutations also have a 20 to 40% lifetime risk of developing ovarian cancer; risk among women with BRCA2 mutations is increased less. Women without a family history of breast cancer in at least 2 1st-degree relatives are unlikely to carry this gene and thus do not require screening for BRCA1 and BRCA2 mutations. Men who carry a BRCA2 mutation also have an increased risk of developing breast cancer. The genes are more common among Ashkenazi Jews.
History of in situ or invasive breast cancer increases risk: Risk of developing cancer in the contralateral breast after mastectomy is about 0.5 to 1%/yr of follow-up.
Early menarche, late menopause, or late 1st pregnancy increases risk. Women who have a 1st pregnancy after age 30 are at higher risk than those who are nulliparous.
History of fibrocystic changes requiring biopsy for diagnosis increases risk slightly. Women with multiple breast lumps but no histologic confirmation of a high-risk pattern should not be considered at high risk. Benign lesions that may slightly increase risk of developing invasive breast cancer include complex fibroadenoma, moderate or florid hyperplasia (with or without atypia), sclerosing adenosis, and papilloma. Atypical ductal or lobular hyperplasia increases risk of breast cancer 4- to 5-fold; risk increases to about 10-fold in patients who also have a family history of invasive breast cancer in a 1st-degree relative.
Oral contraceptive use increases risk very slightly (by about 5 more cases per 100,000 women). Risk increases primarily during the years of contraceptive use and tapers off during the 10 yr after stopping. Risk is highest in women who began to use contraceptives before age 20 (although absolute risk is still very low).
Postmenopausal hormone (estrogen plus a progestin) therapy appears to increase risk modestly after only 3 yr of use. With prolonged use, risk is increased by about 7 or 8 cases per 10,000 women for each year of use. Use of estrogen alone does not appear to increase risk of breast cancer. Selective estrogen-receptor modulators (eg, raloxifene) may reduce risk of developing breast cancer.
Diet may play a role in causing or promoting growth of breast cancers, but conclusive evidence about the effect of a particular diet (eg, one high in fats) is lacking. Obese postmenopausal women are at increased risk, but there is no evidence that dietary modification decreases risk. For obese women who are still menstruating, risk may be decreased.
Exposure to radiation therapy before age 30 increases risk. Mantle-field radiation therapy for Hodgkin lymphoma quadruples risk of breast cancer over the next 20 to 30 yr.
About 203,000 new cases were identified in 2003. It is the 2nd leading cause of cancer death in women (after lung cancer), with about 40,000 deaths in 2003. Male breast cancer accounts for < 1% of total cases; manifestations, diagnosis, and management are the same, although men tend to present later.
Risk Factors
In the US, cumulative risk of developing breast cancer is 12% (1 in 8) by age 95, and risk of dying of it is about 4%. Much of the risk is incurred after age 60 (see Table 1: Breast Disorders: Breast Cancer Risks). These statistics can be misleading because cumulative risk of developing the cancer in any 20-yr period is considerably lower.
Family history of breast cancer in a 1st-degree relative (mother, sister, daughter) doubles or triples risk of developing the cancer, but history in more distant relatives increases risk only slightly. When ≥ 2 1st-degree relatives have breast cancer, risk may be 5 to 6 times higher. About 5% of women with breast cancer carry a mutation in one of the 2 known breast cancer genes, BRCA1 or BRCA2. If relatives of such a woman also carry the gene, they have a 50 to 85% lifetime risk of developing breast cancer. Women with BRCA1 mutations also have a 20 to 40% lifetime risk of developing ovarian cancer; risk among women with BRCA2 mutations is increased less. Women without a family history of breast cancer in at least 2 1st-degree relatives are unlikely to carry this gene and thus do not require screening for BRCA1 and BRCA2 mutations. Men who carry a BRCA2 mutation also have an increased risk of developing breast cancer. The genes are more common among Ashkenazi Jews.
History of in situ or invasive breast cancer increases risk: Risk of developing cancer in the contralateral breast after mastectomy is about 0.5 to 1%/yr of follow-up.
Early menarche, late menopause, or late 1st pregnancy increases risk. Women who have a 1st pregnancy after age 30 are at higher risk than those who are nulliparous.
History of fibrocystic changes requiring biopsy for diagnosis increases risk slightly. Women with multiple breast lumps but no histologic confirmation of a high-risk pattern should not be considered at high risk. Benign lesions that may slightly increase risk of developing invasive breast cancer include complex fibroadenoma, moderate or florid hyperplasia (with or without atypia), sclerosing adenosis, and papilloma. Atypical ductal or lobular hyperplasia increases risk of breast cancer 4- to 5-fold; risk increases to about 10-fold in patients who also have a family history of invasive breast cancer in a 1st-degree relative.
Oral contraceptive use increases risk very slightly (by about 5 more cases per 100,000 women). Risk increases primarily during the years of contraceptive use and tapers off during the 10 yr after stopping. Risk is highest in women who began to use contraceptives before age 20 (although absolute risk is still very low).
Postmenopausal hormone (estrogen plus a progestin) therapy appears to increase risk modestly after only 3 yr of use. With prolonged use, risk is increased by about 7 or 8 cases per 10,000 women for each year of use. Use of estrogen alone does not appear to increase risk of breast cancer. Selective estrogen-receptor modulators (eg, raloxifene) may reduce risk of developing breast cancer.
Diet may play a role in causing or promoting growth of breast cancers, but conclusive evidence about the effect of a particular diet (eg, one high in fats) is lacking. Obese postmenopausal women are at increased risk, but there is no evidence that dietary modification decreases risk. For obese women who are still menstruating, risk may be decreased.
Exposure to radiation therapy before age 30 increases risk. Mantle-field radiation therapy for Hodgkin lymphoma quadruples risk of breast cancer over the next 20 to 30 yr.
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