Dung Thi Le, M.D.

• Associate Professor of Oncology

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0016139/dung-le

With the high dose per fraction muscle relaxant dosage flexeril zanaflex 4 mg buy on line, 39% of patients experienced moderate fibrosis at the primary site spasms by rib cage buy zanaflex paypal. This usually requires two treatments per day spasms diaphragm hiccups 2 mg zanaflex purchase amex, obviating some of the convenience gain hoped for in the elderly muscle relaxant knots 4 mg zanaflex buy fast delivery. While shorter courses of radiation seem feasible and likely effective in older women quad spasms quality 4 mg zanaflex, the question remains whether older women need radiation after breast preservation at all. Standard local treatment for breast cancer has similar disease-free and overall survival benefits in older and younger women, but older women have more deaths from illnesses other than breast cancer (11% vs. A regimen of breast-conserving surgery and breast irradiation was found to yield a 10-year rate of local treatment failure of 4% in older women compared with 13% in women younger than 65 years (39). An alternative approach has been to use tamoxifen alone after lumpectomy as a means of obviating the need for radiation therapy in women with hormone receptor-positive tumors. A retrospective study of patients treated with lumpectomy plus tamoxifen, but without radiation, demonstrated ipsilateral breast cancer recurrence rates of 5. In a controlled clinical trial comparing quadrantectomy versus quadrantectomy plus radiotherapy in postmenopausal women older than 55 years with breast cancers smaller than 2. Two other small studies addressing the same issue, however, showed higher locoregional recurrence rates (about 10%) in women older than 70 years who were treated with local excision and tamoxifen alone, without adjuvant radiation (42,43). The only significant difference in outcome between the two groups was in the incidence of locoregional recurrence. Freedom from in breast recurrence at 10 years was 98% in the group randomized to tamoxifen plus radiation and 91% in the group randomized to tamoxifen alone. The difference in freedom from ultimate mastectomy at 10 years (98% with irradiation and 96% without) did not reach statistical significance. No significant differences were seen between the two groups with regard to distant metastases, all-cause mortality, or breast cancer-specific mortality. Thus, while lesser and lesser courses of radiation are possible, it is unclear that the inconvenience, morbidity, and expense can be justified. Despite this, there was little change in the use of radiation in this older group 1092 SeCtiOn Xiii BreaSt CanCer in SpeCial pOpulatiOnS by 2007, 3 years after the initial publication of 9343 (45). Wide excision of the primary tumor alone in older women has resulted in local control rates ranging from 71% to 97% (41). Subsequent randomized trials including a 2003 Cochrane analysis of 1,571 patients 70 and older fit for surgery and entered on seven randomized trials comparing tamoxifen to surgery showed that although primary endocrine therapy with tamoxifen was not as effective as surgery in preventing local recurrence, tamoxifen had no adverse effect on survival (46). The Cochrane analysis, however, included trials that did not assess hormone receptor status and the time to tumor progression for patients on tamoxifen represents a worst-case scenario. Response durations of 10 to 50 months, however, remain the limiting factor to this approach for most patients, although in one series tumor regression can persisted up to 5 years in one-third of patients (47). For overall survival, the Cochrane analysis hazard ratio for surgery alone versus primary endocrine therapy was 0. These survival data should not be surprising because tamoxifen is an extremely effective adjuvant therapy in hormone receptor-positive patients and likely compensates for the better local control gained with surgery. In women with hormone receptor-positive breast cancer, response rates to neoadjuvant endocrine therapy are high and responses are usually evident within the first few months of starting therapy. However, further reduction in tumor size is frequent with longer durations of therapy. This latter observation is especially important for older women who present with advanced locoregional tumors not amenable to initial surgery. It is also likely that other factors known to predict the benefits of adjuvant endocrine therapy are likely to predict the likelihood of a response to neoadjuvant endocrine therapy, including lower tumor grade, a greater percentage of tumor cells displaying estrogen and progesterone receptors, and a lower proliferative index. A low 21-gene recurrence score obtained from a core biopsy may also be predictive of a response to neoadjuvant endocrine therapy (48). In both the adjuvant and metastatic settings, aromatase inhibitors have proven superior to tamoxifen and this appears also to be true in the neoadjuvant setting. In a prospective randomized trial of 327 postmenopausal women with inoperable hormone receptor-positive tumors, complete and partial responses assessed by breast examination were 55% and 36%, and breast conserving surgery possible in 45% and 35% of patients treated with letrozole or tamoxifen, respectively (49). In another trial of 250 postmenopausal women with hormone receptor-positive primary breast cancer ineligible for breast-conserving surgery, tumor regression was noted in 60% and 41%, and breast-conserving surgery was successful in 48% and 36% of women randomized to letrozole or tamoxifen, respectively (50). There is often concern that neoadjuvant endocrine therapy may be less effective than chemotherapy in causing tumor reduction. In one of the few randomized trials addressing this, neoadjuvant anastrozole or exemestane for three months was equally as effective as four cycles of paclitaxel and doxorubicin in causing tumor reduction and making patients candidates for breast conservation (51). Median time to clinical tumor response was similar (7 to 8 weeks); breast conservation rates were similar, pathologic complete response was seen in 6% of patients with endocrine therapy and 3% with chemotherapy, and disease progression while on treatment was 9% in both groups. In summary, primary endocrine therapy is not an ideal management approach for older women with hormone receptor-positive breast cancer who are fit for surgery, but it does offer those not able to undergo surgery or who refuse surgery the chance of disease control. The majority of older women with estimated survivals of greater than 5 years are likely to have tumor progression with endocrine therapy alone and should be encouraged to undergo surgery. Primary use of endocrine agents is only indicated for patients who refuse surgery or who have life expectancies limited to several years. For older patients who present with advanced locoregional hormone receptor-positive disease not amenable to surgery, neoadjuvant endocrine therapy should be considered; it is likely to be as effective as chemotherapy for reducing tumor size an making such patients candidates for surgery. The decision to recommend chemotherapy is complicated by the fact that many older women have shortened survival due to existing comorbidity and are wary of the potential toxicities of treatment. The major decision is whether to offer chemotherapy, which can be associated with major toxicity. In one study of older patients with serious illness, 74% and 88% patients stated they would "rather die" than accept a treatment that caused loss of independence or cognitive function, respectively (53). Thus the decision to offer adjuvant treatment in older patients must strongly factor in the potential role of toxicity on functional status and quality of life. Our general recommendations for adjuvant therapy in women older than 70 years are outlined in Table 84-3 and are discussed below. Consensus recommendations and reviews for adjuvant therapy in elders have recently been published (54,55). Of note, these proportional reductions in breast cancer relapse and mortality were independent of nodal status, grade, tumor diameter, and chemotherapy use. This small but important risk should be factored in when considering tamoxifen in older women at low risk for recurrence. In one study specifically looking at outcomes by age, women older than 70 years treated with letrozole did not have an increase in side effects when compared to placebo (59). In addition to preventing further bone loss, bisphosphonates may decrease risk of recurrence although this remains controversial. However, older women with hormone receptor-positive breast cancer with estimated survivals of 5 years or less who are frail or who have well-differentiated tumors 1cm are unlikely to benefit. A major issue in older patients taking endocrine therapy is compliance with treatment recommendations and a careful discussion of risks and benefits