Clinical and radiological presentation Mesothelioma can be insidious in its onset with a me dian time from \201rst symptoms to diagnosis of 2 \200\2233 months. Symptoms at presentat ion commonly include non-pleuritic chest pain and dyspnoea. Con- stitutional symptoms such as fever, fatigue, and weight loss are seen in OHO-16(259-294) 11/18/02 8:16 AM Page 287 MESOTHELIOMA 287 30% of patients. Physical examination frequently demonstrates decreased breath sounds and d ullness to percussion due to a pleural effusion or diffuse pleural tumor. Signs of advanced disease are: (cid:2) Chest wall mass (cid:2) Hoarseness (cid:2) Superior vena cava syndrom e (cid:2) Horner \200\231s syndrome (cid:2) Ascites \200\224heralding abdominal involvement (cid:2) Lymphadenopathy \200\224an infrequent \201nding Laboratory results in mesothelio ma are usually unremarkable with no serological tumor marker reproducibly isolated. The rad iological presentation of mesothelioma is non-speci \201c. Pleural effusion is com- mon an d may be associated with pleural thickening and nodularity. The extent of the pleural mass and encasement of the lung is well demonstarted by CT. However, this imaging modality is le ss sensitive in detecting mediastinal or transdiaphragmatic involvement. Magnetic resonance imaging (MRI) of the chest and upper abdomen provides superior de \201n ition of tissue planes, in addition to sagittal and coronal views of the diaphragm and thor ax apices, and is an important adjunct to staging. Diagnosis Thoracoscopy remains the procedure of choice to obtain a patho- logical diagnosis of malignant mesothelioma, with an 80% diagnostic yield. Thoracocentesis and percutaneous pleural biopsy has a yield of only 30 \200\22340%. When thoracoscopy is not possible due to obliteration of the pleural space by the tumor, an open pleural biopsy may be per- formed. Careful planning of the incision site is essential because mesothelioma has a propensity t o implant within chest wall wounds. Exploratory thoracotomy should be avoided. Table 16.6 Brigham Staging System for malignant pleural mesothelioma Stage Description I Disease completely resected within the capsule of the parietal pleura without adenopathy; ipsilateral pleura, lung, pericardium, diaphragm, or ch est wall disease limited to previous biopsy sites II All of Stage I with positive resection margins and/or intrapleural adenopathy III Local extension of disease into the chest wall or mediastinum, heart, or through diaphragm into peritoneum; or with extrapleural lymph node involvement IV Distant metastatic disease OHO-16(259-294) 11/18/02 8:16 AM Page 288 THORACIC CANCER 288 Staging In 1976, Butchart proposed a staging system based on the extent of tumor involvemen t within the chest, but this system correlated poor- ly with survival. Subsequently, altern ative staging systems have been proposed, several based on a TNM concept, although none hav e gained universal acceptance. The Brigham staging system provides a straightforward characteri- zation method, based on k ey disease characteristics, that strati \201es survival. In a series of 183 patients treat ed in a multimodality setting, median survival for patients with stage I, II, and III disea se was 25, 20, and 16 months respectively. Accurate pre-operative pathological staging is best achieved by thoracoscopy for pleural ev aluation, mediastinoscopy for mediastinal nodal involvement, and laparoscopy to rule out pe ritoneal seeding or diaphragmatic involvement when indicated. Treatment Without treatment, the average patient with MPM survives less than one year from the time of diagnosis. As a result of this poor prognosis various therapeutic options have been explored includ- ing: (cid:2) Radiotherapy (cid:2) Chemotherapy Immunotherapy (cid:2) (cid:2) Surgery Individually, each of these modalities has been disappointing when compared to single-modality treatment results. Current experience has shown multimodality therapy t o offer improved survival in selected patient groups. Multimodality therapy should be carri ed out in the context of an approved study protocol by thoracic surgeons experienced in tre ating this disease. At Brigham and Women \200\231s Hospital, Boston, extrapleural pneumon- ectomy followed by c hemotherapy (carboplatin and paclitaxel) and radiotherapy (40.5 Gy) is being used. Recently , 183 patients have been reviewed, demonstrating an overall median survival of 17 months an d 2- and 5-year survival rates of 36% and 14% respectively. Positive predictors for improve d outcome were epithelial histology, negative resection margins after operation, and negati ve extrapleural nodal status. Patients with all three positive predictors enjoyed a 51-mont h median survival with 2- and 5-year survival rates of 68% and 46% respectively. The following novel therapeutic approaches are currently under- going active clinical inves tigation in an