InternalMed_Harrison

InternalMed_Harrison. risk persists throughout life. Similarly, menopause occurring 10 years before the median age of menopause (52 years), whether natural or surgically induced, reduces lifetime breast cancer risk by about 35%. Women who have a first full-term pregnancy by age 18 years have a 30–40% lower risk of breast cancer compared with nulliparous women. Thus, length of menstrual life—particularly the fraction occurring before first full-term pregnancy—is a substantial component of the total risk of breast cancer. These three factors (menarche, age of first full-term pregnancy, and menopause) can account for 70–80% of the variation in breast cancer frequency in different countries. Also, duration of maternal nursing correlates with substantial risk reduction independent of either parity or age at first full-term pregnancy.


InternalMed_Harrison

InternalMed_Harrison. International variation in incidence has provided some of the most important clues on hormonal carcinogenesis. A woman living to age 80 years in North America has one chance in nine of developing invasive breast cancer. Asian women have one-fifth to one-tenth the risk of breast cancer of women in North America or Western Europe. Asian women have substantially lower concentrations of estrogens and progesterone. These differences cannot be explained on a genetic basis because Asian women living in a Western environment have sex steroid hormone concentrations and risks identical to those of their Western counterparts. These migrant women, and more notably their daughters, also differ markedly in height and weight from Asian women in Asia; height and weight are critical regulators of age of menarche and have substantial effects on plasma concentrations of estrogens.


InternalMed_Harrison

InternalMed_Harrison. The role of diet in breast cancer etiology is controversial. While there are associative links between total caloric and fat intake and breast cancer risk, the exact role of fat in the diet is unproven. Increased caloric intake contributes to breast cancer risk in multiple ways: earlier menarche, later age at menopause, and increased post-menopausal estrogen concentrations reflecting enhanced aromatase activities in fatty tissues. On the other hand, central obesity is both a risk factor for occurrence and recurrence of breast cancer. Moderate alcohol intake also increases the risk by an unknown mechanism. Folic acid supplementation appears to modify risk in women who use alcohol but is not additionally protective in abstainers. Recommendations favoring abstinence from alcohol must be weighed against other social pressures and the possible cardioprotective effect of moderate alcohol intake. Chronic low-dose aspirin use is associated with a decreased incidence of breast cancer.


InternalMed_Harrison

InternalMed_Harrison. be weighed against other social pressures and the possible cardioprotective effect of moderate alcohol intake. Chronic low-dose aspirin use is associated with a decreased incidence of breast cancer. Depression is also associated with both occurrence and recurrence of breast cancer.


InternalMed_Harrison

InternalMed_Harrison. Understanding the potential role of exogenous hormones in breast cancer is of extraordinary importance because millions of American women regularly use oral contraceptives and postmenopausal hormone replacement therapy. The most credible meta-analyses of oral contraceptive use suggest that these agents cause a small increased risk of breast cancer. By contrast, oral contraceptives offer a substantial protective effect against ovarian epithelial tumors and endometrial cancers. Hormone replacement therapy (HRT) has a powerful effect on breast cancer risk. Data from the Women’s Health Initiative (WHI) trial showed that conjugated equine estrogens plus progestins increased the risk of breast cancer and adverse cardiovascular events but decreased the risk of bone fractures and colorectal cancer. On balance, there were more negative events with HRT; 6–7 years of HRT nearly doubled the risk of breast cancer. A parallel WHI trial with >12,000 women enrolled testing conjugated estrogens alone


InternalMed_Harrison

InternalMed_Harrison. On balance, there were more negative events with HRT; 6–7 years of HRT nearly doubled the risk of breast cancer. A parallel WHI trial with >12,000 women enrolled testing conjugated estrogens alone (estrogen replacement therapy in women who have had hysterectomies) showed no significant increase in breast cancer incidence. Thus, there are serious concerns about longterm HRT use in terms of cardiovascular disease and breast cancer. The WHI trial of conjugated equine estrogen alone demonstrated few adverse effects for women age <70; however, no comparable safety data are available for other more potent forms of estrogen replacement, and they should not be routinely used as substitutes. HRT in women previously diagnosed with breast cancer increases recurrence rates. Rapid decrease in the number of women on HRT has already led to a coincident decrease in breast cancer incidence.


InternalMed_Harrison

InternalMed_Harrison. In addition to the other factors, radiation is a risk factor in younger women. Women who have been exposed before age 30 years to radiation in the form of multiple fluoroscopies (200–300 cGy) or treatment for Hodgkin’s disease (>3600 cGy) have a substantial increase in risk of breast cancer, whereas radiation exposure after age 30 years appears to have a minimal carcinogenic effect on the breast.


InternalMed_Harrison

InternalMed_Harrison. Because the breasts are a common site of potentially fatal malignancy in women, examination of the breast is an essential part of the physical examination. Unfortunately, internists frequently do not examine breasts in men, and in women, they are apt to defer this evaluation to gynecologists. Because of the plausible association between early detection and improved outcome, it is the duty of every physician to identify breast abnormalities at the earliest possible stage and to institute a diagnostic workup. Women should be trained in breast self-examination (BSE). Although breast cancer in men is unusual, unilateral lesions should be evaluated in the same manner as in women, with the recognition that gynecomastia in men can sometimes begin unilaterally and is often asymmetric.


InternalMed_Harrison

InternalMed_Harrison. Virtually all breast cancer is diagnosed by biopsy of a nodule detected either on a mammogram or by palpation. Algorithms have been developed to enhance the likelihood of diagnosing breast cancer and reduce the frequency of unnecessary biopsy (Fig. 108-1).


InternalMed_Harrison

InternalMed_Harrison. Women should be strongly encouraged to examine their breasts monthly. A potentially flawed study from China has suggested that BSE does not alter survival, but given its safety, the procedure should still be encouraged. At worst, this practice increases the likelihood of detecting a mass at a smaller size when it can be treated with more limited surgery. Breast examination by the physician should be performed in good light so as to see retractions and other skin changes. The nipple and areolae should be inspected, and an attempt should be made to elicit nipple discharge. All regional lymph node groups should be examined, and any lesions should be measured. Physical examination alone cannot exclude malignancy. Lesions with certain features are more likely to be cancerous (hard, irregular, tethered or fixed, or painless lesions). A negative mammogram in the presence of a persistent lump in the breast does not exclude malignancy. Palpable lesions require additional diagnostic procedures,


InternalMed_Harrison

InternalMed_Harrison. or fixed, or painless lesions). A negative mammogram in the presence of a persistent lump in the breast does not exclude malignancy. Palpable lesions require additional diagnostic procedures, including biopsy.


InternalMed_Harrison

InternalMed_Harrison. In premenopausal women, lesions that are either equivocal or nonsuspicious on physical examination should be reexamined in 2–4 Questionable mass “thickening” Reexamine follicular phase menstrual cycle Biopsy Mammogram Solid mass Postmenopausal Patient (with dominant mass) Management by “triple diagnosis” or biopsy Premenopausal Patient Routine screening Mass gone Cyst (see Fig. 108-3) Mass persists Suspicious Aspiration Dominant mass “Benign” FIGURE 108-1 Approach to a palpable breast mass.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 108-1 Approach to a palpable breast mass. weeks, during the follicular phase of the menstrual cycle. Days 5–7 of the cycle are the best time for breast examination. A dominant mass in a postmenopausal woman or a dominant mass that persists through a menstrual cycle in a premenopausal woman should be aspirated by fine-needle biopsy or referred to a surgeon. If nonbloody fluid is aspirated, the diagnosis (cyst) and therapy have been accomplished together. Solid lesions that are persistent, recurrent, complex, or bloody cysts require mammography and biopsy, although in selected patients the so-called triple diagnostic technique (palpation, mammography, aspiration) can be used to avoid biopsy (Figs. 108-1, 108-2, and 108-3). Ultrasound can be used in place of fine-needle aspiration to distinguish cysts from solid lesions. Not all solid masses are detected by ultrasound; thus, a palpable mass that is not visualized on ultrasound must be presumed to be solid.


InternalMed_Harrison

InternalMed_Harrison. Several points are essential in pursuing these management decision trees. First, risk-factor analysis is not part of the decision structure. No constellation of risk factors, by their presence or absence, can be used to exclude biopsy. Second, fine-needle aspiration should be used only in centers that have proven skill in obtaining such specimens and analyzing them. The likelihood of cancer is low in the setting of a “triple negative” (benign-feeling lump, negative mammogram, and negative fine-needle aspiration), but it is not zero. The patient and physician FIGURE 108-2 The “triple diagnosis” technique. FIGURE 108-3 Management of a breast cyst. must be aware of a 1% risk of false negatives. Third, additional technologies such as magnetic resonance imaging (MRI), ultrasound, and sestamibi imaging cannot be used to exclude the need for biopsy, although in unusual circumstances, they may provoke a biopsy.


InternalMed_Harrison

InternalMed_Harrison. Diagnostic mammography should not be confused with screening mammography, which is performed after a palpable abnormality has been detected. Diagnostic mammography is aimed at evaluating the rest of the breast before biopsy is performed or occasionally is part of the triple-test strategy to exclude immediate biopsy. Subtle abnormalities that are first detected by screening mammography should be evaluated carefully by compression or magnified views. These abnormalities include clustered microcalcifications, densities (especially if spiculated), and new or enlarging architectural distortion. For some nonpalpable lesions, ultrasound may be helpful either to identify cysts or to guide biopsy. If there is no palpable lesion and detailed mammographic studies are unequivocally benign, the patient should have routine follow-up appropriate to the patient’s age. It cannot be stressed too strongly that in the presence of a breast lump a negative mammogram does not rule out cancer.


InternalMed_Harrison

InternalMed_Harrison. If a nonpalpable mammographic lesion has a low index of suspicion, mammographic follow-up in 3–6 months is reasonable. Workup of indeterminate and suspicious lesions has been rendered more complex by the advent of stereotactic biopsies. Morrow and colleagues have suggested that these procedures are indicated for lesions that require biopsy but are likely to be benign—that is, for cases in which the procedure probably will eliminate additional surgery. When a lesion is more probably malignant, open biopsy should be performed with a needle localization technique. Others have proposed more widespread use of stereotactic core biopsies for nonpalpable lesions on economic grounds and because diagnosis leads to earlier treatment planning. However, stereotactic diagnosis of a malignant lesion does not eliminate the need for definitive surgical procedures, particularly if breast conservation is attempted. For example, after a breast biopsy with needle localization (i.e., local excision) of a


InternalMed_Harrison

InternalMed_Harrison. not eliminate the need for definitive surgical procedures, particularly if breast conservation is attempted. For example, after a breast biopsy with needle localization (i.e., local excision) of a stereotactically diagnosed malignancy, reexcision may still be necessary to achieve negative margins. To some extent, these issues are decided on the basis of referral pattern and the availability of the resources for stereotactic core biopsies. A reasonable approach is shown in Fig. 108-4.