with patients and families is mandatory. In one study, women older than 80 years were half as likely as younger women to report a discussion about tamoxifen with their doctor (61). Also, from 15% to about 50% of older women discontinue tamoxifen before 5 years (62). Factors related to stopping tamoxifen early include toxicity, being older than 75 years, having increased comorbidity, and of major concern, having breast-conserving surgery without breast radiation. Compliance with aromatase inhibitor use is also a major issue with as many as half of patients discontinuing treatment by 4. Health-care providers must query older patients about compliance at every visit and continuously encourage patients to take their medications. This sample size was insufficient to clearly define the benefits of chemotherapy in this oldest age cohort. However, the proportional benefits of chemotherapy for patients aged 70 years and older are likely to be similar to the benefits in postmenopausal women 50 to 69 years old. For patients aged 50 to 69 years, about 6 months of anthracycline-based chemotherapy reduced the annual breast cancer death rate by about 20%, irrespective of endocrine treatment. Few older women with node-negative, hormone receptor-positive cancers will derive a meaningful survival benefit from chemotherapy. In addition, the natural history of hormone receptor-positive breast cancer in women treated with endocrine therapy indicates that the majority of relapses and the vast majority of cancer deaths occur after 5 years (56). Some older women with hormone receptor-positive cancer undoubtedly will benefit from chemotherapy, and those with estimated survivals exceeding 10 years should be considered for a gene-based assay (OncotypeDx and others) because some may have high 10-year risks of metastases and breast cancer death with endocrine therapy alone and may derive major benefit from chemotherapy (see Chapter 45). For all older women with node-positive tumors, the use of the web-based program Adjuvant! Although helpful, the potential benefits of newer more effective but toxic treatments provided by the program have not been validated independently and may overestimate treatment value. Other estimates of the value of adjuvant chemotherapy in older women with hormone receptor-positive breast cancer may be helpful. Extermann and associates studied the threshold risk of relapse at which adjuvant tamoxifen and chemotherapy offered benefit to women up to age 85 years, including those with and without comorbidity (66). For tamoxifen, the threshold risks of relapse were 11% and 20% for a 1% benefit in 10-year survival for healthy and sick women at age 65 years while for age 85 years, the risks were 28% and 35% for a 1% benefit in 5-year survival for healthy and sick women, respectively (no 10-year survival benefit was seen in this age group). For chemotherapy, the threshold risk of relapse was 19% for a healthy 65-year-old patient and 62% for a sick 85-year-old patient. Although newer chemotherapy regimens are likely to lower the thresholds for treatment, the changes in these thresholds are likely to be very modest. In the 1-19 point scale, higher scores indicated higher risk of grade 3-5 toxicity. Risk of grade 3-5 toxicity was 25% to 32% for scores of 1­5, 50% to 54% for 6­9, and 77% to 89% for 10­19. In this setting chemotherapy is of great value in nodepositive and high-risk node-negative disease. The majority of these patients relapse within 5 years of diagnosis and, except for frail patients and those with a short life expectancy, the major decision is whether to use anthracycline or non-anthracycline chemotherapy. More aggressive treatment regimens using taxanes or longer durations for anthracycline-based therapy have resulted in better outcomes for patients on clinical trials and should be considered in healthy elders. Calculating the benefits of trastuzumab and chemotherapy in elders is challenging and at present Adjuvant! There is a greater risk of cardiac toxicity with trastuzumab in older patients and treatment requires careful monitoring. After 7 years of follow-up of National Surgical Adjuvant Breast and Bowel Project B-31, a randomized trial comparing anthracycline-containing chemotherapy with or without trastuzumab, 4. The majority of patients with cardiac toxicity recover after stopping trastuzumab, and only two cardiac events occurred more than 2 years after trastuzumab initiation (75). The authors have developed a 1096 SeCtiOn Xiii BreaSt CanCer in SpeCial pOpulatiOnS cardiac risk model from this trial that includes patient age that may be of major interest to clinicians caring for elders. The goal of treatment in older women, like in younger women, should be to control symptoms, maintain function, and maximize quality of life. All women, regardless of age, should be managed using the principles outlined in Chapters 70­72. At least 75% of elders have metastases from a hormone receptor-positive primary lesion. These patients should be treated with endocrine therapy until there is clear evidence that the tumor is resistant to treatment. Endocrine agents should be used sequentially, and patients who have responded or had at least several months of stabilization to a specific agent may be rechallenged with the same agent, provided at least 6 months have lapsed since prior use. Once metastases are clearly refractory to endocrine therapy, older patients will be candidates for chemotherapy. For older patients with metastases but with good organ function, metastases that are not rapidly progressing, and with moderate or absent symptoms, treatment with single agent sequential chemotherapy is the best strategy. There is no compelling evidence that there is an optimal sequence of either endocrine therapies or chemotherapeutic agents and, for chemotherapy, we recommend starting treatment with the least toxic agents. Combination chemotherapy is associated with convincingly superior response rates and time to progression compared to single agents but is more toxic and does not lead to convincing improvement in survival. It should be considered for patients with rapidly progressive tumors where even modest progression would be life threatening. Older patients with lytic bone metastasis should be treated with bone resorption inhibitory drugs (bisphosphonates or denosumab). Since these agents are not associated with improved survival, there is no compelling reason to administer these drugs to asymptomatic or minimally symptomatic patients with blastic lesions only. For patients with multiple painful bony metastases, treatment with radioactive pharmaceuticals such as strontium-89 and samarium-153 may result in major palliation with modest toxicity. Endocrine Therapy For patients with metastases that are detected while on adjuvant tamoxifen or whose cancer recurs greater than a year after stopping adjuvant aromatase inhibitors, initial endocrine treatment should be with an aromatase inhibitor. Of note, a recent trial comparing anastrozole alone versus anastrozole and fulvestrant as initial therapy in 694 postmenopausal patients (median age of 65 years) with metastatic breast cancer showed both a significant improvement for the combination for both progression-free (15. At present the combination would appear to be a reasonable choice for the small percentage of older women who present with large volume and/or functionally impairing metastatic disease who have not had prior endocrine therapy. Another 20% to 30% of patients have stable disease with no change in tumor size for at least 24 weeks. As in younger patients, higher response rates and long durations of response to endocrine therapy are more frequently seen in patients with longer diseasefree intervals, those with only bone or soft tissue metastases, or a lesser number of metastatic sites. After tumor progression on initial treatment, subsequent response rates and durations of response are about half that for initial therapy. Optimal use of endocrine therapy is achieved by using agents sequentially until metastases progress. Patients with very slow growing tumors refractory to these agents can be further treated with progestins (megestrol acetate and others), estradiol, and even glucocorticoids. Using endocrine therapy until metastases are convincingly refractory to such treatment allows for a delay in chemotherapy and maintenance of the highest quality of life. A list of endocrine therapies and their potential toxicities are found in Table 84-3. Of note, of 118 patients 70 years and older in the everolimus group, grade 3/4 toxicity was substantial with fatigue in 10%, anemia 10%, hyperglycemia 9%, stomatitis 8%, dyspnea 7%, pneumonitis 5%, neutropenia 3%, and hypertension 3% (81). These results are of interest, and consideration of this combination in older patients who meet the eligibility criteria for this trial is reasonable, although such patients should be carefully monitored for toxicity and should be advised of the high costs of everolimus.