effort to improve treatment survival outcome: OHO-16(259-294) 11/18/02 8:16 AM Page 289 MESOTHELIOMA 289 Intracavitary, hyperthermic chemotherapy (cid:2) (cid:2) Gene therapy Immunotherapy (cid:2) (cid:2) Photodynamic therapy OHO-16(259-294) 11/18/02 8:16 AM Page 290 THORACIC CANCER 290 Thymic tumors Introduction Tumors derived from the thymus (thymomas) comprise approxi- mately 20% of all mediastinal tumors and are the most common tumor in the anterior mediastinum. Thymomas occu r at any age but are rare before the age of 20 and peak between 40 \200\22360 years. The in cid- ence varies somewhat in different countries with high values in the Far East. The aver age in Europe is around 0.5 new cases per year per 100 000. Etiology of these tumors is unk nown; a possible relation to Epstein \200\223Barr virus infection has not been proven. Pathology Most thymomas are slow-growing \200\230low-grade \200\231 malignant tumors. It i s believed that they derive from epithelial elements, but the tumors retain the capacity fo r production of T cells. The T cells are generally of normal phenotype. According to the re lative abundance of epithe- lial and lymphocytic cells, histological subgroups have been de scribed: (cid:2) Epithelial (cid:2) Lymphocytic (cid:2) Mixed or lympho-epithelial type The se cellular characteristics have no clear in \202uence on prognosis. In contrast, the gros s appearance of the tumor is related to clinical prognosis. The presence or absence of an i ntact capsule is of prognos- tic importance and local invasiveness remains the most consist ent factor in predicting outcome. The metastatic potential of thymomas is dif \201cult to assess on the basis of histology and cytological features. A \200\230benign \200\231 thymoma has been de \201ned as a tumor that is well encap- sula ted and does not invade adjacent mediastinal structures; 50 \200\22365% of thymomas \201t this de \201nition. The differentiation between benign and malignant thymoma is, however, dif \201cult and thymomas should in general be regarded as potentially malignant. In all cases where residual tumor is left after surgery, adjuvant therapy should be considered. Presentation and clinical features (cid:2) 30% \200\224no local symptoms (cid:2) Produce paraneoplastic syndromes (cid:2) 70% associated with an immunological phenomenon OHO-16(259-294) 11/18/02 8:16 AM Page 291 THYMIC tumors 291 (cid:2) Antibodies target acetylcholine receptor causing myasthenia gravis (cid:2) Myasthen ia occurs in 10 \200\22315% of patients with thymoma (cid:2) 10 \200\22325% of patients wit h myasthenia have a thymoma (cid:2) Red-cell aplasia occurs in 5% of thymomas (cid:2) 30 \200\22350% of patients with red-cell aplasia have a thymoma In 30%, low platelets or low white-cell count occur (cid:2) (cid:2) Hypogammaglobulinaemia occurs in 5 \200\22310% of patients with thymoma (cid:2) 10% of patients with hypogammaglobulinaemia have a thymoma Many of the patients wit h autoimmune disorders belong to the older age group and removal of the thymoma results in remission in only approximately one-third of these patients. As these symptoms can arise al so in small tumors, the possibility of curative treatment may be better when paraneoplastic syndromes prevail. In the absence of paraneoplastic effects, thymomas are often large befo re they give rise to local symptoms such as cough, dyspnoea, dysphagia, stridor, and chest pain. Superior vena cava obstruction (SVCO) may result. Thymomas are most commonly located within the anterior medi- astinum but half will extend t o the superior mediastinum. CT or MR scanning is necessary to: (cid:2) Direct surgical inte rvention (cid:2) Plan radiotherapy treatment (cid:2) Evaluate treatment response (cid:2) Mo nitor recurrence of disease Treatment and staging Surgery is the treatment of choice for localized disease. Median ster - notomy is the preferred incision for thymectomy, since it provides excellent exposure of the thymoma and the adjacent organs. The stag- ing of disease is based on the surgical \201ndings as well as radiology: Stage I: tumor con \201ned within intact capsule Stage II: pericapsular growth into the me diastinal fat tissue Stage III: invasive growth into the surrounding organs Stage IV: disse minated disease The most effective therapy of thymoma is complete removal, and modern techniques have made it possible to resect even invasive thy- momas. The superior vena cava can be removed and r econstructed and parts of the lung or pleura can be resected when required. In Stage I disease adjuvant treatment is not applied. In all other cases, additional antine oplastic treatment is recommended after surgery. In local disease with or without residual tumor, radio- therapy is recommended in doses of 50 \200\22360 Gy given in 20 \200\22330 fr ac- tions. The treatment is delivered via a linear accelerator often using an OHO-16(259-294) 11/18/02 