InternalMed_Harrison

InternalMed_Harrison. During pregnancy, the breast grows under the influence of estrogen, progesterone, prolactin, and human placental lactogen. Lactation is suppressed by progesterone, which blocks the effects of prolactin. After delivery, lactation is promoted by the fall in progesterone levels, which leaves the effects of prolactin unopposed. The development of a dominant mass during pregnancy or lactation should never be attributed to hormonal changes. A dominant mass must be treated with the same concern in a pregnant woman as any other. Breast Mammographic Abnormality Additional studies including spot magnification, oblique views, aspiration, and ultrasound as indicated. FIGURE 108-4 Approaches to abnormalities detected by mammogram.


InternalMed_Harrison

InternalMed_Harrison. Mammographic Abnormality Additional studies including spot magnification, oblique views, aspiration, and ultrasound as indicated. FIGURE 108-4 Approaches to abnormalities detected by mammogram. cancer develops in 1 in every 3000–4000 pregnancies. Stage for stage, breast cancer in pregnant patients is no different from premenopausal breast cancer in nonpregnant patients. However, pregnant women often have more advanced disease because the significance of a breast mass was not fully considered and/or because of endogenous hormone stimulation. Persistent lumps in the breast of pregnant or lactating women cannot be attributed to benign changes based on physical findings; such patients should be promptly referred for diagnostic evaluation.


InternalMed_Harrison

InternalMed_Harrison. Only about 1 in every 5–10 breast biopsies leads to a diagnosis of cancer, although the rate of positive biopsies varies in different countries and clinical settings. (These differences may be related to interpretation, medico-legal considerations, and availability of mammograms.) The vast majority of benign breast masses are due to “fibrocystic” disease, a descriptive term for small fluid-filled cysts and modest epithelial cell and fibrous tissue hyperplasia. However, fibrocystic disease is a histologic, not a clinical, diagnosis, and women who have had a biopsy with benign findings are at greater risk of developing breast cancer than those who have not had a biopsy. The subset of women with ductal or lobular cell proliferation (about 30% of patients), particularly the small fraction (3%) with atypical hyperplasia, have a fourfold greater risk of developing breast cancer than those women who have not had a biopsy, and the increase in the risk is about ninefold for women in this


InternalMed_Harrison

InternalMed_Harrison. (3%) with atypical hyperplasia, have a fourfold greater risk of developing breast cancer than those women who have not had a biopsy, and the increase in the risk is about ninefold for women in this category who also have an affected first-degree relative. Thus, careful follow-up of these patients is required. By contrast, patients with a benign biopsy without atypical hyperplasia are at little risk and may be followed routinely.


InternalMed_Harrison

InternalMed_Harrison. Breast cancer is virtually unique among the epithelial tumors in adults in that screening (in the form of annual mammography) improves survival. Meta-analysis examining outcomes from every randomized trial of mammography conclusively shows a 25–30% reduction in the chance of dying from breast cancer with annual screening after age 50 years; the data for women between ages 40 and 50 years are almost as positive; however, since the incidence is much lower in younger women, there are more false positives. While controversy continues to surround the assessment of screening mammography, the preponderance of data strongly supports the benefits of screening mammography. New analyses of older randomized studies have occasionally suggested that screening may not work. While the design defects in some older studies cannot be retrospectively corrected, most experts, including panels of the American Society of Clinical Oncology and the American Cancer Society (ACS), continue to believe that


InternalMed_Harrison

InternalMed_Harrison. in some older studies cannot be retrospectively corrected, most experts, including panels of the American Society of Clinical Oncology and the American Cancer Society (ACS), continue to believe that screening conveys substantial benefit. Furthermore, the profound drop in breast cancer mortality rate seen over the past decade is unlikely to be solely attributable to improvements in therapy. It seems prudent to recommend annual or biannual mammography for women past the age of 40 years. Although no randomized study of BSE has ever shown any improvement in survival, its major benefit is identification of tumors appropriate for conservative local therapy. Better mammographic technology, including digitized mammography, routine use of magnified views, and greater skill in mammographic interpretation, combined with newer diagnostic techniques (MRI, magnetic resonance spectroscopy, positron emission tomography, etc.) may make it possible to identify breast cancers even more reliably and


InternalMed_Harrison

InternalMed_Harrison. combined with newer diagnostic techniques (MRI, magnetic resonance spectroscopy, positron emission tomography, etc.) may make it possible to identify breast cancers even more reliably and earlier. Screening by any technique other than mammography is not indicated. However, the ACS suggests that younger women who are BRCA1 or BRCA2 carriers or untested first-degree relatives of women with cancer; women with a history of radiation therapy to the chest between ages 10 and 30 years; women with a lifetime risk of breast cancer of at least 20%; and women with a history of Li-Fraumeni, Cowden, or Bannayan-Riley-Ruvalcaba syndromes may benefit from MRI screening, where the higher sensitivity may outweigh the loss of specificity.


InternalMed_Harrison

InternalMed_Harrison. Correct staging of breast cancer patients is of extraordinary importance. Not only does it permit an accurate prognosis, but in many cases, therapeutic decision-making is based largely on the TNM (primary tumor, regional nodes, metastasis) classification (Table 108-1). Comparison with historic series should be undertaken with caution, as the staging has changed several times in the past 20 years. The current staging is complex and results in significant changes in outcome by stage as compared with prior staging systems. One of the most exciting aspects of breast cancer biology has been its subdivision into at least five subtypes based on gene expression profiling. 1. Luminal A: The luminal tumors express cytokeratins 8 and 18, have the highest levels of estrogen receptor expression, tend to be low grade, are most likely to respond to endocrine therapy, and have a favorable prognosis. They tend to be less responsive to chemotherapy. 2.


InternalMed_Harrison

InternalMed_Harrison. 2. Luminal B: Tumor cells are also of luminal epithelial origin, but with a gene expression pattern distinct from luminal A. Prognosis is somewhat worse that luminal A. 3. Normal breast–like: These tumors have a gene expression profile reminiscent of nonmalignant “normal” breast epithelium. Prognosis is similar to the luminal B group. This subtype is somewhat controversial and may represent contamination of the sample by normal mammary epithelium. 4. HER2 amplified: These tumors have amplification of the HER2 gene on chromosome 17q and frequently exhibit coamplification and overexpression of other genes adjacent to HER2. Historically the clinical prognosis of such tumors was poor. However, with the advent of trastuzumab and other targeted therapies, the clinical outcome of HER2 -positive patients is markedly improving. 5.


InternalMed_Harrison

InternalMed_Harrison. 5. Basal: These estrogen receptor/progesterone receptor–negative and HER2-negative tumors (so-called triple negative) are characterized by markers of basal/myoepithelial cells. They tend to be high grade, and express cytokeratins 5/6 and 17 as well as vimentin, p63, CD10, α-smooth muscle actin, and epidermal growth factor receptor (EGFR). Patients with BRCA mutations also fall within this molecular subtype. They also have stem cell characteristics. Breast-conserving treatments, consisting of the removal of the primary tumor by some form of lumpectomy with or without irra T0 No evidence of primary tumor TIS Carcinoma in situ T1 Tumor ≤2 cm T1a Tumor >0.1 cm but ≤0.5 cm T1b Tumor >0.5 but ≤1 cm T1c Tumor >1 cm but ≤2 cm T2 Tumor >2 cm but ≤5 cm T3 Tumor >5 cm T4 Extension to chest wall, inflammation, satellite lesions, ulcerations


InternalMed_Harrison

InternalMed_Harrison. M0 No distant metastasis M1 Distant metastasis (includes spread to ipsilateral supraclavicular nodes) aClinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination. Abbreviations: IHC, immunohistochemistry; RT-PCR, reverse transcriptase polymerase chain reaction. Source: Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, 7th ed. New York, Springer, 2010; www.springeronline.com.


InternalMed_Harrison

InternalMed_Harrison. diating the breast, result in a survival that is as good as (or slightly tumors (i.e., T2 in size, positive margins, positive nodes). At pres-superior to) that after extensive surgical procedures, such as mas-ent, nearly one-third of women in the United States are managed tectomy or modified radical mastectomy, with or without further by lumpectomy. Breast-conserving surgery is not suitable for all irradiation. Postlumpectomy breast irradiation greatly reduces the patients: it is not generally suitable for tumors >5 cm (or for smaller risk of recurrence in the breast. While breast conservation is associ-tumors if the breast is small), for tumors involving the nipple-areola ated with a possibility of recurrence in the breast, 10-year survival is complex, for tumors with extensive intraductal disease involvat least as good as that after more extensive surgery. Postoperative ing multiple quadrants of the breast, for women with a history of radiation to regional nodes following mastectomy


InternalMed_Harrison

InternalMed_Harrison. disease involvat least as good as that after more extensive surgery. Postoperative ing multiple quadrants of the breast, for women with a history of radiation to regional nodes following mastectomy is also associated collagen-vascular disease, and for women who either do not have with an improvement in survival. Because radiation therapy can also the motivation for breast conservation or do not have convenient reduce the rate of local or regional recurrence, it should be strongly access to radiation therapy. However, these groups probably do not considered following mastectomy for women with high-risk primary account for more than one-third of patients who are treated with 528 mastectomy. Thus, a great many women still undergo mastectomy who could safely avoid this procedure and probably would if appropriately counseled. Sentinel lymph node biopsy (SLNB) is generally the standard of care for women with localized breast cancer and clinically negative axilla. If SLNB is negative, more


InternalMed_Harrison

InternalMed_Harrison. would if appropriately counseled. Sentinel lymph node biopsy (SLNB) is generally the standard of care for women with localized breast cancer and clinically negative axilla. If SLNB is negative, more extensive axillary surgery is not required, avoiding much of the risk of lymphedema following more extensive axillary dissections. In the presence of minimal involvement of a sentinel lymph node, further axillary surgery is not required. An extensive intraductal component is a predictor of recurrence in the breast, and so are several clinical variables. Both axillary lymph node involvement and involvement of vascular or lymphatic channels by metastatic tumor in the breast are associated with a higher risk of relapse in the breast but are not contraindications to breast-conserving treatment. When these patients are excluded, and when lumpectomy with negative tumor margins is achieved, breast conservation is associated with a recurrence rate in the breast of 5% or less. The survival of


InternalMed_Harrison

InternalMed_Harrison. When these patients are excluded, and when lumpectomy with negative tumor margins is achieved, breast conservation is associated with a recurrence rate in the breast of 5% or less. The survival of patients who have recurrence in the breast is somewhat worse than that of women who do not. Thus, recurrence in the breast is a negative prognostic variable for longterm survival. However, recurrence in the breast is not the cause of distant metastasis. If recurrence in the breast caused metastatic disease, then women treated with lumpectomy, who have a higher rate of recurrence in the breast, should have poorer survival than women treated with mastectomy, and they do not. Most patients should consult with a radiation oncologist before making a final decision concerning local therapy. However, a multimodality clinic in which the surgeon, radiation oncologist, medical oncologist, and other caregivers cooperate to evaluate the patient and develop a treatment plan is usually considered a major


InternalMed_Harrison

InternalMed_Harrison. multimodality clinic in which the surgeon, radiation oncologist, medical oncologist, and other caregivers cooperate to evaluate the patient and develop a treatment plan is usually considered a major advantage by patients.


InternalMed_Harrison

InternalMed_Harrison. Adjuvant Therapy The use of systemic therapy after local management of breast cancer substantially improves survival. More than half of the women who would otherwise die of metastatic breast cancer remain disease-free when treated with the appropriate systemic regimen. These data have grown more and more impressive with longer follow-up and more effective regimens.


InternalMed_Harrison

InternalMed_Harrison. Prognostic variaBles The most important prognostic variables are provided by tumor staging. The size of the tumor and the status of the axillary lymph nodes provide reasonably accurate information on the likelihood of tumor relapse. The relation of pathologic stage to 5-year survival is shown in Table 108-2. For most women, the need for adjuvant therapy can be readily defined on this basis alone. In the absence of lymph node involvement, involvement of microvessels (either capillaries or lymphatic channels) in tumors is nearly equivalent to lymph node involvement. The greatest controversy concerns women with intermediate prognoses. There is rarely justification for adjuvant chemotherapy in most women with tumors <1 cm in size whose axillary lymph nodes are negative. HER2positive tumors are a potential exception. Detection of breast cancer cells either in the circulation or bone marrow is associated with an increased relapse rate. The most exciting development in this area is the use


InternalMed_Harrison

InternalMed_Harrison. a potential exception. Detection of breast cancer cells either in the circulation or bone marrow is associated with an increased relapse rate. The most exciting development in this area is the use of gene expression arrays to analyze patterns of tumor gene expression. Several groups have independently defined gene sets that reliably predict disease-free and overall survival far more accu


InternalMed_Harrison

InternalMed_Harrison. Stage 5-Year Survival, % Source: Modified from data of the National Cancer Institute: Surveillance, Epidemiology, and End Results (SEER). rately than any single prognostic variable including the Oncotype DX® analysis of 21 genes. Also, the use of such standardized risk assessment tools such as Adjuvant! Online (www.adjuvantonline .com) is very helpful. These tools are highly recommended in otherwise ambiguous circumstances. Estrogen receptor status and progesterone receptor status are of prognostic significance. Tumors that lack either or both of these receptors are more likely to recur than tumors that have them.


InternalMed_Harrison

InternalMed_Harrison. Estrogen receptor status and progesterone receptor status are of prognostic significance. Tumors that lack either or both of these receptors are more likely to recur than tumors that have them. Several measures of tumor growth rate correlate with early relapse. S-phase analysis using flow cytometry is the most accurate measure. Indirect S-phase assessments using antigens associated with the cell cycle, such as PCNA (Ki67), are also valuable. Tumors with a high proportion (more than the median) of cells in S-phase pose a greater risk of relapse; chemotherapy offers the greatest survival benefit for these tumors. Assessment of DNA content in the form of ploidy is of modest value, with nondiploid tumors having a somewhat worse prognosis.


InternalMed_Harrison

InternalMed_Harrison. Histologic classification of the tumor has also been used as a prognostic factor. Tumors with a poor nuclear grade have a higher risk of recurrence than tumors with a good nuclear grade. Semiquantitative measures such as the Elston score improve the reproducibility of this measurement. Molecular changes in the tumor are also useful. Tumors that over-express erbB2 (HER2/neu) or have a mutated p53 gene have a worse prognosis. Particular interest has centered on erbB2 overexpression as measured by immunohistochemistry or fluorescence in situ hybridization. Tumors that overexpress erbB2 are more likely to respond to doxorubicin-containing regimens; erbB2 overexpression also predicts those tumors that will respond to HER2/neu antibodies (trastuzumab) (Herceptin) and HER2/neu kinase inhibitors.


InternalMed_Harrison

InternalMed_Harrison. Other variables that have also been used to evaluate prognosis include proteins associated with invasiveness, such as type IV collagenase, cathepsin D, plasminogen activator, plasminogen activator receptor, and the metastasis-suppressor gene nm23. None of these has been widely accepted as a prognostic variable for therapeutic decision-making. One problem in interpreting these prognostic variables is that most of them have not been examined in a study using a large cohort of patients.


InternalMed_Harrison

InternalMed_Harrison. adjuvant regimens Adjuvant therapy is the use of systemic therapies in patients whose known disease has received local therapy but who are at risk of relapse. Selection of appropriate adjuvant chemotherapy or hormone therapy is highly controversial in some situations. Meta-analyses have helped to define broad limits for therapy but do not help in choosing optimal regimens or in choosing a regimen for certain subgroups of patients. A summary of recommendations is shown in Table 108-3. In general, premenopausal women for whom any form of adjuvant systemic therapy is indicated should receive multidrug chemotherapy. Antihormone therapy improves survival in premenopausal patients who are estrogen receptor positive and should be added following completion of chemotherapy. Prophylactic surgical or medically induced castration may also be associated with a substantial survival benefit (primarily in estrogen receptor–positive patients) but is not widely used in this country.


InternalMed_Harrison

InternalMed_Harrison. Data on postmenopausal women are also controversial. The impact of adjuvant chemotherapy is quantitatively less clear-cut than in premenopausal patients, particularly in estrogen receptor– positive cases, although survival advantages have been shown. The first decision is whether chemotherapy or endocrine therapy should be used. While adjuvant endocrine therapy (aromatase inhibitors and tamoxifen) improves survival regardless of axillary lymph node status, the improvement in survival is modest for patients in whom multiple lymph nodes are involved. For this reason, it has been usual to give chemotherapy to postmenopausal patients who have no medical contraindications and who have more than one positive lymph node; hormone therapy is commonly given subsequently. For postmenopausal women for whom systemic therapy is warranted but who have a more favorable prognosis (based more commonly on analysis such as the Oncotype DX methodology), hormone therapy may be used alone. Large clinical


InternalMed_Harrison

InternalMed_Harrison. for whom systemic therapy is warranted but who have a more favorable prognosis (based more commonly on analysis such as the Oncotype DX methodology), hormone therapy may be used alone. Large clinical trials have aAs determined by pathologic examination.


InternalMed_Harrison

InternalMed_Harrison. shown superiority for aromatase inhibitors over tamoxifen alone in the adjuvant setting, although tamoxifen appears essentially equivalent in women who are obese and therefore presumably have higher endogenous concentrations of estrogen. Unfortunately the optimal plan is unclear. Tamoxifen for 5 years followed by an aromatase inhibitor, the reverse strategy, or even switching to an aromatase inhibitor after 2–3 years of tamoxifen has been shown to be better than tamoxifen alone. Continuation of tamoxifen for 10 years yields further benefit and is a reasonable decision for women with less favorable prognoses. Unfortunately, multiple studies have revealed very suboptimal adherence to long-term adjuvant endocrine regimens, and every effort should be made to encourage their continuous use. No valid information currently permits selection among the three clinically approved aromatase inhibitors. Concomitant use of bisphosphonates is almost always warranted; however, it is not finally


InternalMed_Harrison

InternalMed_Harrison. No valid information currently permits selection among the three clinically approved aromatase inhibitors. Concomitant use of bisphosphonates is almost always warranted; however, it is not finally settled as to whether their prophylactic use increases survival in addition to just decreasing recurrences in bone.


InternalMed_Harrison

InternalMed_Harrison. Most comparisons of adjuvant chemotherapy regimens show little difference among them, although small advantages for doxorubicincontaining regimens and “dose-dense” regimens are usually seen.


InternalMed_Harrison

InternalMed_Harrison. One approach—so-called neoadjuvant chemotherapy—involves the administration of adjuvant therapy before definitive surgery and radiation therapy. Because the objective response rates of patients with breast cancer to systemic therapy in this setting exceed 75%, many patients will be “downstaged” and may become candidates for breast-conserving therapy. However, overall survival has not been improved using this approach as compared with the same drugs given postoperatively. Patients who achieve a pathologic complete remission after neoadjuvant chemotherapy not unexpectedly have a substantially improved survival. The neoadjuvant setting also provides a wonderful opportunity for the evaluation of new agents. For example, a second HER2 targeting antibody, pertuzumab, has been shown to provide additional benefit when combined with trastuzumab in the neoadjuvant setting.


InternalMed_Harrison

InternalMed_Harrison. Other adjuvant treatments under investigation include the use of taxanes, such as paclitaxel and docetaxel, and therapy based on alternative kinetic and biologic models. In such approaches, high doses of single agents are used separately in relatively dose-intensive cycling regimens. Node-positive patients treated with doxorubicincyclophosphamide for four cycles followed by four cycles of a taxane have a substantial improvement in survival compared with women receiving doxorubicin-cyclophosphamide alone, particularly in women with estrogen receptor–negative tumors. In addition, administration of the same drug combinations at the same dose but at more frequent intervals (every 2 weeks with cytokine support as compared with the standard every 3 weeks) is even more effective. Among the 25% of women whose tumors overexpress HER2/neu, addition of trastuzumab given concurrently with a taxane and then for a year after chemotherapy produces significant improvement in survival. Although longer


InternalMed_Harrison

InternalMed_Harrison. women whose tumors overexpress HER2/neu, addition of trastuzumab given concurrently with a taxane and then for a year after chemotherapy produces significant improvement in survival. Although longer follow-up will be important, this is now the standard care for most women with HER2/neu-positive breast cancers. Cardiotoxicity, immediate and long-term, remains a concern, and further efforts to exploit non-anthracycline-containing regimens are being pursued. Very-high-dose therapy with stem cell transplantation in the adjuvant setting has not proved superior to standard-dose therapy and should not be routinely used.


InternalMed_Harrison

InternalMed_Harrison. A variety of exciting approaches are close to adoption, and the literature needs to be followed attentively. Tyrosine kinase inhibitors such as lapatinib and additional HER2-targeting antibodies such as pertuzumab are very promising. Finally, as described in the next section, a novel class of agents targeting DNA repair—the so-called poly–ADP ribose polymerase (PARP) inhibitors—is likely to have a major effect on breast cancers either caused by BRCA1 or BRCA2 mutations or sharing similar defects in DNA repair in their etiology.


InternalMed_Harrison

InternalMed_Harrison. About one-third of patients treated for apparently localized breast cancer develop metastatic disease. Although a small number of these patients enjoy long remissions when treated with combinations of systemic and local therapy, most eventually succumb to metastatic disease. The median survival for all patients diagnosed with metastatic breast cancer is less than 3 years. Soft tissue, bony, and visceral (lung and liver) metastases each account for approximately one-third of sites of initial relapses. However, by the time of death, most patients will have bony involvement. Recurrences can appear at any time after primary therapy. A very cruel fact about breast cancer recurrences is that at least half of all breast cancer recurrences occur >5 years after initial therapy. It is now clear that a variety of host factors can influence recurrence rates, including depression and central obesity, and these diseases should be managed as aggressively as possible.


InternalMed_Harrison

InternalMed_Harrison. Because the diagnosis of metastatic disease alters the outlook for the patient so drastically, it should rarely be made without a confirmatory biopsy. Every oncologist has seen patients with tuberculosis, gallstones, sarcoidosis, or other nonmalignant diseases misdiagnosed and treated as though they had metastatic breast cancer or even second malignancies such as multiple myeloma thought to be recurrent breast cancer. This is a catastrophic mistake and justifies biopsy for virtually every patient at the time of initial suspicion of metastatic disease. Furthermore, there are well-documented changes in hormone receptor status that can occur and substantially alter treatment decisions.


InternalMed_Harrison

InternalMed_Harrison. The choice of therapy requires consideration of local therapy needs, the overall medical condition of the patient, and the hormone receptor status of the tumor, as well as clinical judgment. Because therapy of systemic disease is palliative, the potential toxicities of therapies should be balanced against the response rates. Several variables influence the response to systemic therapy. For example, the presence of estrogen and progesterone receptors is a strong indication for endocrine therapy. On the other hand, patients 530 with short disease-free intervals, rapidly progressive visceral disease, lymphangitic pulmonary disease, or intracranial disease are unlikely to respond to endocrine therapy. In many cases, systemic therapy can be withheld while the patient is managed with appropriate local therapy. Radiation therapy and occasionally surgery are effective at relieving the symptoms of metastatic disease, particularly when bony sites are involved. Many patients with bone-only or


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InternalMed_Harrison. local therapy. Radiation therapy and occasionally surgery are effective at relieving the symptoms of metastatic disease, particularly when bony sites are involved. Many patients with bone-only or bone-dominant disease have a relatively indolent course. Under such circumstances, systemic chemotherapy has a modest effect, whereas radiation therapy may be effective for long periods. Other systemic treatments, such as strontium-89 and/ or bisphosphonates, may provide a palliative benefit without inducing objective responses. Most patients with metastatic disease, and certainly all who have bone involvement, should receive concurrent bisphosphonates. Because the goal of therapy is to maintain well-being for as long as possible, emphasis should be placed on avoiding the most hazardous complications of metastatic disease, including pathologic fracture of the axial skeleton and spinal cord compression. New back pain in patients with cancer should be explored aggressively on an emergent basis;


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InternalMed_Harrison. of metastatic disease, including pathologic fracture of the axial skeleton and spinal cord compression. New back pain in patients with cancer should be explored aggressively on an emergent basis; to wait for neurologic symptoms is a potentially catastrophic error. Metastatic involvement of endocrine organs can cause profound dysfunction, including adrenal insufficiency and hypopituitarism. Similarly, obstruction of the biliary tree or other impaired organ function may be better managed with a local therapy than with a systemic approach. Many patients are inappropriately treated with toxic regimens into their last days of life. Often oncologists are unwilling to have the difficult conversations that are required with patients nearing the end of life, and not uncommonly, patients and families can pressure physicians into treatments with very little survival value. Palliative care consultation and realistic assessment of treatment expectations need to be reviewed with patients and


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InternalMed_Harrison. families can pressure physicians into treatments with very little survival value. Palliative care consultation and realistic assessment of treatment expectations need to be reviewed with patients and families. We urge consideration of palliative care consultations for patients who have received at least two lines of therapy for metastatic disease.


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InternalMed_Harrison. Endocrine Therapy Normal breast tissue is estrogen dependent. Both primary and metastatic breast cancer may retain this phenotype. The best means of ascertaining whether a breast cancer is hormone dependent is through analysis of estrogen and progesterone receptor levels on the tumor. Tumors that are positive for the estrogen receptor and negative for the progesterone receptor have a response rate of ∼30%. Tumors that are positive for both receptors have a response rate approaching 70%. If neither receptor is present, the objective response rates are <5%. Receptor analyses provide information as to the correct ordering of endocrine therapies as opposed to chemotherapy. Because of their lack of toxicity and because some patients whose receptor analyses are reported as negative respond to endocrine therapy, an endocrine treatment should be attempted in virtually every patient with metastatic breast cancer. Potential endocrine therapies are summarized in Table 108-4. The choice of


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InternalMed_Harrison. to endocrine therapy, an endocrine treatment should be attempted in virtually every patient with metastatic breast cancer. Potential endocrine therapies are summarized in Table 108-4. The choice of endocrine therapy is usually determined by toxicity profile and availability. In most postmenopausal patients, the initial endocrine therapy should be an aromatase inhibitor rather than tamoxifen. For the subset of postmenopausal women who are estrogen receptor–positive but also HER2/neu-positive, response rates to aromatase inhibitors are substantially higher than to tamoxifen. Aromatase inhibitors are not used in premenopausal women because their hypothalamus can respond to estrogen deprivation by producing gonadotropins that promote estrogen synthesis. Newer “pure” antiestrogens that are free of agonistic effects are also effective. Cases in which tumors shrink in response to tamoxifen withdrawal (as well as withdrawal of pharmacologic doses of estrogens) have been reported. A series of


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InternalMed_Harrison. of agonistic effects are also effective. Cases in which tumors shrink in response to tamoxifen withdrawal (as well as withdrawal of pharmacologic doses of estrogens) have been reported. A series of studies with aromatase inhibitors, tamoxifen, and fulvestrant have all shown that the addition of everolimus to the hormonal treatment can lead to significant benefit after progression on the endocrine agent alone. Everolimus (an mTOR inhibitor) in coordination with endocrine agents is now being explored as front-line therapy and in the adjuvant setting. Endogenous estrogen formation may be blocked by analogues of aromatase inhibitors, tamoxifen, and aConsider retreatment with Everolimus in combination for disease progression


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InternalMed_Harrison. Abbreviation: LHRH, luteinizing hormone–releasing hormone. luteinizing hormone–releasing hormone in premenopausal women. Additive endocrine therapies, including treatment with progestogens, estrogens, and androgens, may also be tried in patients who respond to initial endocrine therapy; the mechanism of action of these latter therapies is unknown. Patients who respond to one endocrine therapy have at least a 50% chance of responding to a second endocrine therapy. It is not uncommon for patients to respond to two or three sequential endocrine therapies; however, combination endocrine therapies do not appear to be superior to individual agents, and combinations of chemotherapy with endocrine therapy are not useful. The median survival of patients with metastatic disease is approximately 2 years, although many patients, particularly older persons and those with hormone-dependent disease, may respond to endocrine therapy for 3–5 years or longer.


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InternalMed_Harrison. Chemotherapy Unlike many other epithelial malignancies, breast cancer responds to multiple chemotherapeutic agents, including anthracyclines, alkylating agents, taxanes, and antimetabolites. Multiple combinations of these agents have been found to improve response rates somewhat, but they have had little effect on duration of response or survival. The choice among multidrug combinations frequently depends on whether adjuvant chemotherapy was administered and, if so, what type. Although patients treated with adjuvant regimens such as cyclophosphamide, methotrexate, and fluorouracil (CMF regimens) may subsequently respond to the same combination in the metastatic disease setting, most oncologists use drugs to which the patients have not been previously exposed. Once patients have progressed after combination drug therapy, it is most common to treat them with single agents. Given the significant toxicity of most drugs, the use of a single effective agent will minimize toxicity by sparing


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InternalMed_Harrison. after combination drug therapy, it is most common to treat them with single agents. Given the significant toxicity of most drugs, the use of a single effective agent will minimize toxicity by sparing the patient exposure to drugs that would be of little value. No method to select the drugs most efficacious for a given patient has been demonstrated to be useful.


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InternalMed_Harrison. Most oncologists use either an anthracycline or paclitaxel following failure with the initial regimen. However, the choice has to be balanced with individual needs. One randomized study has suggested that docetaxel may be superior to paclitaxel. A nanoparticle formulation of paclitaxel (Abraxane) is also effective.