This surface is inked by the prosector spasms posterior knee discount 2 mg zanaflex with mastercard, and the specimen is sectioned with cuts perpendicular to the inked surface muscle relaxant voltaren cheap 2 mg zanaflex with visa. The main excision specimen containing the target lesion is usually not oriented and does not necessarily need to be inked kidney spasms causes zanaflex 2 mg order amex. This method allows precise margin designation muscle relaxant johnny english cheap zanaflex 4 mg free shipping, accurate measurement of margin width muscle relaxant overdose buy zanaflex without prescription, and avoids disruption of the tissue secondary to compression at the time of specimen radiography. A study has reported a reduced rate of re-excision for excisions that used this method (28). The cores with Ca2+ and the additional tissue cores without Ca2+ kept separate and placed in formalin-filled specimen container and submitted to pathology. The prosector submits the tissue in separate cassettes indicating whether the tissue contains Ca2+ or not. When reviewing the hematoxylin and eosin (H&E) slides of a case, the pathologist examines the accompanying specimen x-ray to determine if the amount of Ca2+ present in the slides accounts for the amount, size and type of Ca2+ seen in the specimen x-ray. If insufficient Ca2+ are present in the H&E slides, the tissue blocks are x-rayed to verify which block(s) contain Ca2+ and how deep they are into the tissue block. The periductal stroma often displays a cellular fibroblastic proliferation with collagen deposition (desmoplasia), chronic inflammation, and angiogenesis. The stromal response may be very prominent and result in a palpable breast abnormality. The neoplastic cells are orderly assembled into club-shaped micropapillae and/or cribriform spaces; a purely solid architecture is less common. The nuclei have features intermediate between low and high grade, and necrosis and mitotic activity can vary. Immunostains for myoepithelial cells are valuable in resolving this differentiated diagnosis. It is characterized macroscopically and microscopically by cysts filled with viscid and homogenous eosinophilic material that closely resembles thyroid colloid. The full spectrum of these alterations, probably dependent on different treatment agents, has not been fully characterized. There is no consensus or uniform approach to the grading of these unusual variants, although some believe that nuclear features and necrosis are most informative of the biology of the lesion. The cells have abundant and somewhat granular eosinophilic cytoplasm and large nuclei with prominent nucleoli. Twenty-six women underwent breast-conserving surgery and 10 received postoperative radiotherapy. The current model of breast cancer (6), based on morphological, immunophenotypical, molecular features, identifies two main and fairly distinct groups of lesions. The cells have diploid/near-diploid karyotype and are characterized by recurrent chromosomal alterations, namely deletion of 16q (in over 80% of cases) and gains of 1q (in over 75% of cases) and 16p (in over 50% of cases) (40). Studies have also described gains of 5p, 17q, 20q, and losses of 11q, 13q, and 14q. Table 21-1 Highlights key features of the ductal lesions discussed in the chapter. Margin status, nuclear grade, and necrosis are the most predictive parameters of clinical outcome, which is also significantly influenced by adjuvant radiation and hormonal treatment. Use of keratin 35betaE12 as an adjunct in the diagnosis of mammary intraepithelial neoplasia-ductal type­benign and malignant intraductal proliferations. Cytokeratin 5/6 immunohistochemistry assists the differential diagnosis of atypical proliferations of the breast. High frequency of coexistence of columnar cell lesions, lobular neoplasia, and low grade ductal carcinoma in situ with invasive tubular carcinoma and invasive lobular carcinoma. Summary In summary, intraductal proliferative lesions are cytologically and architecturally diverse. Atypical apocrine adenosis of the breast: a clinico-pathologic study of 37 patients with 8. Loss of heterozygosity and allelic imbalance in apocrine metaplasia of the breast: microdissection microsatellite analysis. Atypical apocrine metaplasia in sclerosing lesions of the breast: a study of 51 patients. Microcalcifications associated with ductal carcinoma in situ: mammographic-pathologic correlation. Cytological and architectural heterogeneity in ductal carcinoma in situ of the breast. Noninvasive ductal carcinoma of the breast: the relevance of histologic categorization. Long-term survival of women with basal-like ductal carcinoma in situ of the breast: a population-based cohort study. A molecular genetic analysis of a case associated with atypia and invasive carcinoma. Characterization of breast precancerous lesions and myoepithelial hyperplasia in sclerosing adenosis with apocrine metaplasia. Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection. Hence, based on the evidence available, simple mastectomy was suggested as the standard form of treatment (2). Questions regarding the biology and optimal management of these lesions have returned to the forefront of breast cancer research and practice. Lesions diagnosed in the pre-mammography screening era were typically incidental microscopic findings in biopsies and excision specimens obtained for other reasons (2,4). Furthermore, bilateral lesions are reported in approximately one-third of patients (14,15). Such multifocality in a clinically non-detectable lesion is one of the reasons why planning subsequent management has proven problematic and contentious. Others have also demonstrated the cumulative long-term risk, with one study reporting that over 50% of patients developed beast cancer between 15 and 30 years of follow-up (5). On the other hand, in most studies that report a higher incidence of ipsilateral cancer development, the majority of the cancers are of lobular histology (8,21,23). Normal lobules are seen at the top and bottom center of the picture for comparison. Inset shows typical cytologic detail of the cells with prominent intracytoplasmic lumina and a magenta body. Intracytoplasmic vacuoles, sometimes containing a central eosinophilic dot (known as magenta body), are usually found (2,4,21,30). Type A cells are small, dyshesive cells with scant cytoplasm and nuclei approximately 1. It should be noted, however, that this cytological classification scheme has not been shown to be of clinical utility and does not have a direct correlation with the risk of invasive breast cancer development. Pagetoid spread within the affected terminal duct­lobular unit, whereby the neoplastic cells extend along adjacent ducts between intact overlying epithelium and underlying basement membrane, is frequently observed. The biological and clinical significance of these lesions also remains to be determined. Lobular carcinoma in situ cells (arrowheads) are seen growing beneath, and displacing inward, the luminal epithelium of a duct. A lobular unit is focally and partially filled by characteristic cells with intracytoplasmic lumina (arrowheads). The duct is filled with large, discohesive cells showing apocrine features, intracytoplasmic lumina, and occasional signet ring cells (detailed in insert). In this context, E­cadherin and p120 catenin are particularly helpful (see below) (38,39). In the last decade, molecular genetic studies have provided a wealth of increasingly more coherent data on the pathways of breast cancer evolution and how these findings correlate with morphological features (8,30). E-cadherin is a transmembrane adhesion molecule found in adherens junctions and mediates homophilichomotypic adhesion in epithelial cells; its intracytoplasmic domain is bound to p120 catenin and -catenin. The outer rim of myoepithelial cells show strong membrane staining, whereas the lobular carcinoma in situ cells filling the lumen are uniformly negative. In lesions where a mixed pattern of positively and negatively stained cells are observed, they should be classified as a mixed. The indiscriminate use of E-cadherin in diagnostic breast pathology has led to misunderstandings in regard to the actual diagnostic value of this marker, particularly when a detailed inspection of staining is not performed. Differences in individual patient responses to varying levels of risk also contribute to the wide variations seen in clinical practice (57). Hussain and Cunnick illustrated these issues in a pooled analysis of studies published from 1999 to 2008. More recently, two single-institution series have demonstrated that, with careful exclusion of cases with other high-risk lesions on core biopsy. In both of these series, the cancers identified were small, low-grade malignancies. In the series with the longest follow-up, the probability of developing carcinoma in situ or invasive cancer was 13% in the first 10 years after diagnosis, 26% after 20 years, and 35% by 35 years, or roughly 1% per year (72). Another pervasive misconception is the propensity of lobular cancers to be bilateral, leading to a strong consideration for contralateral prophylactic mastectomy among women diagnosed with unilateral invasive lobular cancer. In both subsets, chemoprevention reduced the risk of developing breast cancer by more than 50%. Among 998 women, 163 (16%) of whom reported chemoprevention use of at least 6 months, there was a significant reduction in the incidence of breast cancer with chemoprevention, 14. Despite these findings, neither tamoxifen nor raloxifene has been widely embraced, and studies addressing patient and physician attitudes toward chemoprevention are limited. Collectively, these findings strongly support the need to improve our efforts to educate both high-risk patients and their health care providers about the benefits of chemoprevention in decreasing breast cancer risk. The current standard of care for prophylactic mastectomy is total mastectomy (with or without reconstruction) with the goal of removing the entire mammary gland as would be performed during therapeutic mastectomy. The desire for nipple preservation in this setting and others is becoming increasingly common, and while this may result in improved cosmesis and patient satisfaction, prospective data supporting this contention and/or the long-term oncologic safety of this approach are not yet available. Patients considering surgery for risk reduction need to be fully aware of all the risks and benefits of this approach, and should be encouraged to consider the impact that prophylactic surgery may have on their quality of life with respect to body image and sexual functioning. If reconstruction is to be pursued, they should also have a reasonable expectation for the most likely cosmetic outcome. Relation between component parts of fibrocystic disease complex and breast cancer. Clonal relatedness between lobular carcinoma in situ and synchronous malignant lesions. Management of lobular carcinoma in-situ and atypical lobular hyperplasia of the breast-a review. Family history of breast and ovarian cancer and the risk of breast carcinoma in situ. Lobular breast cancer: excess familiality observed in the Utah Population Database. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: twelve-year observations concerning lobular carcinoma in situ. Clonality of lobular carcinoma in situ and synchronous invasive lobular carcinoma. Genetic and phenotypic characteristics of pleomorphic lobular carcinoma in situ of the breast. Antibodies targeting p63 react specifically in the cytoplasm of breast epithelial cells exhibiting secretory differentiation. Cancer Genome Atlas Network Comprehensive molecular portraits of human breast tumours. Clinical and biological significance of E-cadherin protein expression in invasive lobular carcinoma of the breast. Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Mammary-specific inactivation of E-cadherin and p53 impairs functional gland development and leads to pleomorphic invasive lobular carcinoma in mice. Genomic alterations in lobular neoplasia: a microarray comparative genomic hybridization signature for early neoplastic proliferation in the breast. Pleomorphic lobular carcinoma of the breast: role of comprehensive molecular pathology in characterization of an entity. Presence of lobular carcinoma in situ does not increase local recurrence in patients treated with breast-conserving therapy. Management of lobular neoplasia diagnosed by core needle biopsy: study of 52 biopsies with follow-up surgical excision. Outcome of atypical lobular hyperplasia and lobular carcinoma in situ diagnosed by core needle biopsy: clinical and surgical follow-up of 30 cases. Lobular in-situ neoplasia on breast core needle biopsy: imaging indication and pathologic extent can identify which patients require excisional biopsy. Classic lobular carcinoma in situ and atypical lobular hyperplasia at percutaneous breast core biopsy: outcomes of prospective excision. Long-term follow-up of lobular neoplasia (atypical lobular hyperplasia/lobular carcinoma in situ) diagnosed on core needle biopsy. Incidental minimal atypical lobular hyperplasia on core needle biopsy: correlation with findings on follow-up excision. Clinical implications of margin involvement by pleomorphic lobular carcinoma in situ. The relation between the presence and extent of lobular carcinoma in situ and the risk of local recurrence for patients with infiltrating carcinoma of the breast treated with conservative surgery and radiation therapy. Is lobular carcinoma in situ as a component of breast carcinoma a risk factor for local failure after breast-conserving therapy A population-based study of bilateral prophylactic mastectomy efficacy in women at elevated risk for breast cancer in community practices. The increased incidence was observed in all age categories, with the greatest rise among women over 50 years of age. After that, the incidence rises steadily to a peak of 102 per 100,000 at ages 65 to 69.