8:16 AM Page 292 THORACIC CANCER 292 anterior and two oblique \201elds, minimizing the dose to the normal lung and the spinal cord. The reported series are not big enough to have suf \201cient statistical power to show sig ni \201cant survival bene \201ts of adjuvant treatment. Radically resected invasive thymo mas have 5- and 10-year survival rates of 80% and 73% respectively. This should be compared with the results after subtotal resection followed by radiotherapy \200\22459% and 54%. Th e rate of recurrence is 3% with Stage I, 13% with Stage II, 27% with Stage III disease, and 54% with Stage IV disease. Paraneoplastic effects such as myaesthenia gravis improve after thymectomy in 30 \200\22350 % of cases. Patients with persistent myaesthenia require medical treatment with anticholine sterase agents and/or immunosuppressants. Recurrent and metastatic thymoma should be treated with systemic treatment. The reported se ries are small, but a commonly used active regimen is cisplatin, doxorubicin, cyclophospham ide. The response rate with combination chemotherapy is 50 \200\22370%. This relatively hig h ef \201cacy has given rise to Phase II studies of adjuvant chemotherapy and neo-adjuvant chemotherapy followed by surgery and radiation, with promising results. Summary The contemporary standard of treatment of thymoma is radical surgery whenever possi ble. Total resection alone is adequate therapy for Stage I thymoma. Adjuvant therapy should be used for local disease with demonstration or suspicion of invasion. Locally advanced, r elapsing, or disseminated disease should be treated with combination chemotherapy including corticosteroids. Cisplatin- based regimens are recommended. OHO-16(259-294) 11/18/02 8:16 AM Page 293 THYMIC tumors 293 OHO-16(259-294) 11/18/02 8:16 AM Page 294 THORACIC CANCER 294 Further reading 1. Non-Small Cell Lung Cancer Collaborative Group (1995) Chemotherapy in non-small cell lun g cancer: a meta-analysis using updated data on individual patients from 52 randomized clin ical trial. British Medical Journal 311, 899 \200\223909. 2. Goldie, J.H., Goldman, A.J., and Gudanuskas, G.A. (1982) Rationale for the use of altern ating non-cross resistant chemotherapy. Cancer Treat Rep 66, 439 \200\22349. 3. Gregor, A., Cull, A., Stephens, R.J. et al. (1997) Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lun g cancer. Eur J Cancer 33: 11, 1752 \200\2238. 4. Healy, E.A. and Abner, A. (1995) Thoracic and cranial radiotherapy for limited-stage small cell lung cancer. Chest 107, 249S \200\22354S. 5. Pignon, J.P., Arriagada, R., Ihde, D.C. et al. (1992) A meta-analysis of thoracic radiotherapy for small cell lung cancer. N Eng J Med 327, 1618 \200\22324. 6. Steward, W.P., Von Pawel, J., Gatzemeier, U. et al. (1998) Effects of granulocyte-macrophage colony-stimulating factor and dose intensi \201cation of V-ICE chem otherapy in small cell lung cancer: a prospective randomized study of 300 patients. J Clin Oncol 16, 642 \200\22350. 7. Sugarbaker, D.J. and Garcia, J.P. (1997) Multimodality therapy for malignant pleural mes othelioma. Chest 112 (Suppl), 272S \200\2235S. OHO-17(295-322) 11/18/02 8:24 AM Page 295 Chapter 17 Breast cancer Epidemiology 298 Genetics of breast cancer 300 Pathology 302 Prognostic factors 304 Breast cancer screening 306 Breast cancer \200\224presentation and staging 310 Management of non-i nvasive breast cancer 312 Management of early breast cancer 314 Management of locally advan ced breast cancer 318 Management of metastatic breast cancer 320 Prevention of breast cance r 322 OHO-17(295-322) 11/18/02 8:24 AM Page 296 BREAST CANCER 296 Much effort has been invested in this most common solid tumor occurring in women. The study of breast cancer has rewarded us with lessons in many aspects of oncological practice: (ci d:2) Population screening (cid:2) Medical genetics (cid:2) Adjuvant therapy (cid:2) Meta-an alyzes (cid:2) Clinical guidelines The bene \201ts of this industry are now visible, with a fall in breast can- cer deaths over the last decade. OHO-17(295-322) 11/18/02 8:24 AM Page 297 BREAST CANCER 297 OHO-17(295-322) 11/18/02 8:24 AM Page 298 BREAST CANCER 298 Epidemiology (cid:2) Commonest female cancer in Europe (200 000 cases per year) (cid:2) 20% of all malig nancies Incidence is increasing by 1% per year (cid:2) (cid:2) Rate of increase is increasing especially in low-risk populations (cid:2) Lifetime risk in USA is 1 in 10 (cid:2) Risk of breast cancer correlates with income per capita (cid :2) Mortality in Western Europe and USA, 15 \200\22325 per 150 000 women In UK \200\22435 000 new breast cancers diagnosed per year (cid:2) \200\22414 000 breast cancer deaths per year (cid:2) Breast cancer deaths in UK is highest in world In UK, recent decrease in breast cancer mortality by 20% (cid:2) Several risk factors have been identi \201ed by epidemiological studies: (cid:2) Age: brea st cancer is very