Diagnostic și tratament în boala hemoroidală [310472]

Constanța

-2016-

Constanța

-2016-

CUPRINS

I am thankfull to Lec. Dr. Ovidiu-[anonimizat]. Thank you.

[anonimizat]-threatening cancer in women. [anonimizat], it is the leading cause of cancer death in women; [anonimizat], it has been surpassed by lung cancer as a cause of cancer death in women. [anonimizat] 29% of all cancers in women and is second only to lung cancer as a cause of cancer deaths.

Many early breast carcinomas are asymptomatic; pain or discomfort is not usually a symptom of breast cancer. Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the patient or healthcare provider.

The general approach to evaluation of breast cancer has become formalized as triple assessment: [anonimizat] ([anonimizat], or both), and needle biopsy. [anonimizat]. Improvements in therapy and screening have led to improved survival rates for women diagnosed with breast cancer.

[anonimizat], are now considered primary treatment for breast cancer. [anonimizat]-[anonimizat].

Adjuvant breast cancer therapies are designed to treat micrometastatic disease or breast cancer cells that have escaped the breast and regional lymph nodes but do not yet have an established identifiable metastasis. [anonimizat] 35-72% of the decrease in mortality.

Over the past 3 decades, [anonimizat]. This has resulted in the development of more targeted and less toxic treatments.

ANATOMY OF THE AXILLA AND BREAST

Anatomy of the axilla.

Limits.

The axilla is a pyramidal space located between the upper part of the thoracic wall and the arm. Its shape and size vary according to the position of the arm. Thus, it almost disappears when the arm is completely abducted. The axilla forms a passageway for the vessels and nerves from the neck to reach the upper limb. Anatomically, the axilla is taken to have an apex, a [anonimizat] (Snell, 1999; Moore & Dalley, 2001).

Apex (or cervicoaxillary margin): This corresponds to the threshold zone between the lower part of the neck and the highest part of the axilla. [anonimizat]: [anonimizat], and anteriorly by the clavicle. The arteries and nerves go through the apex from the neck to the upper limb and the veins and lymph vessels go in the opposite direction (Snell; Moore & Dalley).

Base: [anonimizat], anteriorly, the inferior margins of the pectoralis major muscle (anterior axillary fold) and, posteriorly, the latissimus dorsi (posterior axillary fold) (Fig. 2) (Snell; Moore & Dalley).

Anterior wall: This is formed by the pectoralis major and minor muscles. The whole pectoralis major forms part of the wall, while only the intermediate portion of the pectoralis minor forms part of it. The space between the upper margin of the pectoralis minor and the clavicle is occupied by the clavipectoral fascia, while the space between the lower margin of the pectoralis minor muscle and the dermis at the axillary base is filled by the suspensory ligament of the axilla (suspensorium axillae ligament). In the more cranial portion of the clavipectoral fascia, there is a thickening known as the costocoracoid ligament or Halsted’s ligament (terms not recognized by the anatomical terminology), which extends from the first costosternal articulation to the coracoid process of the scapula (Figs. 2 and 3) (Snell; Moore & Dalley).

Posterior wall: This is formed by the subscapularis muscle in its upper part and the teres major and latissimus dorsi muscles, in its lower part (Fig. 2) (Snell; Moore & Dalley).

Medial wall: This is formed by the first four ribs with their intercostales muscles, and also the upper part of the serratus anterior muscle (Fig. 1) (Snell; Moore & Dalley).

Lateral wall: The anterior and posterior walls converge laterally towards the humerus, and the lateral wall is formed by the tendon of the long head (caput longum) of the biceps brachii muscle and, more medially, the coracobrachialis muscle (Fig. 1) (Snell; Moore & Dalley).

2. Contents of the axilla.

The contents of the axilla consist of the axillaris artery and its branches, the axillaris vein and its tributaries, nerves coming mostly from the plexus brachialis, and finally lymph vessels and axillares lymph nodes. In this proximal portion, these elements are surrounded by the axillary sheath, which is a prolongation of the pre-vertebral portion of the fascia cervicalis. Between these elements, there is adipose tissue and possibly mammary tissue that is cranially projected from the anterior face of the thorax into the axilla (Williams et al.).

The axillares vessels and the branches of the plexus brachialis cross from the apex of the axilla towards its base, along the lateral wall and closer to the anterior wall, with the axillaris vein anteromedial in relation to the artery. Because of the obliquity of the upper ribs, the axillary neurovascular bundle crosses the first intercostal space when it emerges from behind the clavicle (Williams et al. 1989).

2.1. Axillaris artery.

The axillaris artery is a continuation of the subclavia artery. It starts at the lateral margin of the first rib and finishes at the lower margin of the teres major muscle, from which point it starts to be named the brachialis artery (Fig. 4). It is crossed anteriorly by the pectoralis minor muscle, which divides it into three portions: proximal, posterior and distal to the muscle. The first of these is located between the lateral margin of the first rib and the upper margin of the pectoralis minor muscle; the second, posteriorly to the same muscle; and the third, between the lower margin of the pectoralis minor muscle and the lower margin of the teres major muscle (Lockhart et al.; Snell; Moore & Dalley).

The first portion of the axillaris artery originates the thoracica superior artery; the second portion originates the thoracoacromialis artery and the thoracica lateral artery; and the third portion originates the subscapularis artery and the circunflexae humeri anterior and posterior arteries (Lockhart et al.; Williams et al.; Snell; Moore & Dalley).

Thoracica superior artery: This artery projects anteromedially above the upper margin of the pectoralis minor muscle, passing between it and the pectoralis major muscle, and reaches as far as the thoracic wall. It irrigates these muscles and the thoracic wall, together with the thoracica interna artery and intercostalis suprema artery. The intercostalis suprema is sometimes absent.

Thoracoacromialis artery: This is a short branch that is initially covered by the pectoralis minor muscle. It runs along the upper margin of this muscle, penetrates the clavipectoral fascia and divides into pectoralis, acromialis, clavicularis and deltoideus branches.

Thoracica lateralis artery: This follows the lower margin of the pectoralis minor muscle as far as the thoracic wall, and irrigates the pectoralis major, serratus anterior and subscapularis muscles and the axillares lymph nodes. In women, this artery is large and it has lateral mammary branches, curving around the lateral margin of the pectoralis major muscle and heading towards the mammary gland.

Subscapularis artery: This is the largest branch of the axillaris artery. It is usually related to the posteroinferior margin of the subscapularis muscle. It irrigates adjacent muscles and the thoracic wall. It is accompanied distally by the thoracodorsalis nerve, which innervates the latissimus dorsi muscle. At around four centimeters from its origin, it originates the circumflexa scapulae artery, which curves around the lateral margin of the scapula and heads towards the infraspinal fossa, crossing the triangular space between the subscapularis muscle (above), the teres major muscle (below) and the long head (caput longus) of the triceps brachii (laterally).

Circunflexa humeri anterior artery: This is a thin artery that arises from the lateral face of the axillaris artery, distally to the lateral margin of the subscapularis muscle. It runs horizontally behind the coracobrachialis muscle and the short head (caput breve) of the biceps brachii muscle, and anteriorly to the surgical neck of the humerus. It reaches the intertubercular groove of the humerus.

Circunflexa humeri posterior artery: This artery is greater in diameter than the previous artery. It arises from the lateral margin of the subscapularis muscle and runs posteriorly with the axillaris nerve through the quadrangular space delimited above by the subscapularis muscle, the capsule of the shoulder joint and the teres minor muscle; below by the teres major, medially by the long head (caput longum) of the triceps brachii muscle and laterally by the surgical neck of the humerus.

2.2. Axillaris vein.

The axillaris vein is the most anterior and medial structure in the axillary neurovascular bundle, and is located on the medial side of the axillaris artery (Snell). Between these, there are the pectoralis lateralis nerve, the fasciculus medialis of the plexus brachialis and the ulnaris and cutaneus antebrachii medialis nerves. The cutaneus brachii medialis nerve is medial to the axillaris vein, while the axillares lymph nodes of the lateral group are posteromedial to it. The axillaris vein has a pair of valves close to its distal extremity. It is formed by the union of the brachiales veins (the comitantes veins of the brachialis artery) and the basilica vein, at the lower margin of the teres major muscle. It ends at the lateral margin of the first rib, where it becomes the subclavia vein. Although veins are more abundant in the axilla than arteries, they are anatomically very variable and frequently anastomosed (Williams et al.; Drake et al.). The axillaris vein receives tributaries that generally correspond to branches of the axillaris artery with a few exceptions (Lockhart et al.; Williams et al.).

The veins that correspond to the branches of the thoracoacromialis artery do not fuse to penetrate the axillaris vein via a common tributary. Some enter independently, but other are tributaries of the cephalica vein, which is above the pectoralis major muscle and opens into the axillaris vein close to its transition to the subclavia vein.

The axillaris vein directly or indirectly receives the thoracoepigastricae veins. These are formed by anastomoses of the superficial veins coming from the inguinal region, with tributaries of the axillaris vein (usually the lateral thoracica vein), thus constituting a collateral route that allows venous return when the cava inferior vein is obstructed.

2.3. Axillares lymph nodes.

The soft conjunctive tissue of the axillary cavity contains several lymph node groups. Classically, five axillares lymph node groups are described:

pectorales, subscapulares, centrales, humerales and apicales (Fig. 5) (Lockhart et al.; Williams et al.; Romrell & Bland; SBA; Drake et al.).

Pectorales (or anteriores) lymph nodes: This is formed by three to five lymph nodes that are located along the medial wall of the axilla, around the thoracica lateralis vein and the lower margin of the pectoralis minor muscle. This group receives lymph mainly from the anterior thoracic wall, including from the mammary gland. From the pectorales lymph nodes, the lymph passes to the centrales and apicales lymph node groups.

Subscapulares (or posteriores) lymph nodes: This consists of six to seven lymph nodes located along the margin of the posterior axillary wall and the subscapulares vessels. These lymph nodes receive lymph from the posterior face of the thoracic wall and the periscapular region. From this lymph node group, lymphatic efferent fluids go out to the centrales and apicales nodes.

Humerales (or laterales) lymph nodes: This is formed by a group of four to six lymph nodes located medially and posteriorly to the axillaris vein, in the proximal segment of the vein, close to the lateral wall of the axilla.

This group receives almost all the lymph coming from the upper limb, except the lymph transported by the lymphatic vessels that accompany the cephalica vein, which drains directly to the centrales nodes and, from this, to the apicales lymph nodes.

Centrales lymph nodes: This is formed by three or four large lymph nodes located deeply in relation to the pectoralis minor muscle, close to the base of the axilla, in relation to the second portion of the axillaris artery. Because of its location, this group receives the lymph from the pectorales, subscapulares and humerales nodes. All the lymph from this group drains to the apicales lymph nodes.

Apicales lymph nodes: This group is also known as subclavicular lymph nodes (Romrell & Bland) (term not

officially recognized by the present anatomical terminology [SBA]) and is formed by all the lymph nodes located at the axillary apex, which are located along the medial side of the distal part of the axillaris vein and the first portion of the axillaris artery.

The apicales nodes receive lymph coming from all the other axillares lymph node groups, and also the lymph from the lymph nodes that accompany the distal part of the cephalica vein. The efferent lymphatic vessels coming from the apicales nodes join together to form the truncus subclavius, which then joins the truncus jugularis (which drains the lymph from the head and neck) and the truncus bronchomediastinalis (which drains the lymph from the viscera and the thoracic wall), to discharge on the right side into the right lymphatic duct (ductus lymphaticus dexter), and on the left side into the ductus thoracicus. The ductus lymphaticus dexter and the ductus thoracicus discharge into the confluence at the junction of the jugularis interna vein and subclavia vein, on each side.

There are two lymph node groups that, although not located within the axilla, deserve special consideration because of their location close to the axilla (Lockhart et al.; Williams et al.; Romrell & Bland; Drake et al.) .

Interpectorales lymph nodes or «Rotter’s lymph nodes» (SBA): These are difficult to identify during surgery and even in anatomical dissections, and consist of one to four small lymph nodes that are located between the pectoralis major and minor muscles, in association with the pectoral branches of the thoracoacromiales vessels. Their lymph drains directly to centrales lymph nodes, although they may more rarely drain to lymph nodes in the apicales nodes.

Deltopectorales lymph nodes: These nodes are also known as infraclavicular nodes (term not recognized by anatomical terminology [SBA]) and consist of one or two lymph nodes located next to the cephalica vein, in the deltopectoral groove, just below the clavicle. Their efferent fluids penetrate the clavipectoral fascia to drain into the centrales and apicales lymph nodes of the axilla. More rarely, some efferent fluids move anteriorly to the clavicle to end up in the cervicales lymph nodes.

Surgeons usually classify the axillares lymph nodes in levels according to their relationship with the pectoralis minor muscle. Thus, lymph nodes located laterally or below the lower margin of the pectoralis minor muscle are classified as level I lymph nodes. The pectorales (anteriores), subscapulares (posteriores) and humerales (laterales) lymph nodes are included in this level. Lymph nodes located deeply in relation to the pectoralis minor muscle constitute level II lymph nodes and are represented by the centrales lymph nodes and possibly some lymph nodes in the apicales nodes. Finally, lymph nodes located medially or superiorly to the upper margin of the pectoralis minor muscle constitute level III lymph nodes, and these include the apicales lymph nodes (Romrell & Bland).

2.4. Nerves.

Most of the nerves found in the axilla come from the plexus brachialis. Only the intercostobrachialis nerve does not come from this plexus. The plexus brachialis (Fig. 6) is formed anatomically by the primary ventral branches (“roots”, radices) of the four inferior cervical nerves and the first thoracic nerve (C5 to T1). There may possibly be contributions from the primary ventral branches of the fourth cervical nerve and the second thoracic nerve (Lockart et al.; Williams et al.).

After the components of the plexus emerge from the intervertebral foramens, they are positioned between the scalenus anterior and scalenus medius muscles. In the lower part of the neck, the primary ventral branches of the plexus brachialis joint to form three trunks(trunci): superior (C5 and C6), medius (C7) and inferior (C8 and T1). Each trunk bifurcates into anterior and posterior divisions (divisiones) as the plexus runs posteriorly to the clavicle via the apex of the axilla. From the mixing of the fibers from the anterior and posterior divisions of the plexus brachialis, the lateralis, medialis and posterior fascicles are formed. The names of the fascicles refer to their relationships with the second portion of the axillaris artery, i.e. they are respectively lateral, medial and posterior in relation to the second portion of the axillaris artery (Snell; Moore & Dalley).

In accordance with the relationship with the clavicle, the plexus brachialis is, for teaching purposes, divided into the supraclavicular and infraclavicular portions.

In the axilla, the following nerves are found (Lockhart et al.; Williams et al.; Romrell & Bland; SBA; Drake et al.).

Intercostobrachialis nerve: This corresponds to the lateral cutaneous branch of the second intercostalis nerve. It arises from the second intercostal space and runs obliquely towards the arm, where it anastomoses with the cutaneous brachii medialis nerve, which is a branch of the plexus brachialis. A second intercostobrachialis nerve may also occasionally be observed emerging from the third intercostal space.

Thoracicus longus nerve (Bell’s nerve): This originates from the posterior face of the primary ventral branches of C5, C6 and C7. It runs downwards and goes posteriorly to the neurovascular bundle, towards the lateral thoracic wall to innervate the serratus anterior muscle. It is covered by fascia of this muscle.

Subclavius nerve (a branch of the upper trunk of the plexus brachialis): The fibers of this nerve derive mainly from C5 nerve, with contributions from C4 and C6 nerves. It runs downwards to the clavicle and supplies the subclavius muscle.

Pectoralis lateralis nerve (a branch of the fasciculus lateralis of the plexus brachialis): This supplies the pectoralis major muscle, after penetrating the clavipectoral fascia together with the thoracoacromialis artery and cephalica vein (it does not penetrate the pectoralis minor muscle). It sends out a communicating branch to the pectoralis medialis nerve, which innervates the pectoralis minor muscle.

Musculocutaneus nerve (a branch of the fasciculus lateralis of the plexus brachialis): Upon leaving the axilla, this nerve penetrates the coracobrachialis muscle and innervates it. Upon leaving this, it runs between the biceps brachii and brachialis muscles and supplies them. It continues superficially and laterally as a cutaneus antebrachii lateralis nerve in the forearm.

Medianus nerve: This is formed by the lateral and medial roots coming from the fasciculus lateralis and fasciculus medialis, respectively. It innervates most of the flexors and pronators muscles of the forearm and five intrinsic muscles of the hand, and it picks up the sensitivity of the skin of part of the hand and fingers.

Pectoralis medialis nerve (a branch of the fasciculus medialis of the plexus brachialis): This nerve penetrates the pectoralis minor muscle to supply it, and continues to also innervate the pectoralis major muscle.

Cutaneus brachii medialis nerve (a branch of the fasciculus medialis of the plexus brachialis): This is a thin nerve that picks up the sensitivity of the medial face of the arm and the superior medial face of the forearm.

Cutaneus antebrachii medialis nerve (a branch of the fasciculus medialis of the plexus brachialis): This nerve is bigger than the preceding one and is located between the axillaris artery and vein, supplying the skin of the medial face of the forearm.

Ulnaris nerve (a branch of the fasciculus medialis of the plexus brachialis): This runs the whole length of the arm without innervating anything. In the forearm it innervates two flexors muscles and in the hand it is the principal nerve, since it innervates the majority of its intrinsic muscles.

Thoracodorsalis nerve (a branch of the fasciculus posterior of the plexus brachialis): This innervates the latissimus dorsi muscle. It accompanies the subscapularis and thoracodorsalis arteries anteriorly to the subscapularis muscle.

Subscapularis superioris nerve (a branch of the fasciculus posterior of the plexus brachialis): This is located medially to the thoracodorsalis neurovascular bundle and innervates the subscapularis muscle.

Subscapularis inferioris nerve (a branch of the fasciculus posterior of the plexus brachialis): This innervates the teres major muscle and the lower part of the subscapularis muscle. It is located laterally to the thoracodorsalis neurovascular bundle.

Axillaris nerve (a branch of the fasciculus posterior of the plexus brachialis): This supplies the teres minor muscle as it leaves the axillary space through the quadrangular space. It innervates the deltoideus muscle from its deep posterior part and continues as a cutaneus brachii lateralis superioris nerve, innervating the skin on the lower half of the deltoideus muscle.

Radialis nerve (a branch of the fasciculus posterior of the plexus brachialis): This is the biggest nerve in the plexus brachialis. After leaving the axilla, it penetrates the groove of the radialis nerve of the humerus, where it may be damaged in the event of humeral fractures.

It innervates all the extensors muscles of the posterior compartments of the arm and forearm, and also the supinator and brachioradialis muscles. It originates the cutaneus brachii and antebrachii posteriores nerves, and also the cutaneous brachii lateralis inferior nerve.

Injuries to nerves may occur during axillary lymphonodectomy. By respecting the axillaris vein as the most cranial limit of the field of lymph node dissection, the fascicles and different branches of the plexus brachialis will be protected from inadvertent lesion. Nonetheless, some nerves may suffer injury during lymphonodectomy. The intercostobrachialis nerve is frequently sectioned because it crosses the axilla obliquely towards the arm and is located within the product from the lymph node dissection. