Anatomy

1. Anatomy • The breast is composed of 15–20 lobes, which are each composed of several lobules. • Each lobe of the breast terminates in a major (lactiferous) duct (2–4 mm in diameter), which opens through a constricted orifice (0.4–0.7 mm in diam- eter) into the ampulla of the nipple. • Fibrous bands of connective tissue travel through the breast (suspensory ligaments of Cooper), which insert perpendicularly into the dermis and provide structural support. • The axillary tail of Spence extends laterally across the anterior axillary fold. • The upper outer quadrant of the breast contains a greater volume of tissue than do the other quadrants.

2. BLOOD SUPPLY, INNERVATION • Blood supply, innervation, and lymphatics. The breast receives its blood supply from (1) perforating branches of the internal mammary artery; (2) lateral branches of the posterior intercostal arteries; and (3) branches from the axillary artery, including the highest thoracic, lateral thoracic, and pectoral branches of the thoracoacromial artery. • The veins and lymph vessels of the breast follow the course of the arteries with venous drainage being toward the axilla. The vertebral venous plexus of Batson, which invests the vertebrae and extends from the base of the skull to the sacrum, can provide a route for breast cancer metastases to the vertebrae, skull, pelvic bones, and central nervous system.

3. Lateral cutaneous branches of the third through sixth intercostal nerves provide sensory innervation of the breast (lateral mammary branches) and of the anterolateral chest wall. • The intercostobrachial nerve is the lateral cutaneous branch of the second intercostal nerve and may be visualized during surgical dissection of the axilla. • Resection of the intercostobrachial nerve causes loss of sensation over the medial aspect of the upper arm.

4. LYMPHATICS • The boundaries for lymph drainage of the axilla are not well demarcated, and there is considerable variation in the position of the axillary lymph nodes. • The 6 axillary lymph node groups recognized by surgeons are (1) the axillary vein group (lateral); (2) the external mammary group (anterior or pectoral); (3) the scapular group (posterior or subscapular); (4) the central group; (5) the subclavicular group (apical); and (6) the interpectoral group (Rotter’s).

5. The lymph node groups are assigned levels according to their relationship to the pectoralis minor muscle. • Lymph nodes located lateral to or below the lower border of the pectoralis minor muscle are referred to as level I lymph nodes, which include the axillary vein, external mammary, and scapular groups. • Lymph nodes located superficial or deep to the pectoralis minor muscle are referred to as level II lymph nodes, which include the central and interpectoral groups. • Lymph nodes located medial to or above the upper border of the pectoralis minor muscle are referred to as level III lymph nodes, which make up the subclavicular group. • The axillary lymph nodes usually receive more than 75 percent of the lymph drainage from the breast.

6. Selected Benign Breast Disorders and DiseasesCYSTS • Cysts: In practice, the first investigation of palpable breast masses is frequently needle biopsy, which allows for the early diagnosis of cysts. A 21-gauge needle attached to a 10-mL syringe is placed directly into the mass. The volume of a typical cyst is 5–10 mL, but it may be 75 mL or more. • If the fluid that is aspirated is not bloodstained, then the cyst is aspirated to dryness, the needle is removed, and the fluid is discarded as cytologic examination of such fluid is not cost-effective. After aspiration, the breast is carefully palpated to exclude a residual mass. If one exists, ultrasound examination is performed to exclude a persistent cyst, which is reaspirated if present. • If the mass is solid, a tissue specimen is obtained. • When cystic fluid is bloodstained, 2 mL of fluid are taken for cytology. • The mass is then imaged with ultrasound and any solid area on the cyst wall is biopsied by needle. • The two cardinal rules of safe cyst aspiration are (1) the mass must disappear completely after aspiration, and (2) the fluid must not be bloodstained. If either of these conditions is not met, then ultrasound, needle biopsy, and perhaps excisional biopsy are recommended.

7. Selected Benign Breast Disorders and DiseasesFIBROADENOMAS • Fibroadenomas: Removal of all fibroadenomas has been advocated irrespective of patient age or other considerations, and solitary fibroadenomas in young women are frequently removed to alleviate patient concern. • Yet most fibroade- nomas are self-limiting and many go undiagnosed, so a more conservative approach is reasonable. • Careful ultrasound examination with core-needle biopsy will provide for an accurate diagnosis. • Subsequently, the patient is counseled concerning the biopsy results, and excision of the fibroadenoma may be avoided.