rare before the age of 20 and rare below 30 years. The incidence of breas t cancer doubles every 10 years until the menopause, when the rate of increase slows and in some coun- tries plateaus. (cid:2) Geography: there is a seven-fold variation in incidence between countries, with low rates in the Far East. Migrants from low- incidence countries assume the risk in the host country within two generations. (cid:2) Age at menarche and menopause: early menarche and late menopause increase the risk. Ovarian ablation before 35 years reduces the risk of breast cancer by 60%; menopause after the age of 55 years doubles the risk. (cid:2) Age at \201rst pregnancy: nulliparity and late age at \201rst pregnancy increas e the risk. A woman whose \201rst pregnancy is at 30 years has double the risk of breast cancer compared with \201rst pregnancy at <20 years. (cid:2) Family history: genetic predisposition accounts for around 10% of breast cancers. (cid:2) Exogenous oestrogens: use of oral contraceptives for >4 years before \201rst preg nancy increases the risk of pre-menopausal breast cancer. The use of unopposed oestrogens i n hormone replacement therapy for 10 \200\22315 years is associated with an increase in bre ast cancer. Combined preparations also increase the risk, but the magnitude of effect is un certain. OHO-17(295-322) 11/18/02 8:24 AM Page 299 EPIDEMIOLOGY 299 (cid:2) Diet: associations have been shown with high dietary fat intake, obesity, and alcohol consumption. (cid:2) Benign breast disease: previous breast surgery for severe atypical epithelial hyper plasia is associated with a four-fold increase in risk. (cid:2) Radiation: exposure to ioni zing radiation at an early age e.g. treat- ment of Hodgkin \200\231s. Mammographic screenin g is associated with a decrease in breast cancer deaths but the effects of screening younge r women are uncertain. Male breast cancer is rare (0.7% of all male cancers) with a peak inci- dence 10 years late r than women. It may occur in association with Klinefelter \200\231s syndrome. OHO-17(295-322) 11/18/02 8:24 AM Page 300 BREAST CANCER 300 Genetics of breast cancer It is estimated that 5 \200\22310% of female breast cancer is due to inheritance of a mutat ed copy of either BRCA1 or BRCA2. Women who inherit a mutated copy of either gene have an e levated lifetime risk of breast cancer \200\224up to 87% by the age of 70 years. There is p articular risk of pre-menopausal breast cancer, often before the age of 40 years; there is an associated risk of ovarian cancer (greater with BRCA1); and male carriers are at risk of prostate cancer. Some ethnic groups are at particular risk for carriage of these mutations (estimated 2% of US Ashkenazi Jews). Other genes contribute less frequently to familial breast cancer. It is hypothesized that a taxia telangiectasia heterozygotes are at risk, but this is as yet unproven. Breast cancer occurs with mutation in PTEN (Cowden disease), MSH1 or MSH2 (HNPCC), and p53 (Li Fraumeni s yndrome). The management of hereditary breast cancer is essentially that of non-hereditary disease. L ess clear is how to manage asymptomatic female members of these families. Guidelines sugges t referral to medical genetic clinics for counseling, advice on risks, consideration of tes ting for mutations of BRCA1 and BRCA2, and referral for appro- priate further management. C urrently, the options open to these women are: (cid:2) Prophylactic surgery: bilateral subc utaneous mastectomy does reduce the incidence of breast cancer in these women but its impac t on survival is uncertain. (cid:2) Screening: is of unproven bene \201t in this setting, with uncertainty about the a ge of \201rst testing, frequency of testing, and the value and risks of frequent mammogra phy. (cid:2) Breast cancer prevention trials. OHO-17(295-322) 11/18/02 8:24 AM Page 301 GENETICS OF BREAST CANCER 301 Table 17.1 Eligibility criteria for referral to breast cancer families \200\231 clinic (cid:2) Mother or sister developed breast cancer aged <40 years (cid:2) Mother or sister developed breast cancer aged <50 years and another maternal relati ve had cancer of the breast, ovary, endometrium, or a sarcoma <65 years (cid:2) Mother or sister developed breast cancer aged 50 \200\22365 years and another maternal relative had cancer of the breast, ovary, endometrium, colorectum, or a sarcoma <5 0 years (cid:2) Mother or sister developed double primary cancer (breast plus any of ovary, endometrium, colon, or sarcoma) with at least one tumor before age 50 years and brea st cancer before 65 years (cid:2) Dominant history of breast cancer \200\2244 or more cases of breast or ovarian cancer on same side of the family at any age (cid:2) Cancer of colorectum, ovary, endometrium, or sarcoma in mother or father before age 50 years, and at least one \201rst-degree relative with breast cancer age <50 years (cid:2) Two or more cancers of