In a Milan series of 216 patients operated on between 1970 and 1989 spasms in your back buy generic zanaflex 2 mg, the average disease-free interval was 32 months for benign phyllodes tumors muscle relaxant tmj cheap zanaflex 4 mg with visa, 22 months for malignant spasms back muscles zanaflex 4 mg order online, and 18 months for borderline phyllodes tumors (65) spasms left side under rib cage purchase zanaflex 4 mg on line. Although surgical margins remain the best predictor of local recurrence muscle relaxant methocarbamol addiction zanaflex 2 mg overnight delivery, two studies suggest that tumor necrosis is also linked to an increased local recurrence risk. In the large phyllodes series of 293 patients from Memorial Sloan-Kettering with median follow-up of 42 months, fibroproliferation was found to be significantly associated with a higher actuarial local recurrence rate. While no other series have described fibroproliferation as a local recurrence risk factor, this histologic feature was not specifically analyzed or referenced in prior studies (Table 62-2). In addition, Geisler and colleagues observed that there was a trend toward a higher rate of locoregional recurrences and metastases with high-grade lesions, but neither high grade nor large tumor size was a statistically significant predictor of recurrence or survival (26). When phyllodes tumors recur after lumpectomy, wide reexcision is performed if possible, although management sometimes requires mastectomy. Patient Follow-up After resection of a phyllodes tumor, patients should be followed for local recurrence in the original tumor bed, which generally will be apparent on clinical examination. August and Kearney recommend clinical breast examinations and breast imaging studies twice per year for the first 5 years, then on an annual basis (50). Routine breast ultrasound examination of the lumpectomy site can be considered, or can be reserved for diagnostic work-up of clinical findings. Anderson series of 101 patients, 8 patients developed distant metastases, with an actuarial 10-year rate of 13% (2). Overall survival in the series was 88%, 79%, and 62% at 5, 10, and 15 years, respectively. For patients with nonmalignant (benign or borderline) and malignant phyllodes tumors, the overall survival was 91% and 82%, respectively, at 5 years, and 79% and 42%, respectively, at 10 years. In a review of 67 reported cases of metastatic phyllodes tumors, Kessinger and colleagues reported that the average survival time after diagnosis of metastasis was 30 months. Metastatic lesions have been reported as early as initial presentation of the primary tumor and as late as 12 years after diagnosis. Stromal overgrowth, which is a required feature for malignant phyllodes tumors, is the most consistent histologic predictor of metastatic behavior (Table 62-3) (2,28,67­70). Anderson series, large tumor size, infiltrative borders, necrosis, and increased mitotic index were associated with increased metastatic risk, but only stromal overgrowth was an independent predictor of distant failure in multivariate analysis. As with sarcomas, distant pulmonary metastases may be resectable for cure in selected cases (71). Other metastatic sites can include bone, liver, heart, distant lymph nodes, distant soft tissue locations such as the forearm, the thyroid, and the pancreas (66,70,72). When used for treatment of metastatic disease, guidelines for treating sarcoma, ratherthanbreastcarcinoma,shouldbefollowed. Predictive Recurrence Models While several have been studied, no individual, or combination of, immunohistochemical tumor markers has been found to be more predictive of metastasis than standard histologic analysis. Multifactor scoring systems have been proposed to better predict recurrence risk for phyllodes tumors. Meneses and colleagues developed a system for assessing degree of histological aggressiveness based on specific histological parameters, including stromal-to-gland ratio, tumor margins, mitotic index, and degree of stromal pleomorphism (55). The descriptive epidemiology of malignant cystosarcoma phyllodes tumors of the breast. Clinicopathologic features and longterm outcomes of 293 phyllodes tumors of the breast. Bilateral cystosarcoma phyllodes of the breast: a case report of malignant form with contralateral benign form. Coexistence of breast cystosarcoma phyllodes and bilateral in situ lobular carcinoma. Malignant phyllodes tumor in the right breast and invasive lobular carcinoma within fibroadenoma in the other: case report. Malignant phyllodes tumour with intraductal and invasive carcinoma and lymph node metastasis. Distinction of phyllodes tumor from fibroadenoma: a reappraisal of an old problem. Fine needle aspiration cytology of fibroadenoma with multinucleated stromal giant cells. Long-term follow-up result of benign phyllodes tumor of the breast diagnosed and excised by ultrasoundguided vacuum-assisted breast biopsy. National surgical patterns of care for primary surgery and axillary staging of phyllodes tumors. Management of non metastatic phyllodes tumors of the breast: Review of the literature. World Health Organization classification of tumors: tumors of the breast and female genital organs. The treatment and prognosis of patients with phyllodes tumor of the breast: an analysis of 170 cases. Quantification of the morphologic features of fibroepithelial tumors of the breast. Predicting clinical behaviour of breast phyllodes tumours: a nomogram based on histological criteria and surgical margins. Proliferating activity in differential diagnosis of benign phyllodes tumor and cellular fibroadenomas: is it helpful Pathologic, immunohistochemical, and molecular features of benign and malignant phyllodes tumors of the breast. Malignant phyllodes tumours of the breast display increased stromal p53 protein expression. Evidence for transformation of fibroadenoma of the breast to malignant phyllodes tumor. Molecular classification of breast phyllodes tumors: validation of the histologic grading scheme and insights into malignant progression. Phyllodes tumour of the breast: clinical follow-up of 33 cases of this rare disease. Retrospective analysis of 25 women with malignant cystosarcoma phyllodes treatment results. A prospective, multi-institutional study of adjuvant radiotherapy after resection of malignant phyllodes tumors. Cystosarcoma phyllodes malignum: a case report of a successive triple modality treatment. Risk factors for recurrence and death after primary surgical treatment of malignant phyllodes tumors. Surgical treatment of phyllodes tumors of the breast: retrospective review of 172 cases. Long-term outcomes of malignant phyllodes tumors patients: an institutional experience. A clinicopathologic study of twenty-six hypercellular periductal stromal tumors of the breast. Delayed cardiac metastasis from phyllodes breast tumor presenting as cardiogenic shock. The majority of cases are associated with an underlying malignancy and prognosis is dependent upon the stage of the underlying cancer (3). The first description of Paget-like features was in 1307 by John of Arderne who recorded the several-year evolution of nipple ulceration in a male priest, with the subsequent development of a breast cancer. It was in 1874 that Sir James Paget recorded the association of the clinical findings with an underlying breast cancer in 15 patients, although he speculated that the chronic skin condition was benign. It was Thin, in 1881, who concluded that the nipple lesion was not a benign entity, but a malignant one. He postulated that the nipple lesion contained cells that were related to the underlying cancer which had extended to the nipple through the major lactiferous sinuses which we refer to today as Pagetoid spread. The most widely accepted one is the epidermotropic theory, first described by Jacobeus, who suggested that the Paget cells arise in breast ducts and spread through the lactiferous sinuses to the nipple epidermis. In addition, heregulin alpha, a motility factor released by normal epidermal keratinocytes can induce chemotaxis of the Paget cells to migrate into the overlying nipple epidermis (6). This in situ transformation theory is thought to occur in pre-existing benign intraepidermal clear cells of the nipple areolar complex, or Toker cells, which are thought to have migrated from nonneoplastic ducts (7). Other studies have identified desmosomal attachments between the Paget cells and adjacent keratinocytes supporting the in situ development of the Paget cell (9). The cells are between the normal keratinocytes of the nipple epidermis, occurring singly in the superficial layers and in clusters toward the basement membrane. Serous fluid can seep through the disrupted keratinocyte layer, resulting in the crusting and scaling of the nipple skin. Paget cells can traverse the epithelium and, thus, sometimes are found in the superficial layers. The basement membrane of the lactiferous sinuses is in continuity with the basement membrane of the skin. Paget cells do not invade through the dermal basement membrane and therefore are a form of carcinoma in situ. This was not significantly different from female (61 years) and male (67 years) patients with ductal breast cancer. This may be accounted for the increased use of mammography and finding cancers at an earlier stage before they develop Pagetoid features. There are probably less than 50 cases described in the world medical literature and most are case reports. The most common initial presentation is erythema and mild eczematous scaling which progresses to crusting, skin erosion, and ulceration, with exudation or frank discharge. Toker cells can be distinguished from Paget cells by their lack of nuclear pleomorphism or cytologic atypia and their absence of mucin (19). The majority of patients who present with a palpable mass have an underlying invasive cancer and thus have a worse prognosis. Patients who present with a palpable mass also have a higher rate of nodal positivity (3,20). The diagnosis can be obtained by scrape cytology, a superficial epidermal shave biopsy, a punch biopsy, a wedge incision biopsy, or nipple excision (19). The ideal specimen contains adequate epidermis to provide Paget cells and a lactiferous duct. Paget cells may be distributed in a patchy fashion throughout the nipple, so additional specimen sampling may be required to secure the diagnosis. In one study, mucin was present in 55% of 20 patients and, thus, was not informative in 45% of patients (22). Paget cells can phagocytose melanin from adjacent epidermal melanocytes and may be mistaken for melanoma if immunohistochemistry is not performed (22). Toker cells are concentrated within the basal layer or arranged into glandular structures growing up to the spinous layer. In the majority of cases the Toker cells were cytologically bland and benign, while in 27. Of the 324 patients in the 11 series, 174 (54%) had normal mammograms (2,13,15,16,23). These retrospective studies included patients accrued in the late 1970s, when xeromammography was still in use and retroareolar spot compression views were not routine. Mammographic findings include skin, nipple, and areolar thickening, nipple retraction, subareolar or more diffuse malignant microcalcifications, and a discrete mass or architectural distortion (24). In addition, it cannot map the true distribution of the underlying pathology and, therefore, has limited value in determining the appropriate surgical procedure (24). In a more recent series from Memorial Sloan Kettering in 23 patients who had a negative mammogram, 65% had an underlying malignancy confined to the central quadrant of the breast implying that perhaps a negative mammogram may indicate suitability for breast conservation. Although the data is encouraging, the overall sensitivity of mammograms in this series was only 34%. However, if the mammogram was positive, it accurately predicted the extent of disease in 82% of patients, supporting the role of mammography in treatment planning (25). However, in 13% of patients the mammogram did not demonstrate the mass seen on ultrasound and only documented microcalcifications. There was clear asymmetry with regard to both morphology and enhancement when pathologic nipples were compared to their healthy counterpart. The linear or triangular enhancement of the involved nipple was seen in all 8 patients. Nipple morphologic change consisting of flattening, areolar thickening, or asymmetry was seen in 7 of 8 patients. Technetium-99 methoxyisobutylisonitrile uptake is increased in breast cancer; this is thought to be due to the increased blood flow from angiogenesis and increased cellular metabolism. These include nipple excision alone, radiotherapy alone, central lumpectomy or quadrantectomy with or without the addition of radiation therapy, and mastectomy. Treatment options have followed the evolution of surgical options for patients with an invasive breast cancer. Several studies have shown that 20 % to 40% of mastectomy specimens have multicentric or multifocal cancers which were underestimated in the mammogram and which potentially would mandate a mastectomy in this subgroup of patients (2). Paone and Baker (35) reported that in 12% of cases, the underlying cancer was 2cm or more from the nipple while Ikeda et al. Others have reported a 50% incidence of peripherally located tumors, the majority of those with a negative mammogram (38). Complete removal of the nipple areolar complex is mandatory in patients undergoing breast conservation regardless of the extent of nipple involvement. There have been several series published which have reported high local recurrence rates with central lumpectomy alone. With a median of 6 years of follow-up, 11 patients (33%) experienced a local recurrence, of which 10 were invasive with 6 developing metastatic disease. Despite negative margins on pathologic exam, at a median follow-up of 56 months, 40% of patients had a local recurrence. Other studies have reported low recurrence rates; however, there were limited numbers of patients and the length of follow-up was not specified (35). The majority of patients did not have an underlying mass (97%) or mammographic abnormality (84%). All patients received whole breast irradiation to a median dose of 50 Gy with a boost to the tumor bed in 97% of cases for a total medial dose of 61.