8. Selected Benign Breast Disorders and DiseasesSCLEROSING DISORDERS • Sclerosing Disorders: The clinical significance of sclerosingadenosis lies in its mimicry of cancer. • It may be confused with cancer on physical exam- ination, by mammography, and at gross pathologic examination. • Excisional biopsy and histologic examination are frequently necessary to exclude the diagnosis of cancer. • The diagnostic work-up for radial scars and complex scle- rosing lesions frequently involves stereoscopic biopsy. • It is usually not possible to differentiate these lesions with certainty from cancer by mammography features, hence biopsy is recommended.

9. Selected Benign Breast Disorders and DiseasesPERIDUCTAL MASTITIS • Periductal Mastitis: Painful and tender masses behind the nipple-areola complex are aspirated with a 21-gauge needle attached to a 10-mL syringe. • Any fluid obtained is submitted for cytology and for culture using a trans- port medium appropriate for the detection of anaerobic organisms. • Women are started on a combination of metronidazole and dicloxacillin while awaiting the results of culture. • A subareolar abscess usually is unilocular and often is associated with a single duct system. Preoperative ultrasound will accurately delineate its extent • The surgeon may either undertake simple drainage with a view toward formal surgery, should the problem recur, or proceed with definitive surgery. • In a woman of childbearing age, simple drainage is preferred, but if there is an anaerobic infection, recurrent infection frequently develops. • Recurrent abscess with fistula is a difficult problem and may be treated by fistulectomy or by major duct excision, depending on the circumstances. • Antibiotic therapy is useful for recurrent infection after fistula excision, and a 2–4-week course is recommended prior to total duct excision.

10. Selected Benign Breast Disorders and DiseasesNIPPLE INVERSION • Nipple Inversion: More women request correction of congenital nipple inversion than request correction for the nipple inversion that occurs secondary to duct ectasia. • surgical complications of altered nipple sensation, nipple necrosis, and postoperative fibrosis with nipple retraction. • Because nipple inversion is a result of shortening of the subareolar ducts, a complete division of these ducts is necessary for permanent correction of the disorder.

11. INFECTIOUS AND INFLAMMATORY DISORDERS OF THE BREASTBacterial Infection • Bacterial infection. Staphylococcus aureus and Streptococcus species are the organisms most frequently recovered from nipple discharge from an infected breast. • Breast abscesses are typically seen in staphylococcal infections and present with point tenderness, erythema, and hyperthermia. • These abscesses are related to lactation and occur within the first few weeks of breast-feeding. Progression of a staphylococcal infection may result in subcutaneous, sub- areolar, interlobular (periductal), and retromammary abscesses (unicentric or multicentric), • necessitating operative drainage of fluctuant areas. • Preoperative ultrasonography is effective in delineating the extent of the needed drainage procedure, which is best accomplished via circumareolar incisions or incisions paralleling Langer lines. • Although staphylococcal infections tend to be more localized and may be located deep in the breast tissues, streptococcal infections usually present with diffuse superficial involvement. • They are treated with local wound care, including warm compresses, and the administration of intravenous antibiotics (penicillins or cephalosporins). • Breast infections may be chronic, possibly with recurrent abscess formation. • In this situation, cultures are taken to identify acid-fast bacilli, anaerobic and aerobic bacteria, and fungi. • Uncommon organisms may be encountered and long-term antibiotic therapy may be required.

12. INFECTIOUS AND INFLAMMATORY DISORDERS OF THE BREASTHidradenitis Suppurativa • Hidradenitissuppurativa. Hidradenitissuppurativa of the nipple-areolacomplexor axilla is a chronic inflammatory condition that originates within the accessory areolar glands of Montgomery or within the axillary sebaceous glands. • When located in and about the nipple-areola complex, this disease may mimic other chronic inflammatory states, Paget disease of the nipple, or invasive breast cancer. • Involvement of the axillary skin is often multifocal and contiguous. • Antibiotic therapy with incision and drainage of fluctuant areas is appropriate treatment. • Complete excision of the involved areas may be required and may necessitate coverage with advancement flaps or split-thickness skin grafts.