breast, colorectum, ovary, endometrium, or sarcoma in close relatives of father with at least one before age 50 years OHO-17(295-322) 11/18/02 8:24 AM Page 302 BREAST CANCER 302 Pathology Breast cancer is more common in the left breast and around 50% arise in the upper outer qua drant. The commonest pathology is ductal carcinoma. Ductal carcinoma in situ(DCIS) 90% of breast carcinomas arise in the ducts of the breast. T hey begin as atypical proliferation of ductal epithelium that eventually \201ll and plug the ducts with neoplastic cells. As long as the tumor remains within the con \201nes of th e ductal basement membrane it is classi \201ed as DCIS. Localized DCIS is impalpable but o ften visible on mammo- graphy as an area of microcalci \201cation. Not all DCIS will inevi tably progress, but the probability of development of invasive cancer is estimated at 30 \200\22350%. Lobular carcinoma in situ These pre-invasive lesions carry a risk not only of ipsilateral i nvasive lobular carcinoma but also of contralateral breast cancer. They typi- cally are nei ther palpable nor contain microcalci \201cation. Invasive ductal carcinoma This accounts for 75% of breast cancers. The malignant cells are associated with a \201brous stroma which can be dense (scirrhous carcin- oma). The tumor invades through breast tissue into the lymphatics and vascular spaces, to gain access to th e regional nodes (axillary and, less often, internal mammary) and the systemic circulation. Table 17.2 Histological types of breast malignancy Invasive ductal carcinoma (cid:2) No special type Combined with other type Medullary carcinoma Mucinous carcinoma Paget \200\231s disease Invasive lobular carcinoma (cid:2) (cid:2) Mixed lobular and ductal carcinoma (cid:2) Sarcoma (various) (cid:2) Lymphoma (cid:2) Metastases (e.g. breast cancer, small cell lung cancer) OHO-17(295-322) 11/18/02 8:24 AM Page 303 PATHOLOGY 303 The histological grade of the tumor is assessed from three features (tubule formation, nucl ear pleomorphism, and mitotic frequency) and predicts the behavior of the tumor. Estrogen a nd proges- terone receptor status is commonly assessed by immunocyto- chemistry. Other biol ogical markers (e.g. c-erbB2) may be of value both as a predictor of prognosis and as a gui de to therapy. Ductal carcinoma of special type A number of pathological variants are identi \201ed with relatively good prognosis, namely medullary carcinoma, tubular carcinoma, and mucinous carc inoma. Paget \200\231s disease of the breast is ductal carcinoma of the excretory ducts wit h involvement of the skin of the nipple and areola. Invasive lobular carcinoma Lobular carcinomas account for 5 \200\22310% of breast cancers. About 20% develop contralateral breast cancer. OHO-17(295-322) 11/18/02 8:24 AM Page 304 BREAST CANCER 304 Prognostic factors Survival after a diagnosis of breast cancer is dependent upon: (cid:2) Eradication of the p rimary tumor (cid:2) Loco-regional disease, particularly axillary and/or internal mam- mary nodes (cid:2) Any systemic metastases The latter determines the prognosis for the vast majority o f women and is closely correlated with a number of recognized prognostic factors: (cid:2) T umor size (cid:2) Number of involved axillary nodes (cid:2) Tumor grade (cid:2) Estrogen re ceptor status (ER) The usefulness of other biological factors (c-erbB2, markers of angio- g enesis, cathepsin D, etc.) is currently being explored. OHO-17(295-322) 11/18/02 8:24 AM Page 305 PROGNOSTIC FACTORS 305 OHO-17(295-322) 11/18/02 8:24 AM Page 306 BREAST CANCER 306 Breast cancer screening There have been at least seven randomized controlled trials of mammographic screening over the last 30 years. The HIP study of New York and the Two Counties Study from Sweden both sh owed a 30% reduction in mortality in the >50-year-old age group who were screened with mamm ography. Meta-analysis of all the published trials con \201rms a signi \201cant bene \201t for the over-50s. None of the trials published so far have shown a mortality bene \201t for women under the age of 50 years, although two meta-analyzes report a 14% but non-signi \201cant reduction in mortality. Screening the under-50 age group remains a controversial area and in the UK a current trial is recruiting over 200 000 women to address this question. Imaging modality The aim of screening for this disease is to identify pre-invasive disease or invasive disease before dissemination (through the lymphatics or blood). There is no evi dence that simple breast self-examination is an effective means of screening for breast can cer. X-ray mammography is the most sensitive technique for detecting breast cancer and is a lso the most speci \201c. Mammography is most sensitive once involution of the breast tiss ue has occurred (i.e. once the menopause has taken place). The test is less sensitive in wo men with dense breasts \200\224that is those with