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The value of preoperative staging chest computed tomography to detect asymptomatic lung and liver metastasis in patients with primary breast carcinoma muscle relaxant injection for back pain order discount zanaflex line. The study did not state how many biopsies were performed for falsepositive findings spasms toddler purchase zanaflex 4 mg visa. Special caution should be taken in appropriately staging new breast cancer patients spasms right arm discount zanaflex 2 mg online. One recent study prospectively examined 103 women with newly diagnosed breast cancer with tumors 2 cm spasms pelvic area 4 mg zanaflex purchase with amex. Thus spasms lung buy zanaflex once a day, it is not recommended as part of routine staging for nonmetastatic breast cancer, and whether it can be used in the adjuvant or neoadjuvant settings to assess response to chemotherapy is not yet clear. Although elevated levels of these markers at the time of breast cancer diagnosis have been shown to correlate with early relapse and death from disease, results have been somewhat conflicting (25­27). Thus, their use as a prognostic marker in the newly diagnosed breast cancer patient is debatable. More importantly, however, these markers have never been proven to be predictive of benefit from treatment. Although baseline levels of circulating tumor cells have been proven to be prognostic for progression-free and overall survival in patients with metastatic breast cancer (30), their significance in early stage breast cancer is less clear. Approximately 10% to 24% of patients with nonmetastatic breast cancer have one or more circulating tumor cells in their blood prior to beginning systemic therapy (29,31). Interestingly, no primary tumor characteristic, including tumor size or pathologic lymph node status, accurately correlated with presence of 1 or more circulating tumor cells. Similarly, women with four or more positive lymph nodes are much more likely than those with N0 or N1 disease to have distant metastatic disease (37). Advanced imaging modalities in early stage breast cancer: preoperative use in the United States Medicare population. Surgical removal of primary tumor and axillary lymph nodes in women with metastatic breast cancer at first presentation: A randomized controlled trial. Changes in the surgical management of patients with breast carcinoma based on preoperative magnetic resonance imaging. Breast cancer evaluation and follow-up: a survey of the Ohio Chapter of the American College of Surgeons. Baseline staging tests after a new diagnosis of breast cancer: further evidence of their limited indications. The clinical use of staging bone scan in patients with breast carcinoma: reevaluation by the 2003 American Joint Committee on Cancer staging system. Bone scan and liver ultrasound scan in the preoperative staging for primary breast cancer. Prospective study of 2-[18F] fluorodeoxyglucose positron emission tomography in the assessment of regional nodal spread of disease in patients with breast cancer: an Ontario Clinical Oncology Group Study. Evaluation of the evidence on staging imaging for detection of asymptomatic distant metastases in newly diagnosed breast cancer. Prognostic relevance of circulating tumor cells in the peripheral blood of primary breast cancer patients. Staging is useful in (a) estimating prognosis for an individual patient, (b) comparing the results of different treatment programs, and (c) it may help in selecting treatment for an individual patient. The founding organizations include the American Cancer Society, the American College of Surgeons, the American Society of Clinical Oncology, Centers for Disease Control and Prevention, National Cancer Institute, and the College of American Pathologists. Since the last edition, the development and use of multi-gene diagnostic tests, such as Oncotype Dx and MammaPrint, have increased substantially and it is anticipated that there will be further developments along these lines. Such patients are treated with initial systemic therapy, discussed in the chapter on locally-advanced and inflammatory breast cancer (Chapters 58 and 59). The current version is the Seventh Edition of the system and is provided later in this chapter (1). Pathologic staging can be performed in patients treated with initial definitive surgery or in patients treated with initial (pre-operative or neoadjuvant) systemic therapy followed by definitive surgery. Pathologic (posttreatment) size should be estimated based on the best combination of gross and microscopic histological findings. While the histologic presence of invasive carcinoma invading dermal lymphatics is supportive of the diagnosis, it is not required, nor is dermal lymphatic invasion without typical clinical findings sufficient for a diagnosis of inflammatory breast cancer. When six or more sentinel nodes are identified on gross examination of pathology specimens the (sn) modifier should be omitted. Metastases (M) · Created new M0(i+) category, defined by presence of either disseminated tumor cells detectable in bone marrow or circulating tumor cells or found incidentally in other tissues (such as ovaries removed prophylactically) if not exceeding 0. Assuming that they do not have clinically and/or radiographically detectable metastases, patients with M0(i+) are staged according to T and N. Note: Definition of posttreatment ypT remains controversial and an area in transition. Microscopic confirmation of the diagnosis is mandatory, and the histologic type and grade of carcinoma should be recorded. Nodes (N) · Classification of isolated tumor cell clusters and single cells is more stringent. Anatomy Primary Site the mammary gland, situated on the anterior chest wall, is composed of glandular tissue with a dense fibrous stroma. If the tumor size is slightly less than or greater than a cutoff for a given T classification, it is recommended that the size be rounded to the millimeter reading that is closest to the cutoff. Designation should be made with the subscript "c" or "p" modifier to indicate whether the T classification was determined by clinical (physical examination or radiologic) or pathologic measurements, respectively. Multiple major and minor ducts connect the milksecreting lobular units to the nipple. Small milk ducts course throughout the breast, converging into larger collecting ducts that open into the lactiferous sinus at the base of the nipple. Glandular tissue is more abundant in the upper, outer portion of the breast; as a result, half of all breast cancers occur in this area. Chest Wall the chest wall includes ribs, intercostal muscles, and serratus anterior muscle, but not the pectoral muscles. Regional Lymph Nodes the breast lymphatics drain by way of three major routes: axillary, transpectoral, and internal mammary. Metastasis to any other lymph node, including cervical or contralateral internal mammary lymph nodes, is classified as distant (M1). Level I (low-axilla): lymph nodes lateral to the lateral border of pectoralis minor muscle. Internal mammary (ipsilateral): lymph nodes in the intercostal spaces along the edge of the sternum in the endothoracic fascia. Supraclavicular: lymph nodes in the supraclavicular fossa, a triangle defined by the omohyoid muscle and tendon (lateral and superior border), the internal jugular vein (medial border), and the clavicle and subclavian vein (lower border). Adjacent lymph nodes outside of this triangle are considered to be lower cervical nodes (M1) (1). Metastatic Sites Tumor cells may be disseminated by either the lymphatic or the blood vascular system. The four major sites of involvement are bone, lung, brain, and liver, but tumor cells are also capable of metastasizing to many other sites. Confirmation of clinically detected metastatic disease by fine-needle aspiration without excision biopsy is designated with an (f) suffix, for example, cN3a(f). Pathologic classification (pN) is used for excision or sentinel lymph node biopsy only in conjunction with a pathologic T assignment. The modifier "sn" is used only if a sentinel node evaluation was performed after treatment. Classification based solely on sentinel lymph node biopsy without subsequent axillary lymph node dissection is designated (sn) for "sentinel node," for example, pN0(sn). If a patient was designated to have detectable distant metastases (M1) before chemotherapy, the patient will be designated as M1 throughout. A cancer can be classified pT for pathologic stage grouping if there is only microscopic, but not macroscopic, involvement at the margin. If the primary tumor is invasive and not only microinvasive, resection of at least the low axillary lymph nodes (Level I)-that is, those lymph nodes located lateral to the lateral border of the pectoralis minor muscle- should be performed for pathologic (pN) classification. Alternatively, one or more sentinel lymph nodes may be resected and examined for pathologic classification. Certain histologic tumor types (pure tubular carcinoma <1 cm, pure mucinous carcinoma <1 cm, and microinvasive carcinoma) have a very low incidence of axillary lymph node metastasis and do not usually require an axillary lymph node dissection. Cancerous nodules in the axillary fat adjacent to the breast, without histologic evidence of residual lymph node tissue, are classified as regional lymph node metastases (N). Pathologic stage grouping includes any of the following combinations of pathologic and clinical classifications: pT pN pM, or pT pN cM, or cT cN pM. The pathologic tumor size for the T classification is a measurement of the invasive component only. The size of the primary tumor is measured for T classification before any tissue is removed for special studies, such as for estrogen receptors. In patients who have received multiple core biopsies, measuring only the residual lesion may result in significantly underclassifying the T component and thus understaging the tumor. In such cases, original tumor size should be reconstructed on the basis of a combination of imaging and all histologic findings. The extent of tissue examined pathologically for clinical staging is not so great as that required for pathologic staging (see next section, Pathologic Staging). Imaging findings are considered elements of staging if they are collected within 4 months of diagnosis in the absence of disease progression or through completion of surgery(ies), whichever is longer. Such imaging findings would include the size of the primary tumor and of chest wall