13. INFECTIOUS AND INFLAMMATORY DISORDERS OF THE BREASTMondor's Disease • Mondor’s disease. This variant of thrombophlebitis involves the superficial veins of the anterior chest wall and breast. • In 1939, Mondor described the condition as “string phlebitis,” a thrombosed vein presenting as a tender, cord- like structure. • Typically, a woman presents with acute pain in the lateral aspect of the breast or the anterior chest wall. • A tender, firm cord is found to follow the distribution of one of the major superficial veins. • Most women have no evidence of thrombophlebitis in other anatomic sites. • When the diagnosis is uncertain, or when a mass is present near the tender cord, biopsy is indicated. • Therapy for Mondor disease includes the liberal use of antiinflammatory medications and warm compresses that are applied along the symptomatic vein. • Restriction of motion of the ipsilateral extremity and shoulder and brassiere support of the breast are important. • The process usually resolves within 4–6 weeks. When symptoms persist or are refractory to therapy, excision of the involved vein segment is appropriate.

14. RISK FACTORS FOR BREAST CANCER Hormonal Risk Factors • Increased exposure to estrogen is associated with an increased risk for developing breast cancer, whereas reducing exposure isthoughtto be protective • Correspondingly, factors that increase the number of menstrual cycles, such as early menarche,nulliparity, and late menopause, are associated with increased risk • Moderate levels of exercise and a longer lactation period,factors that decrease the total number of menstrual cycles, are protective. • Olderage at first live birth is associated with an increased risk ofbreastcancer. • There is an association between obesity and increased breast cancer risk

15. RISK FACTORS FOR BREAST CANCER • Nonhormonal Risk Factors • Radiation (radiation therapy for Hodgkin's lymphoma have a breast cancer risk that is 75 times greater) • Studies also suggest that the risk of breast cancer increases as the amount ofalcohol a woman consumes increases. • high fat content diet

16. Risk Assessment • The average lifetime risk of breast cancer for newborn U.S. females is 12%. • A software program incorporating the Gail model is available from the National Cancer Institute at http://bcra.nci.nih.gov/brc. • Claus and colleagues

17. Factors Associated with Increased Risk of Breast Cancer • White • Older • Family history; Breast cancer in mother, sister, or daughter (especially bilateral or premenopausal) • BRCA1 or BRCA2 mutation • Endometrial cancer • Proliferative forms of fibrocystic disease • Cancer in other breast • Early menarche (under age 12) • Late menopause (after age 50) • Nulliparous or late first pregnancy

18. screening mammography • Routine use of screening mammography in women 50 years of age reduces mortality from breast cancer by 33%. • This reductioncomes without substantial risks and at an acceptable economic cost. • However, the use of screening mammography in women<50 years of age is more controversial for several reasons: (a) breast density is greater and screening mammography is lesslikely to detect early breast cancer; (b) screening mammography results in more false-positive test findings, which results inunnecessary biopsies; and (c) younger women are less likely to have breast cancer, so fewer young women will benefit from screening. • Current recommendations are that women undergo baseline mammography at age 35 and then have annual mammographic screening beginning at age 40.

20. Incidence of Sporadic, Familial, and Hereditary Breast Cancer • Sporadic breast cancer 65–75% • Familial breast cancer 20–30% • Hereditary breast cancer 5–10% • BRCA1 a 45% • BRCA2 35% • p53a (Li-Fraumeni syndrome) 1% • STK11/LKB1a (Peutz-Jeghers syndrome) <1% • PTENa (Cowden disease) <1% • MSH2/MLH1a (Muir-Torre syndrome) <1% • ATMa (Ataxia-telangiectasia) <1% • Unknown 20% • Both BRCA1 and BRCA2 function as tumor-suppressor genes, and for each gene,loss of both alleles is required for the initiation of cancer.

21. BRCA MutationsBRCA1 • Five to 10% of breast cancers are caused by inheritance of germline mutations such as BRCA1 and BRCA2, which are inherited inan autosomal dominant fashion with varying penetrance • BRCA1 is located on chromosome arm 17q, spans agenomic region of approximately 100 kilobases (kb) of DNA, and contains 22 coding exons • Data accumulated since the isolation of the BRCA1 gene suggest a rolein transcription, cell-cycle control, and DNA damage repair pathways. • More than 500 sequence variations in BRCA1 have been identified.

22. predisposing genetic factor in as many as 45% ofhereditary breast cancers and in at least 80% of hereditary ovarian cancers. • Female mutation carriers have up to a 90% lifetimerisk for developing breast cancer and up to a 40% lifetime risk for developing ovarian cancer • Approximately 50% of children of carriers inherit the trait.

23. In general, BRCA1-associated breast cancers are invasive ductal carcinomas, are poorly differentiated, and are hormone receptor negative. • BRCA1-associated breast cancers have a number of distinguishing clinical features, such as an early age ofonset compared with sporadic cases; a higher prevalence of bilateral breast cancer; and the presence of associated cancers insome affected individuals, specifically ovarian cancer and possibly colon and prostate cancers.

24. BRCA2 • BRCA2 is located on chromosome arm 13q and spans a genomic region of approximately 70 kb of DNA. The 11.2-kb codingregion contains 26 coding exons • The biologic function of BRCA2 isnot well defined, but like BRCA1, it is postulated to play a role in DNA damage response pathways. • BRCA2 messenger RNA also is expressed at high levels in the late G1 and S phases of the cell cycle. • The mutational spectrum of BRCA2 is notas well established as that of BRCA1. To date, >250 mutations have been found

25. The breast cancer risk for BRCA2 mutationcarriers is close to 85%, and the lifetime ovarian cancer risk, while lower than for BRCA1, is still estimated to be close to 20%. • Breast cancer susceptibility in BRCA2 families is an autosomal dominant trait and has a high penetrance. • Approximately 50% ofchildren of carriers inherit the trait. • Unlike male carriers of BRCA1 mutations, men with germline mutations in BRCA2 have anestimated breast cancer risk of 6%, which represents a 100-fold increase over the risk in the general male population.

26. BRCA2- associated breast cancers are invasive ductal carcinomas, which are more likely to be well differentiated and to express hormonereceptors than are BRCA1-associated breast cancers. • BRCA2-associated breast cancer has a number of distinguishing clinicalfeatures, such as an early age of onset compared with sporadic cases, a higher prevalence of bilateral breast cancer, and thepresence of associated cancers in some affected individuals, specifically ovarian, colon, prostate, pancreatic, gallbladder, bileduct, and stomach cancers, as well as melanoma. • The 6174delT mutation is found in Ashkenazi Jews with a prevalence of 1.2%. Another BRCA2 founder mutation, 999del5, is observed in Icelandic and Finnish populations.

27. CANCER PREVENTION FOR BRCA MUTATION CARRIERS • Risk management strategies for BRCA1 and BRCA2 mutation carriers include the following: 1. Prophylactic mastectomy and reconstruction 2. Prophylactic oophorectomy and hormone replacement therapy 3. Intensive surveillance for breast and ovarian cancer 4. Chemoprevention

28. Chemoprevention • Despite a 49% reduction in the incidence of breast cancer inhigh-risk women taking tamoxifen, it is too early to recommend the use of tamoxifen uniformly for BRCA mutation carriers. • Cancers arising in BRCA1 mutation carriers are usually high grade and are most often hormone receptor negative. • Approximately66% of BRCA1-associated DCIS lesions are estrogen receptor negative, which suggests early acquisition of the hormoneindependentphenotype. Tamoxifen appears to be more effective at preventing estrogen receptor–positive breast cancers.

29. EPIDEMIOLOGY AND NATURAL HISTORY OF BREAST CANCER • Breast cancer is the most common site-specific cancer in women and is the leading cause of death from cancer for women aged 20 to 59 years

30. PRIMARY BREAST CANCER • More than 80% of breast cancers show productive fibrosis that involves the epithelial and stromal tissues.

31. With growth of the cancer and invasion of the surrounding breast tissues, the accompanying desmoplastic response entraps and shortens Cooper'ssuspensory ligaments to produce a characteristic skin retraction.

32. Localized edema (peau d'orange) develops when drainage oflymph fluid from the skin is disrupted.

33. With continued growth, cancer cells invade the skin, and eventually ulceration occurs. Asnew areas of skin are invaded, small satellite nodules appear near the primary ulceration.