predominantly glandular tissue or residua l stromal tissue. Breast ultrasound, useful for focal abnormalities, is also useful in detecting impalpable l esions. Telediaphanography (infrared scanning of the breast tissue) has both low sensitivit y and speci \201city. Magnetic resonance imaging with dynamic intravenous contrast is a ve ry sensi- tive technique but variable speci \201city has been reported. Mammographic technique The breast is compressed to \202atten the breast tissue to reduce move- ment, overlapping shadows, and radiation dose. The uniform thick- ness of the tissue improves image quality and contrast. Low-energy radiation is passed through the breast, res ulting in a high-contrast image. The image is recorded on X-ray \201lm presently, but in the future will be digitally recorded, with display on a high-resolution computer screen. Two views of each breast are performed \200\224one in the lateral oblique position diagonal ly across the chest, the other in the cranio-caudal position. Some 7% of women \201nd the examination very painful, and a large proportion \201nd it uncomfortable. The compressio n of the breast tissue lasts only a few seconds. OHO-17(295-322) 11/18/02 8:24 AM Page 307 BREAST CANCER SCREENING 307 Table 17.3 Indications for referral to breast clinic (cid:2) Screen-detected breast cancer (cid:2) Breast lump \200\224any new discrete lump \200\224new lump in pre-existing nodularity \200\224asymmetrical nodularity persisting after menstruation \200\224abscess/in \202ammation which does not settle after one course of antibiotics \200\224persistent or recurrent cyst (cid:2) Pain \200\224associated with a lump \200\224intractable pain which interferes with the patients life and fails to respond to simple measures (well-supporting bra, simple analgesics, abstention from caffein e, evening primrose oil) \200\224unilateral persistent pain in post-menopausal women (cid:2) Nipple discharge \200\224in any women age >50 years \200\224in younger women if blood-stained, persistent single duct or bilateral, suf \201cient to stain clothes (cid:2) Nipple retraction, distortion, or eczema (cid:2) Change in breast skin contour Radiation dose A low radiation dose of approximately 2 mGy per examination is used. The rad iation risk is 1 \200\2232 excess cancers per million women screened after a latent period of 10 years in the post-menopausal age group but is higher in women under 30 years. The dos e to the breast is approximately \201ve times that of a chest X-ray. Organization of the UK Breast Screening Program In the UK, women aged 50 \200\22364 years a re invited through their GP, to attend either a breast screening center or a mobile van for mammog- raphy every three years. Women aged over 64 years can self-refer every three years . It was thought that the over 64-year-old age group would be less likely to take up screen ing, but this has not been substantiated in European screening programs. The 65 \200\22369- year-old age group will in the future be formally invited for screening as there is a highe r yield of cancers in this older age group. The under-50 age group will not be invited unti l the UK CCCR age trial, screening 40 \200\22349-year- olds, is completed. The mammograms are read by a consultant radiologist. If an abnor- mality is seen which is t hought to be suspicious, the woman is recalled OHO-17(295-322) 11/18/02 8:24 AM Page 308 BREAST CANCER 308 to an assessment clinic at the breast screening center. A clinical exam- ination is perform ed at the recall visit with further X-rays, an ultra- sound examination, and a needle test for cytology or core biopsy if appropriate. Women thought to have cancer are referred promp tly to a breast surgeon who will arrange appropriate treatment. An average of 72% of women accept the invitation to be screened and approximately 5% of wom en are recalled for further tests; 5 cancers per 1000 women screened are found. The quality of the UK program is monitored rigorously, with regular checks on all aspects o f screening. Performance data on breast screening centers, as well as individuals within th e center, are moni- tored annually. Interval cancers These are cancers that occur in the interval between two screening episode s. They fall into \201ve categories: (cid:2) True interval cancer: where a cancer appears in the 3-year interval and was not present on the previous screening mammogram. (cid:2) False negative: where the lesion was present on the previous screen- ing mammogram. (cid:2) Technical: where the cancer was not on the \201lm due to its position. (cid:2) Ma mographically occult: where the cancer is not visualized on either the screening mammogram or at the time of diagnosis. (cid:2) Unclassi \201able: no mammogram taken at the time of diagnosis. There are approximately 12 interval cancers per 1 0 000 women screened in the \201rst two years after screening and 13 interval