InternalMed_Harrison

InternalMed_Harrison. The use of a humanized antibody to erbB2 (trastuzumab [Herceptin]) combined with paclitaxel can improve response rate and survival for women whose metastatic tumors overexpress erbB2. A novel antibody conjugate (ADC) that links trastuzumab to a cytotoxic agent has been approved for management of HER2-positive breast cancer. The magnitude of the survival extension is modest in patients with metastatic disease. Similarly, the use of bevacizumab (Avastin) has improved the response rate and response duration to paclitaxel. Objective responses in previously treated patients may also be seen with gemcitabine, vinca alkaloids, capecitabine, vinorelbine, and oral etoposide, as well as a new class of agents, epothilones. There are few comparative trials of one agent versus another in metastatic disease. It is a sad fact that choices are often influenced by aggressive marketing of new very expensive agents that have not been shown to be superior to other generic agents. Platinum-based agents


InternalMed_Harrison

InternalMed_Harrison. disease. It is a sad fact that choices are often influenced by aggressive marketing of new very expensive agents that have not been shown to be superior to other generic agents. Platinum-based agents have become far more widely used in both the adjuvant and advanced disease settings for some breast cancers, particularly those of the “triple-negative” subtype.


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InternalMed_Harrison. high-dose chemotheraPy including autologous Bone marrow transPlantation Autologous bone marrow transplantation combined with high doses of single agents can produce objective responses even in heavily pretreated patients. However, such responses are rarely durable and do not alter the clinical course for most patients with advanced metastatic disease.


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InternalMed_Harrison. Between 10 and 25% of patients present with so-called locally advanced, or stage III, breast cancer at diagnosis. Many of these cancers are technically operable, whereas others, particularly cancers with chest wall involvement, inflammatory breast cancers, or cancers with large matted axillary lymph nodes, cannot be managed with surgery initially. Although no randomized trials have shown any survival benefit for neoadjuvant regimens as compared to adjuvant therapy, this approach has gained widespread use. More than 90% of patients with locally advanced breast cancer show a partial or better response to multidrug chemotherapy regimens that include an anthracycline. Early administration of this treatment reduces the bulk of the disease and frequently makes the patient a suitable candidate for salvage surgery and/or radiation therapy. These patients should be managed in multimodality clinics to coordinate surgery, radiation therapy, and systemic chemotherapy. Such approaches produce


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InternalMed_Harrison. for salvage surgery and/or radiation therapy. These patients should be managed in multimodality clinics to coordinate surgery, radiation therapy, and systemic chemotherapy. Such approaches produce long-term disease-free survival in about 30–50% of patients. The neoadjuvant setting is also an ideal time to evaluate the efficacy of novel treatments because the effect on the tumor can be directly assessed.


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InternalMed_Harrison. Women who have one breast cancer are at risk of developing a contralateral breast cancer at a rate of approximately 0.5% per year. When adjuvant tamoxifen or an aromatase inhibitor is administered to these patients, the rate of development of contralateral breast cancers is reduced. In other tissues of the body, tamoxifen has estrogen-like effects that are beneficial, including preservation of bone mineral density and long-term lowering of cholesterol. However, tamoxifen has estrogen-like effects on the uterus, leading to an increased risk of uterine cancer (0.75% incidence after 5 years on tamoxifen). Tamoxifen also increases the risk of cataract formation. The Breast Cancer Prevention Trial (BCPT) revealed a >49% reduction in breast cancer among women with a risk of at least 1.66% taking the drug for 5 years. Raloxifene has shown similar breast cancer prevention potency but may have different effects on bone and heart. The two agents have been compared in a prospective randomized


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InternalMed_Harrison. the drug for 5 years. Raloxifene has shown similar breast cancer prevention potency but may have different effects on bone and heart. The two agents have been compared in a prospective randomized prevention trial (the Study of Tamoxifen and Raloxifene [STAR] trial). The agents are approximately equivalent in preventing breast cancer with fewer thromboembolic events and endometrial cancers with raloxifene; however, raloxifene did not reduce noninvasive cancers as effectively as tamoxifen, so no clear winner has emerged. A newer selective estrogen receptor modulator (SERM), lasofoxifene, has been shown to reduce cardiovascular events in addition to breast cancer and fractures, and further studies of this agent should be watched with interest. It should be recalled that prevention of contralateral breast cancers in women diagnosed with one cancer is a reasonable surrogate for breast cancer prevention because these are second primaries not recurrences. In this regard, the aromatase


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InternalMed_Harrison. breast cancers in women diagnosed with one cancer is a reasonable surrogate for breast cancer prevention because these are second primaries not recurrences. In this regard, the aromatase inhibitors are all considerably more effective than tamoxifen; however, they are not approved for primary breast cancer prevention. It remains puzzling that agents with the safety 531 profile of raloxifene, which can reduce breast cancer risk by 50% with additional benefits in preventing osteoporotic fracture, are still so infrequently prescribed. They should be far more commonly offered to women than they are.


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InternalMed_Harrison. Breast cancer develops as a series of molecular changes in the epithelial cells that lead to ever more malignant behavior. Increased use of mammography has led to more frequent diagnoses of noninvasive breast cancer. These lesions fall into two groups: ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (lobular neoplasia). The management of both entities is controversial.


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InternalMed_Harrison. Ductal Carcinoma In Situ Proliferation of cytologically malignant breast epithelial cells within the ducts is termed DCIS. Atypical hyperplasia may be difficult to differentiate from DCIS. At least one-third of patients with untreated DCIS develop invasive breast cancer within 5 years. However, many low-grade DCIS lesions do not appear to progress over many years; therefore, many patients are overtreated. Unfortunately there is no reliable means of distinguishing patients who require treatment from those who may be safely observed. For many years, the standard treatment for this disease was mastectomy. However, treatment of this condition by lumpectomy and radiation therapy gives survival that is as good as the survival for invasive breast cancer treated by mastectomy. In one randomized trial, the combination of wide excision plus irradiation for DCIS caused a substantial reduction in the local recurrence rate as compared with wide excision alone with negative margins, although


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InternalMed_Harrison. trial, the combination of wide excision plus irradiation for DCIS caused a substantial reduction in the local recurrence rate as compared with wide excision alone with negative margins, although survival was identical in the two arms. No studies have compared either of these regimens to mastectomy. Addition of tamoxifen to any DCIS surgical/radiation therapy regimen further improves local control. Data for aromatase inhibitors in this setting are not available.


InternalMed_Harrison

InternalMed_Harrison. Several prognostic features may help to identify patients at high risk for local recurrence after either lumpectomy alone or lumpectomy with radiation therapy. These include extensive disease; age <40; and cytologic features such as necrosis, poor nuclear grade, and comedo subtype with overexpression of erbB2. Some data suggest that adequate excision with careful determination of pathologically clear margins is associated with a low recurrence rate. When surgery is combined with radiation therapy, recurrence (which is usually in the same quadrant) occurs with a frequency of ≤10%. Given the fact that half of these recurrences will be invasive, about 5% of the initial cohort will eventually develop invasive breast cancer. A reasonable expectation of mortality for these patients is about 1%, a figure that approximates the mortality rate for DCIS managed by mastectomy. Although this train of reasoning has not formally been proved valid, it is reasonable to recommend that patients who


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InternalMed_Harrison. 1%, a figure that approximates the mortality rate for DCIS managed by mastectomy. Although this train of reasoning has not formally been proved valid, it is reasonable to recommend that patients who desire breast preservation, and in whom DCIS appears to be reasonably localized, be managed by adequate surgery with meticulous pathologic evaluation, followed by breast irradiation and tamoxifen. For patients with localized DCIS, axillary lymph node dissection is unnecessary. More controversial is the question of what management is optimal when there is any degree of invasion. Because of a significant likelihood (10–15%) of axillary lymph node involvement even when the primary lesion shows only microscopic invasion, it is prudent to do at least a sentinel lymph node sampling for all patients with any degree of invasion. Further management is dictated by the presence of nodal spread.


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InternalMed_Harrison. Lobular Neoplasia Proliferation of cytologically malignant cells within the lobules is termed lobular neoplasia. Nearly 30% of patients who have had adequate local excision of the lesion develop breast cancer (usually infiltrating ductal carcinoma) over the next 15–20 years. Ipsilateral and contralateral cancers are equally common. Therefore, lobular neoplasia may be a premalignant lesion that suggests an elevated risk of subsequent breast cancer, rather than a form of malignancy itself, and aggressive local management seems unreasonable. Most patients should be treated with an SERM or an aromatase inhibitor (for postmenopausal women) for 5 years and 532 followed with careful annual mammography and semiannual physical examinations. Additional molecular analysis of these lesions may make it possible to discriminate between patients who are at risk of further progression and require additional therapy and those in whom simple follow-up is adequate.


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InternalMed_Harrison. Breast cancer is about 1/150th as frequent in men as in women; 1720 men developed breast cancer in 2006. It usually presents as a unilateral lump in the breast and is frequently not diagnosed promptly. Given the small amount of soft tissue and the unexpected nature of the problem, locally advanced presentations are somewhat more common. When male breast cancer is matched to female breast cancer by age and stage, its overall prognosis is identical. Although gynecomastia may initially be unilateral or asymmetric, any unilateral mass in a man older than age 40 years should receive a careful workup including biopsy. On the other hand, bilateral symmetric breast development rarely represents breast cancer and is almost invariably due to endocrine disease or a drug effect. It should be kept in mind, nevertheless, that the risk of cancer is much greater in men with gynecomastia; in such men, gross asymmetry of the breasts should arouse suspicion of cancer. Male breast cancer is best managed


InternalMed_Harrison

InternalMed_Harrison. mind, nevertheless, that the risk of cancer is much greater in men with gynecomastia; in such men, gross asymmetry of the breasts should arouse suspicion of cancer. Male breast cancer is best managed by mastectomy and axillary lymph node dissection or SLNB. Patients with locally advanced disease or positive nodes should also be treated with irradiation. Approximately 90% of male breast cancers contain estrogen receptors, and approximately 60% of cases with metastatic disease respond to endocrine therapy. No randomized studies have evaluated adjuvant therapy for male breast cancer. Two historic experiences suggest that the disease responds well to adjuvant systemic therapy, and, if not medically contraindicated, the same criteria for the use of adjuvant therapy in women should be applied to men.


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InternalMed_Harrison. The sites of relapse and spectrum of response to chemotherapeutic drugs are virtually identical for breast cancers in either sex. Despite the availability of sophisticated and expensive imaging techniques and a wide range of serum tumor marker tests, survival is not influenced by early diagnosis of relapse. Surveillance guidelines are given in Table 108-5. Despite pressure from patients and their families, routine computed tomography scans (or other imaging) are not recommended. SERMs) Patient education about symptoms Ongoing of recurrence Coordination of care Ongoing Complete blood count Serum chemistry studies Chest radiographs Bone scans Ultrasound examination of the liver Computed tomography of chest, abdomen, or pelvis Tumor markers CA 15-3, CA 27-29, CEA Abbreviations: CEA, carcinoembryonic antigen; SERM, selective estrogen receptor modulator. Source: Recommended Breast Cancer Surveillance Guidelines, ASCO Education Book, Fall, 1997. Robert J. Mayer


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InternalMed_Harrison. Source: Recommended Breast Cancer Surveillance Guidelines, ASCO Education Book, Fall, 1997. Robert J. Mayer Upper gastrointestinal cancers include malignancies arising in the esophagus, stomach, and small intestine. Cancer of the esophagus is an increasingly common and extremely lethal malignancy. The diagnosis was made in 18,170 Americans in 2014 and led to 15,450 deaths. Almost all esophageal cancers are either squamous cell carcinomas or adenocarcinomas; the two histologic subtypes have a similar clinical presentation but different causative factors.


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InternalMed_Harrison. Worldwide, squamous cell carcinoma is the more common cell type, having an incidence that rises strikingly in association with geographic location. It occurs frequently within a region extending from the southern shore of the Caspian Sea on the west to northern China on the east, encompassing parts of Iran, central Asia, Afghanistan, Siberia, and Mongolia. Familial increased risk has been observed in regions with high incidence, although gene associations are not yet defined. High-incidence “pockets” of the disease are also present in such disparate locations as Finland, Iceland, Curaçao, southeastern Africa, and northwestern France. In North America and western Europe, the disease is more common in blacks than whites and in males than females; it appears most often after age 50 and seems to be associated with a lower socioeconomic status. Such cancers generally arise in the cervical and thoracic portions of the esophagus.


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InternalMed_Harrison. A variety of causative factors have been implicated in the development of squamous cell cancers of the esophagus (Table 109-1). In the United States, the etiology of such cancers is primarily related to excess alcohol consumption and/or cigarette smoking. The relative risk increases with the amount of tobacco smoked or alcohol consumed, with these factors acting synergistically. The consumption of whiskey is linked to a higher incidence than the consumption of wine or beer. Squamous cell esophageal carcinoma has also been associated with the ingestion of nitrates, smoked opiates, and fungal toxins in pickled vegetables, as well as mucosal damage caused by such physical insults as long-term exposure to extremely hot tea, the ingestion of lye, radiation-induced strictures, and chronic achalasia. The presence of an esophageal web in association with glossitis and iron deficiency (i.e., Plummer-Vinson or Paterson-Kelly syndrome) and congenital some etioLogiC faCtors assoCiateD With


InternalMed_Harrison

InternalMed_Harrison. achalasia. The presence of an esophageal web in association with glossitis and iron deficiency (i.e., Plummer-Vinson or Paterson-Kelly syndrome) and congenital some etioLogiC faCtors assoCiateD With squamous CeLL CanCer of the esophagus


InternalMed_Harrison

InternalMed_Harrison. Nitrates (converted to nitrites) Smoked opiates Fungal toxins in pickled vegetables Esophageal web with glossitis and iron deficiency (i.e., Plummer-Vinson or Paterson-Kelly syndrome) Congenital hyperkeratosis and pitting of the palms and soles (i.e., tylosis palmaris et plantaris) ? Dietary deficiencies of selenium, molybdenum, zinc, and vitamin A some etioLogiC faCtors assoCiateD With aDenoCarCinoma of the esophagus hyperkeratosis and pitting of the palms and soles (i.e., tylosis palmaris et plantaris) have each been linked with squamous cell esophageal cancer, as have dietary deficiencies of molybdenum, zinc, selenium, and vitamin A. Patients with head and neck cancer are at increased risk of squamous cell cancer of the esophagus.


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InternalMed_Harrison. For unclear reasons, the incidence of squamous cell esophageal cancer has decreased somewhat in both the black and white populations in the United States over the past 40 years, whereas the rate of adenocarcinoma has risen sevenfold, particularly in white males (male-tofemale ratio of 6:1). Whereas squamous cell cancers comprised the vast majority of esophageal cancers in the United States as recently as 40–50 years ago, more than 75% of esophageal tumors are now adenocarcinomas, with the incidence of this histologic subtype continuing to increase rapidly. Understanding the cause for this increase is the focus of current investigation.


InternalMed_Harrison

InternalMed_Harrison. Several strong etiologic associations have been observed to account for the development of adenocarcinoma of the esophagus (Table 109-2). Such tumors arise in the distal esophagus in association with chronic gastric reflux, often in the presence of Barrett’s esophagus (replacement of the normal squamous epithelium of the distal esophagus by columnar mucosa), which occurs more commonly in obese individuals. Adenocarcinomas arise within dysplastic columnar epithelium in the distal esophagus. Even before frank neoplasia is detectable, aneuploidy and p53 mutations are found in the dysplastic epithelium. These adenocarcinomas behave clinically like gastric adenocarcinomas, although they are not associated with Helicobacter pylori infections. Approximately 15% of esophageal adenocarcinomas overexpress the HER2/neu gene.


InternalMed_Harrison

InternalMed_Harrison. About 5% of esophageal cancers occur in the upper third of the esophagus (cervical esophagus), 20% in the middle third, and 75% in the lower third. Squamous cell carcinomas and adenocarcinomas cannot be distinguished radiographically or endoscopically.


InternalMed_Harrison

InternalMed_Harrison. Progressive dysphagia and weight loss of short duration are the initial symptoms in the vast majority of patients. Dysphagia initially occurs with solid foods and gradually progresses to include semisolids and liquids. By the time these symptoms develop, the disease is already very advanced, because difficulty in swallowing does not occur until >60% of the esophageal circumference is infiltrated with cancer. Dysphagia may be associated with pain on swallowing (odynophagia), pain radiating to the chest and/or back, regurgitation or vomiting, and aspiration pneumonia. The disease most commonly spreads to adjacent and supraclavicular lymph nodes, liver, lungs, pleura, and bone. Tracheoesophageal fistulas may develop, primarily in patients with upper and mid-esophageal tumors. As with other squamous cell carcinomas, hypercalcemia may occur in the absence of osseous metastases, probably from parathormone-related peptide secreted by tumor cells (Chap. 121).


InternalMed_Harrison

InternalMed_Harrison. Attempts at endoscopic and cytologic screening for carcinoma in patients with Barrett’s esophagus, while effective as a means of detecting high-grade dysplasia, have not yet been shown to reduce the likelihood of death from esophageal adenocarcinoma. Esophagoscopy should be performed in all patients suspected of having an esophageal abnormality, to both visualize and identify a tumor and also to obtain histopathologic confirmation of the diagnosis. Because the population of persons at risk for squamous cell carcinoma of the esophagus (i.e., smokers and drinkers) also has a high rate of cancers of the lung and the head and neck region, endoscopic inspection of the larynx, trachea, 533 and bronchi should also be carried out. A thorough examination of the fundus of the stomach (by retroflexing the endoscope) is imperative as well. The extent of tumor spread to the mediastinum and para-aortic lymph nodes should be assessed by computed tomography (CT) scans of the chest and abdomen and by


InternalMed_Harrison

InternalMed_Harrison. the endoscope) is imperative as well. The extent of tumor spread to the mediastinum and para-aortic lymph nodes should be assessed by computed tomography (CT) scans of the chest and abdomen and by endoscopic ultrasound. Positron emission tomography scanning provides a useful assessment of the presence of distant metastatic disease, offering accurate information regarding spread to mediastinal lymph nodes, which can be helpful in defining radiation therapy fields. Such scans, when performed sequentially, appear to provide a means of making an early assessment of responsiveness to preoperative chemotherapy.


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InternalMed_Harrison. The prognosis for patients with esophageal carcinoma is poor. Approximately 10% of patients survive 5 years after the diagnosis; thus, management focuses on symptom control. Surgical resection of all gross tumor (i.e., total resection) is feasible in only 45% of cases, with residual tumor cells frequently present at the resection margins. Such esophagectomies have been associated with a postoperative mortality rate of approximately 5% due to anastomotic fistulas, subphrenic abscesses, and cardiopulmonary complications. Although debate regarding the comparative benefits of trans-thoracic versus transhiatal resections has continued, experienced thoracic surgeons are now favoring minimally invasive transthoracic esophagectomies. Endoscopic resections of superficial squamous cell cancers or adenocarcinomas are being examined but have not yet been shown to result in a similar likelihood of survival as observed with conventional surgical procedures. Similarly, the value of endoscopic


InternalMed_Harrison

InternalMed_Harrison. or adenocarcinomas are being examined but have not yet been shown to result in a similar likelihood of survival as observed with conventional surgical procedures. Similarly, the value of endoscopic ablation of dysplastic lesions in an area of Barrett’s esophagus on reducing subsequent mortality from esophageal carcinoma is uncertain. Some experts have advocated fundoplication surgery (i.e., the removal of the gastroesophageal junction) as a means of cancer prevention in patients with Barrett’s esophagus; again, objective data are not yet available to fully assess the risks versus benefits of this invasive procedure. About 20% of patients who survive a total surgical resection live for 5 years. The evaluation of chemotherapeutic agents in patients with esophageal carcinoma has been hampered by ambiguity in the definition of “response” and the debilitated physical condition of many treated individuals, particularly those with squamous cell cancers. Nonetheless, significant reductions in


InternalMed_Harrison

InternalMed_Harrison. by ambiguity in the definition of “response” and the debilitated physical condition of many treated individuals, particularly those with squamous cell cancers. Nonetheless, significant reductions in the size of measurable tumor masses have been reported in 15–25% of patients given single-agent treatment and in 30–60% of patients treated with drug combinations that include cisplatin. In the small subset of patients whose tumors overexpress the HER2/neu gene, the addition of the monoclonal antibody trastuzumab (Herceptin) appears to further enhance the likelihood of benefit, particularly in patients with gastroesophageal lesions. The use of the antiangiogenic agent bevacizumab (Avastin) seems to be of limited value in the setting of esophageal cancer. Combination chemotherapy and radiation therapy as the initial therapeutic approach, either alone or followed by an attempt at operative resection, seems to be beneficial. When administered along with radiation therapy, chemotherapy


InternalMed_Harrison

InternalMed_Harrison. therapy as the initial therapeutic approach, either alone or followed by an attempt at operative resection, seems to be beneficial. When administered along with radiation therapy, chemotherapy produces a better survival outcome than radiation therapy alone. The use of preoperative chemotherapy and radiation therapy followed by esophageal resection appears to prolong survival compared with surgery alone according to several randomized trials and a meta-analysis; some reports suggest that no additional benefit accrues when surgery is added if significant shrinkage of tumor has been achieved by the chemoradiation combination.


InternalMed_Harrison

InternalMed_Harrison. For the incurable, surgically unresectable patient with esophageal cancer, dysphagia, malnutrition, and the management of tracheoesophageal fistulas are major issues. Approaches to palliation include repeated endoscopic dilatation, the surgical placement of a gastrostomy or jejunostomy for hydration and feeding, endoscopic placement of an expansive metal stent to bypass the tumor, and radiation therapy. Incidence and Epidemiology For unclear reasons, the incidence and mortality rates for gastric cancer have decreased in the


InternalMed_Harrison

InternalMed_Harrison. Incidence and Epidemiology For unclear reasons, the incidence and mortality rates for gastric cancer have decreased in the United States during the past 80 years, although the disease remains the second most frequent cause of worldwide cancer-related death. The mortality rate from gastric cancer in the United States has dropped in men from 28 to 5.8 per 100,000 persons, whereas in women, the rate has decreased from 27 to 2.8 per 100,000. Nonetheless, in 2014, 22,220 new cases of stomach cancer were diagnosed in the United States, and 10,990 Americans died of the disease. Although the incidence of gastric cancer has decreased worldwide, it remains high in such disparate geographic regions as Japan, China, Chile, and Ireland.


InternalMed_Harrison

InternalMed_Harrison. The risk of gastric cancer is greater among lower socioeconomic classes. Migrants from highto low-incidence nations maintain their susceptibility to gastric cancer, whereas the risk for their offspring approximates that of the new homeland. These findings suggest that an environmental exposure, probably beginning early in life, is related to the development of gastric cancer, with dietary carcinogens considered the most likely factor(s).


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InternalMed_Harrison. Pathology About 85% of stomach cancers are adenocarcinomas, with 15% due to lymphomas, gastrointestinal stromal tumors (GISTs), and leiomyosarcomas. Gastric adenocarcinomas may be subdivided into two categories: a diffuse type, in which cell cohesion is absent, so that individual cells infiltrate and thicken the stomach wall without forming a discrete mass; and an intestinal type, characterized by cohesive neoplastic cells that form glandlike tubular structures. The diffuse carcinomas occur more often in younger patients, develop throughout the stomach (including the cardia), result in a loss of distensibility of the gastric wall (so-called linitis plastica, or “leather bottle” appearance), and carry a poorer prognosis. Diffuse cancers have defective intercellular adhesion, mainly as a consequence of loss of expression of E-cadherin. Intestinal-type lesions are frequently ulcerative, more commonly appear in the antrum and lesser curvature of the stomach, and are often preceded by a


InternalMed_Harrison

InternalMed_Harrison. consequence of loss of expression of E-cadherin. Intestinal-type lesions are frequently ulcerative, more commonly appear in the antrum and lesser curvature of the stomach, and are often preceded by a prolonged precancerous process, often initiated by H. pylori infection. Although the incidence of diffuse carcinomas is similar in most populations, the intestinal type tends to predominate in the high-risk geographic regions and is less likely to be found in areas where the frequency of gastric cancer is declining. Thus, different etiologic factor(s) are likely involved in these two subtypes. In the United States, ∼30% of gastric cancers originate in the distal stomach, ∼20% arise in the midportion of the stomach, and ∼40% originate in the proximal third of the stomach. The remaining 10% involve the entire stomach.


InternalMed_Harrison

InternalMed_Harrison. Etiology The long-term ingestion of high concentrations of nitrates found in dried, smoked, and salted foods appears to be associated with a higher risk. The nitrates are thought to be converted to carcinogenic nitrites by bacteria (Table 109-3). Such bacteria may be introduced exogenously through the ingestion of partially decayed nitrate-Converting BaCteria as a faCtor in the Causation of gastriC CarCinomaa Exogenous sources of nitrate-converting bacteria: Bacterially contaminated food (common in lower socioeconomic classes, who have a higher incidence of the disease; diminished by improved food preservation and refrigeration) Helicobacter pylori infection


InternalMed_Harrison

InternalMed_Harrison. Endogenous factors favoring growth of nitrate-converting bacteria in the stomach: Decreased gastric acidity Prior gastric surgery (antrectomy) (15to 20-year latency period) Atrophic gastritis and/or pernicious anemia ? Prolonged exposure to histamine H2-receptor antagonists aHypothesis: Dietary nitrates are converted to carcinogenic nitrites by bacteria.


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InternalMed_Harrison. foods, which are consumed in abundance worldwide by the lower socioeconomic classes. Bacteria such as H. pylori may also contribute to this effect by causing chronic inflammatory atrophic gastritis, loss of gastric acidity, and bacterial growth in the stomach. Although the risk for developing gastric cancer is thought to be sixfold higher in people infected with H. pylori, it remains uncertain whether eradicating the bacteria after infection has already occurred actually reduces this risk. Loss of acidity may occur when acid-producing cells of the gastric antrum have been removed surgically to control benign peptic ulcer disease or when achlorhydria, atrophic gastritis, and even pernicious anemia develop in the elderly. Serial endoscopic examinations of the stomach in patients with atrophic gastritis have documented replacement of the usual gastric mucosa by intestinal-type cells. This process of intestinal metaplasia may lead to cellular atypia and eventual neoplasia. Because the


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InternalMed_Harrison. gastritis have documented replacement of the usual gastric mucosa by intestinal-type cells. This process of intestinal metaplasia may lead to cellular atypia and eventual neoplasia. Because the declining incidence of gastric cancer in the United States primarily reflects a decline in distal, ulcerating, intestinal-type lesions, it is conceivable that better food preservation and the availability of refrigeration for all socioeconomic classes have decreased the dietary ingestion of exogenous bacteria. H. pylori has not been associated with the diffuse, more proximal form of gastric carcinoma or with cancers arising at the gastroesophageal junction or in the distal esophagus. Approximately 10–15% of adenocarcinomas appearing in the proximal stomach, the gastroesophageal junction, and the distal esophagus overexpress the HER2/neu gene; individuals whose tumors demonstrate this over-expression benefit from treatment directed against this target (i.e., trastuzumab [Herceptin]).


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InternalMed_Harrison. Several additional etiologic factors have been associated with gastric carcinoma. Gastric ulcers and adenomatous polyps have occasionally been linked, but data on a cause-and-effect relationship are unconvincing. The inadequate clinical distinction between benign gastric ulcers and small ulcerating carcinomas may, in part, account for this presumed association. The presence of extreme hypertrophy of gastric rugal folds (i.e., Ménétrier’s disease), giving the impression of polypoid lesions, has been associated with a striking frequency of malignant transformation; such hypertrophy, however, does not represent the presence of true adenomatous polyps. Individuals with blood group A have a higher incidence of gastric cancer than persons with blood group O; this observation may be related to differences in the mucous secretion, leading to altered mucosal protection from carcinogens. A germline mutation in the E-cadherin gene (CDH1), inherited in an autosomal dominant pattern and coding for


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InternalMed_Harrison. in the mucous secretion, leading to altered mucosal protection from carcinogens. A germline mutation in the E-cadherin gene (CDH1), inherited in an autosomal dominant pattern and coding for a cell adhesion protein, has been linked to a high incidence of occult diffuse-type gastric cancers in young asymptomatic carriers. Duodenal ulcers are not associated with gastric cancer.


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InternalMed_Harrison. Clinical Features Gastric cancers, when superficial and surgically curable, usually produce no symptoms. As the tumor becomes more extensive, patients may complain of an insidious upper abdominal discomfort varying in intensity from a vague, postprandial fullness to a severe, steady pain. Anorexia, often with slight nausea, is very common but is not the usual presenting complaint. Weight loss may eventually be observed, and nausea and vomiting are particularly prominent in patients whose tumors involve the pylorus; dysphagia and early satiety may be the major symptoms caused by diffuse lesions originating in the cardia. There may be no early physical signs. A palpable abdominal mass indicates long-standing growth and predicts regional extension.


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InternalMed_Harrison. Gastric carcinomas spread by direct extension through the gastric wall to the perigastric tissues, occasionally adhering to adjacent organs such as the pancreas, colon, or liver. The disease also spreads via lymphatics or by seeding of peritoneal surfaces. Metastases to intraabdominal and supraclavicular lymph nodes occur frequently, as do metastatic nodules to the ovary (Krukenberg’s tumor), periumbilical region (“Sister Mary Joseph node”), or peritoneal cul-de-sac (Blumer’s shelf palpable on rectal or vaginal examination); malignant ascites may also develop. The liver is the most common site for hematogenous spread of tumor.


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InternalMed_Harrison. The presence of iron-deficiency anemia in men and of occult blood in the stool in both sexes mandates a search for an occult gastrointestinal tract lesion. A careful assessment is of particular importance in patients with atrophic gastritis or pernicious anemia. Unusual clinical features associated with gastric adenocarcinomas include migratory thrombophlebitis, microangiopathic hemolytic anemia, diffuse seborrheic keratoses (so-called Leser-Trélat sign), and acanthosis nigricans. Diagnosis The use of double-contrast radiographic examinations has been supplanted by esophagogastroscopy and CT scanning for the evaluation of patients with epigastric complaints.


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InternalMed_Harrison. Diagnosis The use of double-contrast radiographic examinations has been supplanted by esophagogastroscopy and CT scanning for the evaluation of patients with epigastric complaints. Gastric ulcers identified at the time of such endoscopic procedure may appear benign but merit biopsy in order to exclude a malignancy. Malignant gastric ulcers must be recognized before they penetrate into surrounding tissues, because the rate of cure of early lesions limited to the mucosa or submucosa is >80%. Because gastric carcinomas are difficult to distinguish clinically or endoscopically from gastric lymphomas, endoscopic biopsies should be made as deeply as possible, due to the submucosal location of lymphoid tumors. The staging system for gastric carcinoma is shown in Table 109-4. Data from ACS in the United States No. of 5-Year Stage TNM Features Cases, % Survival, % Abbreviations: ACS, American Cancer Society; TNM, tumor, node, metastasis.