34. The size of the primary breast cancercorrelates with disease-free and overall survival, but there is a close association between cancer size and axillary lymph node involvement

35. AXILLARY LYMPH NODE METASTASES • As the size of the primary breast cancer increases, some cancer cells are shed into cellular spaces and transported via thelymphatic network of the breast to the regional lymph nodes, especially the axillary lymph nodes. Lymph nodes that containmetastatic cancer are at first ill defined and soft but become firm or hard with continued growth of the metastatic cancer. • the most important prognostic correlate of disease-free and overallsurvival is axillary lymph node status

36. DISTANT METASTASES • At approximately the twentieth cell doubling, breast cancers acquire their own blood supply (neovascularization). • Thereafter,cancer cells may be shed directly into the systemic venous blood to seed the pulmonary circulation via the axillary and intercostalveins or the vertebral column via Batson's plexus of veins, which courses the length of the vertebral column. • These cells arescavenged by natural killer lymphocytes and macrophages. • Successful implantation of metastatic foci from breast cancerpredictably occurs after the primary cancer exceeds 0.5 cm in diameter, which corresponds to the twenty-seventh cell doubling. • Common sites of involvement, in order of frequency, are bone, lung,pleura, soft tissues, and liver.

37. HISTOPATHOLOGY OF BREAST CANCER • Carcinoma in Situ • LOBULAR CARCINOMA IN SITU • DUCTAL CARCINOMA IN SITU • InvasiveBreastCarcinoma 1. Paget's disease of the nipple 2. Invasiveductalcarcinoma 3. Adenocarcinoma with productive fibrosis (scirrhous, simplex, NST), 80% (invasive ductal carcinoma of no special type) 4. Medullarycarcinoma, 4% 5. Mucinous (colloid) carcinoma, 2% 6. Papillarycarcinoma, 2% 7. Tubularcarcinoma, 2% 8. Invasive lobular carcinoma, 10% 9. Rare cancers (adenoid cystic, squamous cell, apocrine)

38. Carcinoma in Situ • Cancer cells are in situ or invasive depending on whether or not they invade through the basement membrane • Foote and Stewart published a landmark description of LCIS, which distinguished it from DCIS • In the late 1960s, Gallagher and Martin publishedtheir study of whole-breast sections and described a stepwise progression from benign breast tissue to in situ cancer andsubsequently to invasive cancer. They coined the term minimal breast cancer (LCIS, DCIS, and invasive cancers smaller than 0.5cm in size) and stressed the importance of early detection • It is now recognized that each type of minimal breast cancer has adistinct clinical and biologic behavior.

39. Lobular Carcinoma In Situ • LCIS originates from the terminal duct lobular units and develops only in the female breast. It is characterized by distention and distortion of the terminal duct lobular units • LCIS may be observed in breast tissues that contain microcalcifications, but the calcifications associated with LCIS typically occur in adjacent tissues. This neighborhood calcification is a feature that is unique to LCIS and contributes to its diagnosis. • The frequency of LCIS in the general population cannot be reliably determined because it usually presents as an incidental finding. • The average age at diagnosis is 45 years, which is approximately 15 to 25 years younger than the age at diagnosis for invasive breast cancer.

40. Lobular Carcinoma In Situ • Invasive breast cancer develops in 25% to 35% of women with LCIS. • Invasive cancer may develop in either breast, regardless of which breast harbored the initial focus of LCIS, and is detected synchronously with LCIS in 5% of cases. • In women with a history of LCIS, up to 65% of subsequent invasive cancers are ductal, not lobular, in origin. For these reasons, LCIS is regarded as a marker of increased risk for invasive breast cancer rather than as an anatomic precursor. • Individuals should be counseled regarding their risk of developing breast cancer and appropriate risk reduction strategies, including observation with screening, chemoprevention, and risk-reducing bilateral mastectomy.

41. Ductal Carcinoma In Situ. • Published series suggest a detection frequency of 7% in all biopsy tissue specimens. • DCIS, which carries a high risk for progression to an invasive cancer. • Histologically, DCIS is characterized by a proliferation of the epithelium that lines the minor ducts, resulting in papillary growths within the duct lumina. • papillarygrowthpattern, cribriformgrowthpattern, solidgrowthpattern, comedogrowthpattern, • Calcium deposition occurs in the areas of necrosis and is a common feature seen on mammography. *FigureFrom: The Breast. Schwartz's Principles of Surgery, 10e, 2014