cancers app ear in the third year. One- or two-view screening The UK NHS Breast Screening Program was initially funded for one X-ray (lateral oblique view) of each breast. A large trial comparing one-view with two-vie w mammography has shown that the second view results in a 24% increase in detection rate co mpared with single- view mammography. All women attending screening for the \201rst time have two views per- formed and screeni ng centers are encouraged to perform two-view mammography on all women. The additional radi ation dose for the second view is very low. Frequency of mammography Many European countries offer screening every two years, whereas t he UK service is currently funded to perform screening every three years. There is a large ongoing UK trial looking at the question of frequency of screening. Although there is almos t certainly increased detection of OHO-17(295-322) 11/18/02 8:24 AM Page 309 BREAST CANCER SCREENING 309 cancers when screening every two years, it may be that the large costs associated with more frequent screening will outweigh the bene \201t. Screening for high-risk groups Women thought to have strong family history of breast cancer are rec- ommended to have genetic counseling and not assessment. If they are found to be a t more than 16% risk, then mammographic screening is recommended. Meta-analysis of screenin g data of 40 \200\22350-year-olds suggests there is a non-signi \201cant bene \201t of ma mmography. At pre- sent, annual mammography is performed, with data being systemati- cally collected. The MRC have funded a multi-center trial to determine the place of magnetic reso nance imaging in the detection of asymptomatic breast cancer. Women who are BRCA1, BRCA2, o r p53 gene carriers, or at 50% risk of being a gene carrier, are being recruited into this study of annual MRI and mammography. Features of screen-detected breast cancer The expected outcome of breast cancer screening i s a reduction in breast cancer deaths. Other useful measures are the pathological fea- ture s of screen-detected tumors, which should re \202ect earlier disease compared with symptom atic women. This has been con \201rmed in a number of studies that show: (cid:2) 10 \200 \22320% screen-detected disease is non-invasive (cid:2) >30% invasive cancers are less than 10 mm diameter (cid:2) <20% cancers are Grade 3 tumors (cid:2) 70 \200\22380% of patients are node negative OHO-17(295-322) 11/18/02 8:24 AM Page 310 BREAST CANCER 310 Breast cancer \200\224presentation and staging The diagnosis of breast cancer is made by \200\230triple assessment \200\231: (cid:2) Clin ical examination (cid:2) Bilateral mammography (cid:2) FNA cytology or core biopsy This com bined approach to assessment has >90% sensitivity and speci \201city. The axilla is staged surgically. In the absence of locally advanced breast cancer or symptoms of metastatic dis ease or bio- chemical abnormality, routine radiological staging with CXR, CT scan, and isot ope bone scan has not been found useful. The TNM staging system is commonly used. OHO-17(295-322) 11/18/02 8:24 AM Page 311 BREAST CANCER \200\224PRESENTATION AND STAGING 311 Table 17.4 TNM staging system Tis Carcinoma in situ, non-in \201ltrating intraductal carcinoma, or Paget \200\231s disease o f the nipple with no demonstrable tumor T0 No evidence of primary tumor T1 Tumor <2 cm T2 Tumor >2 cm but <5 cm T3 Tumor >5 cm T4 Any size with extension to chest wall or skin T4a Fixation to chest wall only T4b Oedema, in \201ltration, or ulceration of skin Ipsilateral satellite nodules T4c Both aand bpresent NX Regional nodes cannot be assessed N0 No regional node metastases N1 Mobile ipsilateral axillary node metastases N2 Fixed ipsilateral axillary node metastases N3 Ipsilateral internal mammary node metastases OHO-17(295-322) 11/18/02 8:24 AM Page 312 BREAST CANCER 312 Management of non-invasive breast cancer DCIS and LCIS are rarely symptomatic although extensive pre- invasive disease may present w ith a mass or thickening of breast tissue. Treatment options (cid:2) Simple mastectomy 95% cure rate Rarely relapse, due to micro-invasive cancer No need for axillary dissection (cid:2) Wide excision alone \200\22430% recurrence at 5 years (cid:2) Wide excision + radio therapy \200\22415% recurrence at 5 years The management of LCIS is controversial; Bilatera l breast excision of LCIS should be followed by close surveillance. Few surgeons would inst ead advocate bilateral subcutaneous mastectomies and immediate reconstruction. OHO-17(295-322) 11/18/02 8:24 AM Page 313 MANAGEMENT OF NON-INVASIVE BREAST CANCER 313 OHO-17(295-322) 11/18/02 8:24 AM Page 314 BREAST CANCER 314 Management of early breast cancer Early breast cancer is de \201ned as disease that can be completely extir- pated by surger y, that is T1 \200\2233, N0 \200\2231 tumors. The management of this disease comprises: (ci d:2) Treatment of the breast