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InternalMed_Harrison. Complete surgical removal of the tumor with resection of adjacent lymph nodes offers the only chance for cure. However, this is possible in less than a third of patients. A subtotal gastrectomy is the treatment of choice for patients with distal carcinomas, whereas total or near-total gastrectomies are required for more proximal tumors. The inclusion of extended lymph node dissection in these procedures appears to confer an added risk for complications without providing a meaningful enhancement in survival. The prognosis following complete surgical resection depends on the degree of tumor penetration into the stomach wall and is adversely influenced by regional lymph node involvement and vascular invasion, characteristics found in the vast majority of American patients. As a result, the probability of survival after 5 years for the 25–30% of patients able to undergo complete resection is ∼20% for distal tumors and <10% for proximal tumors, with recurrences continuing for at least 8


InternalMed_Harrison

InternalMed_Harrison. probability of survival after 5 years for the 25–30% of patients able to undergo complete resection is ∼20% for distal tumors and <10% for proximal tumors, with recurrences continuing for at least 8 years after surgery. In the absence of ascites or extensive hepatic or peritoneal metastases, even patients whose disease is believed to be incurable by surgery should be offered resection of the primary lesion. Reduction of tumor bulk is the best form of palliation and may enhance the probability of benefit from subsequent therapy. In high-incidence regions such as Japan and Korea, where the use of endoscopic screening programs has identified patients with superficial tumors, the use of laparoscopic gastrectomy has gained popularity. In the United States and western Europe, the use of this less invasive surgical approach remains investigational.


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InternalMed_Harrison. Gastric adenocarcinoma is a relatively radioresistant tumor, and the adequate control of the primary tumor requires doses of external-beam irradiation that exceed the tolerance of surrounding structures, such as bowel mucosa and spinal cord. As a result, the major role of radiation therapy in patients has been palliation of pain. Radiation therapy alone after a complete resection does not prolong survival. In the setting of surgically unresectable disease limited to the epigastrium, patients treated with 3500–4000 cGy did not live longer than similar patients not receiving radiotherapy; however, survival was prolonged slightly when 5-fluorouracil (5-FU) plus leucovorin was given in combination with radiation therapy (3-year survival 50% vs 41% for radiation therapy alone). In this clinical setting, the 5-FU likely functions as a radiosensitizer.


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InternalMed_Harrison. The administration of combinations of cytotoxic drugs to patients with advanced gastric carcinoma has been associated with partial responses in 30–50% of cases; responders appear to benefit from treatment. Such drug combinations have generally included cisplatin combined with epirubicin or docetaxel and infusional 5-FU or capecitabine, or with irinotecan. Despite the encouraging response rates, complete remissions are uncommon, the partial responses are transient, and the overall impact of multidrug therapy on survival has been limited; the median survival time for patients treated in this manner remains less than 12 months. As with adenocarcinomas arising in the esophagus, the addition of bevacizumab (Avastin) to chemotherapy regimens in treating gastric cancer appears to provide limited benefit. However, preliminary results utilizing another antiangiogenic compound—ramucirumab (Cyranza)—in the treatment of gastric cancer are encouraging. The use of adjuvant chemotherapy alone


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InternalMed_Harrison. benefit. However, preliminary results utilizing another antiangiogenic compound—ramucirumab (Cyranza)—in the treatment of gastric cancer are encouraging. The use of adjuvant chemotherapy alone following the complete resection of a gastric cancer has only minimally improved survival. However, combination chemotherapy administered before and after surgery (perioperative treatment) as well as postoperative chemotherapy combined with radiation therapy reduces the recurrence rate and prolongs survival.


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InternalMed_Harrison. Primary lymphoma of the stomach is relatively uncommon, accounting for <15% of gastric malignancies and ∼2% of all lymphomas. The stomach is, however, the most frequent extranodal site for lymphoma, and gastric lymphoma has increased in frequency during the past 536 35 years. The disease is difficult to distinguish clinically from gastric adenocarcinoma; both tumors are most often detected during the sixth decade of life; present with epigastric pain, early satiety, and generalized fatigue; and are usually characterized by ulcerations with a ragged, thickened mucosal pattern demonstrated by contrast radiographs or endoscopic appearance. The diagnosis of lymphoma of the stomach may occasionally be made through cytologic brushings of the gastric mucosa but usually requires a biopsy at gastroscopy or laparotomy. Failure of gastroscopic biopsies to detect lymphoma in a given case should not be interpreted as being conclusive, because superficial biopsies may miss the deeper lymphoid


InternalMed_Harrison

InternalMed_Harrison. gastroscopy or laparotomy. Failure of gastroscopic biopsies to detect lymphoma in a given case should not be interpreted as being conclusive, because superficial biopsies may miss the deeper lymphoid infiltrate. The macroscopic pathology of gastric lymphoma may also mimic adenocarcinoma, consisting of either a bulky ulcerated lesion localized in the corpus or antrum or a diffuse process spreading throughout the entire gastric submucosa and even extending into the duodenum. Microscopically, the vast majority of gastric lymphoid tumors are lymphomas of B-cell origin. Histologically, these tumors may range from well-differentiated, superficial processes (mucosa-associated lymphoid tissue [MALT]) to high-grade, large-cell lymphomas. Like gastric adenocarcinoma, infection with H. pylori increases the risk for gastric lymphoma in general and MALT lymphomas in particular. Large-cell lymphomas of the stomach spread initially to regional lymph nodes (often to Waldeyer’s ring) and may then


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InternalMed_Harrison. the risk for gastric lymphoma in general and MALT lymphomas in particular. Large-cell lymphomas of the stomach spread initially to regional lymph nodes (often to Waldeyer’s ring) and may then disseminate.


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InternalMed_Harrison. Primary gastric lymphoma is a far more treatable disease than adenocarcinoma of the stomach, a fact that underscores the need for making the correct diagnosis. Antibiotic treatment to eradicate


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InternalMed_Harrison. H. pylori infection has led to regression of about 75% of gastric MALT lymphomas and should be considered before surgery, radiation therapy, or chemotherapy is undertaken in patients having such tumors. A lack of response to such antimicrobial treatment has been linked to a specific chromosomal abnormality, i.e., t(11;18). Responding patients should undergo periodic endoscopic surveillance because it remains unclear whether the neoplastic clone is eliminated or merely suppressed, although the response to antimicrobial treatment is quite durable. Subtotal gastrectomy, usually followed by combination chemotherapy, has led to 5-year survival rates of 40–60% in patients with localized high-grade lymphomas. The need for a major surgical procedure has been questioned, particularly in patients with preoperative radiographic evidence of nodal involvement, for whom chemotherapy (CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone]) plus rituximab is highly effective therapy. A


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InternalMed_Harrison. with preoperative radiographic evidence of nodal involvement, for whom chemotherapy (CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone]) plus rituximab is highly effective therapy. A role for radiation therapy is not defined because most recurrences develop at distant sites.


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InternalMed_Harrison. Leiomyosarcomas and GISTs make up 1–3% of gastric neoplasms. They most frequently involve the anterior and posterior walls of the gastric fundus and often ulcerate and bleed. Even those lesions that appear benign on histologic examination may behave in a malignant fashion. These tumors rarely invade adjacent viscera and characteristically do not metastasize to lymph nodes, but they may spread to the liver and lungs. The treatment of choice is surgical resection. Combination chemotherapy should be reserved for patients with metastatic disease. All such tumors should be analyzed for a mutation in the c-kit receptor. GISTs are unresponsive to conventional chemotherapy; yet ∼50% of patients experience objective response and prolonged survival when treated with imatinib mesylate (Gleevec) (400–800 mg PO daily), a selective inhibitor of the c-kit tyrosine kinase. Many patients with GIST whose tumors have become refractory to imatinib subsequently benefit from sunitinib (Sutent) or


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InternalMed_Harrison. (400–800 mg PO daily), a selective inhibitor of the c-kit tyrosine kinase. Many patients with GIST whose tumors have become refractory to imatinib subsequently benefit from sunitinib (Sutent) or regorafenib (Stivarga), other inhibitors of the c-kit tyrosine kinase.


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InternalMed_Harrison. Small-bowel tumors comprise <3% of gastrointestinal neoplasms. Because of their rarity and inaccessibility, a correct diagnosis is often delayed. Abdominal symptoms are usually vague and poorly defined, and conventional radiographic studies of the upper and lower intestinal tract often appear normal. Small-bowel tumors should be considered in the differential diagnosis in the following situations: (1) recurrent, unexplained episodes of crampy abdominal pain; (2) intermittent bouts of intestinal obstruction, especially in the absence of inflammatory bowel disease (IBD) or prior abdominal surgery; (3) intussusception in the adult; and (4) evidence of chronic intestinal bleeding in the presence of negative conventional and endoscopic examination. A careful small-bowel barium study should be considered in such a circumstance; the diagnostic accuracy may be improved by infusing barium through a nasogastric tube placed into the duodenum (enteroclysis). Alternatively, capsule endoscopic


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InternalMed_Harrison. be considered in such a circumstance; the diagnostic accuracy may be improved by infusing barium through a nasogastric tube placed into the duodenum (enteroclysis). Alternatively, capsule endoscopic procedures have been used.


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InternalMed_Harrison. The histology of benign small-bowel tumors is difficult to predict on clinical and radiologic grounds alone. The symptomatology of benign tumors is not distinctive, with pain, obstruction, and hemorrhage being the most frequent symptoms. These tumors are usually discovered during the fifth and sixth decades of life, more often in the distal rather than the proximal small intestine. The most common benign tumors are adenomas, leiomyomas, lipomas, and angiomas.


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InternalMed_Harrison. Adenomas These tumors include those of the islet cells and Brunner’s glands as well as polypoid adenomas. Islet cell adenomas are occasionally located outside the pancreas; the associated syndromes are discussed in Chap. 113. Brunner’s gland adenomas are not truly neoplastic but represent a hypertrophy or hyperplasia of submucosal duodenal glands. These appear as small nodules in the duodenal mucosa that secrete a highly viscous alkaline mucus. Most often, this is an incidental radiographic finding not associated with any specific clinical disorder.