42. Ductal Carcinoma In Situ. • The risk for invasive breast cancer is increased nearly fivefold in women with DCIS • The invasive cancers are observed in the ipsilateral breast, usually in the same quadrant as the DCIS that was originally detected, which suggests that DCIS is an anatomic precursor of invasive ductal carcinoma

43. DCIS is now frequently classifiedbased on nuclear grade and the presence of necrosis

45. Invasive Breast Carcinoma • Invasive breast cancers have been described as lobular or ductal in origin • About 80% of invasive breast cancers are described as invasive ductal carcinoma of no special type (NST). These cancers generally have a worse prognosis than special-type cancers. • Foote and Stewart originally proposed the following classification for invasive breast cancer. • Paget’s disease of thenipple • Invasive ductalcarcinoma—Adenocarcinomawithproductivefibrosis (scirrhous, simplex, NST), 80% • Medullarycarcinoma, 4% • Mucinous (colloid) carcinoma, 2% • Papillarycarcinoma, 2% • Tubularcarcinoma, 2% • Invasive lobular carcinoma, 10% • Rarecancers (adenoidcystic, squamouscell, apocrine)

46. Paget’s disease of the nipple • Paget’s disease of the nipple was described in 1874. • It frequently presents as a chronic, eczematous eruption of the nipple, which may be subtle but may progress to an ulcerated, weeping lesion. • Paget’s disease usually is associated with extensive DCIS and may be associated with an invasive cancer. • A palpable mass may or may not be present. • A nipple biopsy specimen will show a population of cells that are identical to the underlying DCIS cells (pagetoid features or pagetoid change). Pathognomonic of this cancer is the presence of large, pale, vacuolated cells (Paget cells) in the rete pegs of the epithelium. Paget’s disease may be confused with superficial spreading melanoma. Differentiation from pagetoid intraepithelial melanoma is based on the presence of S-100 antigen immunostaining in melanoma and carcinoembryonic antigen immunostaining in Paget’s disease. • Surgical therapy for Paget’s disease may involve lumpectomy or mastectomy, depending on the extent of involvement of the nipple-areolar complex and the presence of DCIS or invasive cancer in the underlying breast parenchyma.

47. Invasive ductal carcinoma • Invasive ductal carcinoma of the breast with productive fibrosis (scirrhous, simplex, NST) accounts for 80% of breast cancers and presents with macroscopic or microscopic axillary lymph node metastases in up to 25% of screen-detected cases and up to 60% of symptomatic cases. • This cancer occurs most frequently in perimenopausal or postmenopausal women in the fifth to sixth decades of life as a solitary, firm mass. • It has poorly defined margins and its cut surfaces show a central stellate configuration with chalky white or yellow streaks extending into surrounding breast tissues. • In a large patient series, 75% of ductal cancers showed estrogen receptor expression.

48. Invasive lobular carcinoma • Invasive lobular carcinoma accounts for 10% of breast cancers. • Special stains may confirm the presence of intracytoplasmic mucin, which may displace the nucleus (signet-ring cell carcinoma). • At presentation, invasive lobular carcinoma varies from clinically inapparent carcinomas to those that replace the entire breast with a poorly defined mass. • It is frequently multifocal, multicentric, and bilateral. Because of its insidious growth pattern and subtle mammographic features, invasive lobular carcinoma may be difficult to detect. • Over 90% of lobular cancers express estrogen receptor.

49. DIAGNOSIS OF BREAST CANCER • In~30% of cases, the woman discovers a lump in her breast. Other less frequent presenting signs and symptoms of breast cancer include: • (a) breast enlargement or asymmetry; • (b) nipple changes, retraction, or discharge; • (c) ulceration or erythema of the skin of the breast; • (d) an axillary mass; and • (e) musculoskeletal discomfort. • Breast pain usually is associated with benign disease. • Diagnosis of breastcancer; • Examination • Imaging Techniques; Mammography, Ductography, Ultrasonography, MagneticResonance Imaging • Breast Biopsy;

50. Examination • Symmetry, size, and shape of the breast are recorded, as well as any evidence of edema (peaud’orange), nipple or skin retraction, or erythema. • Careful palpation of supraclavicular and parasternal sites also is performed. • A diagram of the chest and contiguous lymph node sites is useful for recording location, size, consistency, shape, mobility, fixation, and other characteristics of any palpable breast mass or lymphadenopathy