and axilla (cid:2) Pathological staging to direct adjuvant the rapy (cid:2) Adjuvant therapy \200\224endocrine, chemotherapy, radiotherapy (cid:2) Follow- up Breast surgery All patients require removal of the primary tumor with either wide local exc ision or mastectomy. Halsted mastectomy was the operation most extensively applied to breas t cancer patients during the \201rst half of the twentieth century, but it has gradually been replaced by a variety of less radical operations. Total mastectomy and axillary dissection is a less mutilating opera- tion preserving the pe ctoralis major muscle and its neurovascular bundle. Quadrantectomy, introduced at the begin ning of the 1970s, is a breast-conserving operation that removes the primary cancer with a margin of 2.0 cm of normal breast tissue. Lumpectomy is an opera- tion that provides for th e removal of the tumor mass with a limited portion of normal tissue (1 cm). Randomized trials comparing breast-conserving surgery followed by radiotherapy with mastect omy alone have demonstrated similar local control rates and survival. Breast conservation i s not always suit- able for women with multifocal disease and large tumors in small breasts . Some patients simply prefer mastectomy, not least because of the possible avoidance of ra diotherapy. Either treatment should afford a local recurrence rate of <10% after 10 years. Breast reconstruction can be done either at the time of primary surgery or at a later date \200\224streetcar \202ap, latissimus dorsi \202ap, and implants all have a role. Treatment of the axilla (cid:2) Clinical assessment is inaccurate (cid:2) 30% of involved nodes are impalpable (cid :2) Surgery \200\224axillary node sampling (>4 nodes) (diagnostic) \200\224axillary clearance levels, I, II, and III (therapeutic); lymphodema and arm pain are complications OHO-17(295-322) 11/18/02 8:24 AM Page 315 MANAGEMENT OF EARLY BREAST CANCER 315 \200\224sentinel node biopsy: \200\224removal of \201rst node which contains secondary deposit \200\224ongoing UK trial \200\224use either blue dye or 99MTc colloid \200\224negative s entinel node avoids clearance Loco-regional radiotherapy Breast irradiation has been shown to reduce the risk of local re cur- rence after breast-conserving surgery from about 30% to <10% at 10 years. Typically, t he whole breast is treated with tangential \201elds to a dose of 50 Gy in 25 fractions (o r an equivalent dose-fractionation regimen), with care taken to minimize the volume of lung and heart irradiated. Although a boost of 10 \200\22315 Gy is commonly delivered to the tu mor bed, using electrons or 192Ir implant, its bene \201ts are unproven. (cid:2) Older tec hniques \200\224cardiac side-effects (cid:2) Modern techniques \200\224safe \200\224may improve survival Irradiation of axilla \200\224not required if clearance performed (cid:2) (cid:2) Radiation to axilla may cause lymphodema and brachial neuro- pathy Adjuvant systemic therapy Breast cancer patients who remain disease-free after local and re gional treatment may eventually relapse and die of overt metastases. The cur- rent hypothes is ascribes the failure to obtain a cure to occult micro- metastases in distant organs, alr eady present at the time of \201rst surgery. The risk of harboring occult metastases is l ow in cases with a small carcinoma and negative nodes and increases with the size of the pr imary carcinoma and number of axillary metastatic nodes. There have been many trials among women with operable breast cancer, examining the effects of systemic treatment, either endocrine maneuvers or chemotherapy or both, on the survival of these patients. The basis of all these therapies is the reduction or eradication of micr oscopic systemic metastatic disease in women in whom all macroscopic local tumor has been e ffectively removed. In 1992 the Early Breast Cancer Trialists \200\231 Collaborative Group published an overview of 133 randomized trials involving 75 000 women with early breast can cer1 \200\2233. This has had major impact, setting standards of care for adjuvant therapy f or this disease. Adjuvant endocrine therapy (cid:2) 60% of breast cancers are estrogen receptor positive (cid:2) Ovarian ablation \200 \224improves survival in women under 50 years \200\224morbidity of vascular disease and osteoporosis OHO-17(295-322) 11/18/02 8:24 AM Page 316 BREAST CANCER 316 (cid:2) Tamoxifen \200\224improves disease-free and overall survival \200\224all women, especially post-menopausal \200\224little bene \201t if ER negative \200\2245 years is suf \201cient: better than 2 years; no need for longer \200\22410% increase in survival for node-positive disease \200\2245% increase in surviva l for node-negative disease (cid:2) Side-effects of tamoxifen \200\224menopausal symptoms \200\224endometrial cancer, 4-fold increase in risk \200\224decreases contralateral breast cancer risk Adjuvant chemotherapy