invasion, and the presence or absence of regional or distant metastasis. Imaging findings and surgical findings obtained after a patient has been treated with neoadjuvant chemotherapy, hormonal therapy, immunotherapy, or radiation therapy are not considered elements of initial staging. This Classification Pathologic Staging Pathologic staging includes all data used for clinical staging, plus data from surgical exploration and resection as well as pathologic examination of the primary carcinoma, regional lymph nodes, and metastatic sites (if applicable), including not less than excision of the primary carcinoma with no macroscopic tumor in any margin of resection by pathologic Carcinoma in situ, with no evidence of an invasive component, is classified as Tis, with a subclassification indicating type. Multiple Simultaneous Ipsilateral Primary Carcinomas the following guidelines are used in classifying multiple simultaneous ipsilateral primary (infiltrating, macroscopically measurable) carcinomas. These criteria do not apply to one macroscopic carcinoma associated with multiple separate microscopic foci. Most conservatively, tumors are defined as arising independently only if they occur in different quadrants of the breast. Enter into the record that this is a case of multiple simultaneous ipsilateral primary carcinomas. Simultaneous Bilateral Breast Carcinomas Each carcinoma is staged as a separate primary carcinoma in a separate organ. Thus, the term inflammatory carcinoma should not be applied to a patient with neglected locally advanced cancer of the breast presenting late in the course of her disease. On imaging, there may be a detectable mass and characteristic thickening of the skin over the breast. This clinical presentation is due to tumor emboli in dermal lymphatics, which may or may not be apparent on skin biopsy. It is important to remember that inflammatory carcinoma is primarily a clinical diagnosis. Involvement of the dermal lymphatics alone does not indicate inflammatory carcinoma in the absence of clinical findings. In addition to the clinical picture, however, a biopsy is still necessary to demonstrate cancer either in the dermal lymphatics or in the breast parenchyma itself. Metastases to the ipsilateral internal mammary nodes are designated as N3b when they are detected by imaging studies or by clinical examination and when they occur in conjunction with metastasis to the axillary lymph nodes. In patients who are pathologically node positive with one or more tumor deposits greater than 2 mm, cases with 1 to 3 positive axillary lymph nodes are classified pN1a, cases with 4 to 9 positive axillary lymph nodes are classified pN2a, and cases with 10 or more positive axillary lymph nodes are classified pN3a. Cases with histologically confirmed metastasis to the internal mammary nodes, detected by sentinel lymph node dissection but not by imaging studies (excluding lymphoscintigraphy) or clinical examination, are classified as pN1b if occurring in the absence of metastasis to the axillary lymph nodes and as pN1c if occurring in the presence of metastases to one to three axillary lymph nodes. A case in which the classification is based only on sentinel lymph node dissection is given the additional designation (sn) for "sentinel node"- for example, pN1(sn). For a case in which an initial classification is based on a sentinel lymph node dissection but a standard axillary lymph node dissection is subsequently performed, the classification is based on the total results of the axillary lymph node dissection. Isolated Tumor Cells and Micrometastases Skin of Breast Dimpling of the skin, nipple retraction, or any other skin change except those described under T4b and T4d may occur in T1, T2, or T3 without changing the classification. Cases in which no regional lymph node metastasis is detected are designated N0 or pN0. Cases in which only micrometastases are detected (none greater than 2 mm) are classified pN1mi. A negative clinical history and examination are sufficient to designate a case as M0; extensive imaging or other testing is not required. If the measurement is made by physical examination, the examiner will use the major headings (T1, T2, or T3). Classification is based on axillary lymph node dissection with or without sentinel lymph node dissection. Classification based solely on sentinel lymph node dissection without subsequent axillary lymph node dissection is designated (sn) for "sentinel node,". The Nottingham combined histologic grade (Elston-Ellis modification of Scarff-BloomRichardson grading system) is recommended. The grade for a tumor is determined by assessing morphologic features (tubule formation, nuclear pleomorphism, and mitotic count), assigning a value of 1 (favorable) to 3 (unfavorable) for each feature, and adding together the scores for all three categories. A combined score of 3 to 5 points is designated as grade 1; a combined score of 6 or 7 points is grade 2; a combined score of 8 or 9 points is grade 3. Over the past century, the procedure has evolved considerably from the initial descriptions by Halsted and Meyer in the mid-1890s. In 1894, William Stewart Halsted published the Johns Hopkins Hospital experience with radical mastectomy, reporting a remarkable local regional control rate of 73% with no operative mortality (1). The actuarial survival rate was double that of untreated patients, with a 5-year survival rate of 40%, despite the advanced stage of many of the tumors and the lack of any adjuvant therapy. At that time, the success of the procedure was attributed to the en bloc removal of the breast and its draining lymphatics, and, after this report, the radical mastectomy remained the standard of care until the 1970s.

This lesion can be mistaken for a poorly differentiated carcinoma or a large cell lymphoma when melanin pigment is not readily seen muscle relaxant agents generic zanaflex 2 mg free shipping. Excision margins for primary cutaneous melanoma: updated pooled analysis of randomized controlled trials muscle relaxant youtube zanaflex 4 mg buy fast delivery. This procedure also identifies patients who might be candidates for clinical trials of adjuvant systemic therapy muscle relaxant wpi 3968 buy zanaflex visa. If it is not clear whether the tumor is a primary breast cancer versus a metastasis muscle relaxant you mean whiskey discount zanaflex 2 mg on-line, it should be treated with curative intent as a primary breast cancer muscle relaxant 800 mg zanaflex 2 mg purchase. If the tumor is clearly metastatic but its origin is uncertain, treatment planning should take into account the most probable histologic diagnosis and primary site of the tumor as well as the potential efficacy of systemic treatments available for the presumed primary tumor. As metastases to the breast are rare and have diverse origins, a multidisciplinary approach is necessary to determine optimal treatment. MetaStaSeS tO the BreaSt the incidence rate of metastases to the breast from extramammary sites ranges from 1. The most common presentation is the development of metastasis from the contralateral breast by a cross-lymphatic route, especially in premenopausal women. Other malignancies that can metastasize to the breast include non-Hodgkin lymphomas, leukemias, melanomas, lung cancer, gastric cancer, and ovarian cancer. Rare cases of metastases from fallopian tube cancer, ovarian dysgerminoma, renal cancer, medullary thyroid cancer, carcinoid, medulloblastoma, malignant schwannoma, and pharyngeal carcinoma have been reported (66­68). Radiographic imaging using mammography and ultrasonography are not sufficient to determine whether a tumor is primary or metastatic. A fine-needle aspiration and/or a core needle biopsy are needed to make the diagnosis. Pathologic assessment for metastases to the breast includes conventional histology, immunohistochemistry, cytogenetics, flow cytometry, and electron microscopy analysis. Clinically, it is important to differentiate bilateral primary tumors from metastatic tumors that coexist with a primary breast cancer. All suspicious lesions should be biopsied to clarify the overall diagnosis and treatment approach. Factors suggesting contralateral metastatic breast cancer include short diseasefree interval, multiple breast lesions, and known metastatic breast cancer at other distant sites (68). Factors suggesting non-breast metastatic disease include location in fat or subcutaneous tissue as opposed to breast parenchyma, lack of in situ disease histologically, bilateral or multiple lesions, and lack of microcalcifications on mammography (64,69). Metastatic breast cancer to the contralateral breast is treated with systemic therapy directed to the primary tumor. Prognostic factors in primary breast sarcomas: a series of patients with long-term follow-up. Soft-tissue sarcoma after treatment for breast cancer-a Swedish population-based study. Increased risk of soft-tissue sarcoma after radiotherapy in women with breast cancinoma. Primary breast sarcoma; clinicopathologic series from the Mayo Clinic and review of the literature. Primary follicular and marginalzone lymphoma of the breast: clinical features, prognostic factors and outcome: a study by the International Extranodal Lymphoma Study Group. Primary and secondary breast lymphoma: prevalence, clinical signs and radiological features. Update on the melanoma staging system: the importance of sentinel node staging and primary tumor mititic rate. Molecular upstaging based on paraffin-embedded sentinel lymph nodes: ten-year follow-up confirms prognostic utility in melanoma patients. Highly sensitive multivariable assay detection of melanocytic differentiation antigens and angiogenesis biomarkers in sentinel lymph nodes with melanoma micrometastases. Metastases to the breast from non-mammary malignancies: primary tumors, prevalence, clinical signs and radiological features. Stromal sarcoma of the breast with lung metastases showing a clinical complete response to doxorubicin plus ifosfamide treatment: report of a case. Nine breast angiosarcomas after conservative treatment for breast carcinoma: a survey from French comprehensive Cancer Centers. Angiosarcoma of the breast; a clinicopathologic analysis of cases from the last 10 years. Hemangiomas and angiosarcomas of the breast; diagnostic utility of cell cycle markers with emphasis on Ki-67. Atypical vascular lesions after surgery and radiation of the breast: a clinicopathologic study of 32 cases analyzing histologic heterogeneity and association with angiosarcoma. Primary osteogenic sarcoma of the breast: a clinicopathologic analysis of 50 cases. A review of a large multi-institutional series of malignant matrix-producing breast tumours. Primary and metastatic rhabdomyosarcoma in the breast: neoplasma of adolescent females, a report from the Intergroup Rhadbdomyosarcoma Study. Primary malignant fibrous histiocytoma (myxofibrosarcoma/pleomorphic sarcoma not otherwise specified) of the breast: clinicopathologic study of 19 cases. Young breast cancer patients can be faced not only with the diagnosis and treatment of their breast cancer, but also with concerns regarding fertility, future pregnancies and, for some, breast cancer diagnosis and treatment during pregnancy. Since women seem to be delaying childbirth to later ages than in previous generations, the incidence of breast cancer and pregnancy, as well as the importance of future pregnancies subsequent to successful treatment for breast cancer, must be considered as part of the informed decision process when discussing treatment of breast cancer with younger women. We will review the diagnosis and treatment of breast cancer and concurrent pregnancy, the prognosis for those treated during pregnancy, effects of treatment for children exposed to systemic therapies in utero and, for women with successfully treated primary breast cancer, the breast cancer prognosis in relation to future pregnancies. In a large retrospective population-based study in California between 1991 and 1997, there were 1. In women under the age of 50 who are diagnosed with breast cancer, approximately 0. As women delay childbearing, the incidence of breast cancer coinciding with pregnancy may increase since the frequency of breast cancer diagnosis increases with age (4). The diagnosis of breast cancer was more common among women over 35 years of age (5). In patients with breast cancer with a recent past pregnancy, some retrospective analyses have shown a worse prognosis. For each 1-year increment in the time between the latest previous pregnancy and breast cancer diagnosis, the risk of dying decreased by 15% (relative risk 0. These studies were not able to control for delay in diagnosis, treatment, or treatment modalities of the breast cancer. Future translational research may help identify whether or not there is a true biologic difference in breast cancers diagnosed soon after pregnancy to account for these differences. A recent case-control study concludes that current or recent pregnancy is associated with adverse pathologic features but breast cancer survival is not impaired (9). Due to the physiologic changes in the breast that occur during pregnancy and lactation, including increased size and density of the breast tissue, there may be a delay in diagnosis of breast cancer as these physiologic changes can obscure detection (10). Pregnancy-associated physiologic changes in the breast may be even more pronounced in patients under the age of 30 (16). Therefore, women diagnosed with breast cancer during pregnancy often present with an advanced tumor stage and axillary lymph node involvement. Given the concern for delay of diagnosis, palpable masses or breast distortions persisting over 2 weeks should be investigated. Few studies, with small numbers of patients, have evaluated the potential increased risk in hereditary breast cancer patients (10,11). Given the risk of a deleterious mutation in women who develop breast cancer at an early age, genetic counseling should be part of the clinical discussion and evaluation for all such patients. This level is substantially below the level of 5 rad, a level at which multiple studies have shown no known increase in congenital malformations or growth retardation (18). One study diagnosed 100% of the breast masses as well as axillary metastases in 18 of 20 women (19). Ultrasound was also shown to be effective for evaluating response to preoperative chemotherapy in the pregnant breast (19). Gadolinium has been shown to cross the placenta and be associated with fetal abnormalities in animal models (20,21). Animal studies have shown diverse fetal effects and gadolinium is considered a pregnancy category C drug (Table 65-1). There have been no controlled human studies to date, however; several studies have observed no significant toxicity when gadolinium has been given during human pregnancy. But there does remain some controversy as to the safety of gadolinium during pregnancy and therefore should be used with caution. Staging and Diagnosis of Breast Cancer during Pregnancy Biopsy Any clinically suspicious breast mass requires biopsy, even if the ultrasound and mammogram are equivocal or nondiagnostic. Animal studies do not indicate a risk to the fetus and there are no controlled human studies or animal studies to show an adverse effect on the fetus, but well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. Studies have shown that the drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women. Studies in animal or humans have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk clearly outweighs any positive benefit. Core or excisional biopsies can be performed safely with local anesthesia, with only one found report of the development of a milk fistula after a core needle biopsy (22). Pathology of Breast Cancer Diagnosed during Pregnancy the majority of breast cancer cases are infiltrating ductal adenocarcinomas with one prospective cohort showing 84% with poorly differentiated tumors (23). Staging procedures may need to be modified for the pregnant breast cancer patient with safety considerations for both the patient and the fetus. Staging is important, however, for better understanding of the full extent of disease, informing treatment recommendations, considering the potential influence of the treatment on cancer outcome and the potential impact of cancer treatment on the fetus and pregnancy. Radiation exposure for the fetus and outcomes regarding different imaging modalities are available (28). Guidelines have been established regarding imaging and staging during pregnancy (29,30). However, staging procedures need to be tailored to minimize fetal radiation exposure, provide adequate information to determine disease stage, and provide sufficient knowledge for informed decisions for clinicians and patients. Recommended initial staging should include the following: complete history and physical examination with special attention to breast and nodal basin examinations; comprehensive metabolic panel; and complete blood count with differential. It is important to note that pregnant patients may have anemia due to the increase in circulating plasma volume. They may have increases in serum alkaline phosphatase level that can be doubled or tripled due to the pregnancy itself. The physical examination of the breast and nodal basins needs to include tumor measurements when possible and an assessment of extent of clinical nodal involvement. Radionuclide scanning, including bone scanning, has very limited safety data in the pregnant patient, and should be considered only if absolutely necessary with aggressive hydration and frequent voiding. Locoregional Therapy Surgery and Anesthesia Breast surgery can be safely performed in all trimesters of pregnancy; however, patients and surgeons may choose to wait until after the 12th week of gestation when the risk of spontaneous abortion may be lower (29). Multiple studies evaluating the risks of anesthesia during pregnancy have not shown an increase in fetal abnormalities. Mazze and Kallen reported on a registry of 5,405 pregnant patients who had any kind of surgery during pregnancy. They observed no difference in the risk of fetal malformation when they compared the pregnant group to 720,000 women who did not have a surgical procedure during pregnancy. There was, however, an increase in the frequency of low- and very-low-birth-weight infants. This was attributed to the underlying illness or trauma necessitating the surgery (32). A recent review of surgery in the pregnant patient recommends that the preferred timing for surgical intervention is 16 to 20 weeks of gestation (34). Although in the majority of published reports patients opt for mastectomies for breast cancer treatment due to concerns regarding radiation therapy, breast-conserving surgery is an option, especially in women in the third trimester of pregnancy who can receive radiation therapy after delivery. With the potential of preoperative chemotherapy during pregnancy, breast-conserving surgery can be done later in the pregnancy or after delivery (35). Safety and efficacy of sentinel lymph node biopsies is currently an area of clinical interest. The sensitivity and specificity of sentinel lymph node biopsies in the pregnant woman with breast cancer has not been well established. Estimated radiation exposure to the fetus is low and calculated to a maximum of 4. However, isosulfan blue dye mapping is not recommended due to concerns of unknown effects for the fetus as well as risk of anaphylaxis for the patient. Sensitivity of sentinel lymph node mapping may be significantly decreased without using isosulfan blue. The concern with sentinel node procedure in the pregnant patient is not the technical aspects of the procedure but the accuracy of the diagnostic information obtained as a result of the procedure. Sentinel node excision has not been subjected to the same rigorous study in the pregnant population as in the nonpregnant population (37). Therefore prudent and careful clinical evaluation prior to the procedure is warranted. Systemic Therapy Chemotherapy Systemic chemotherapeutic agents are designed as antiproliferative drugs. Categories A and B agents generally felt to be safe for use in pregnant patients, with Category C reporting some teratogenic or embryocidal effects in animal studies but no information in humans. Although most chemotherapeutic agents are Category D, there are data demonstrating that systemic chemotherapy can be given safely during pregnancy during the second and third trimester. Clinical consideration for the use of systemic therapies should be similar in pregnant and nonpregnant patients. Despite limited knowledge regarding pharmacokinetics of chemotherapeutic agents in breast cancer due to the physiologic changes of pregnancy (increased plasma volume, altered renal and hepatic function, and third spacing potential), several published patient cohorts have described successful administration of chemotherapies to pregnant breast cancer patients.

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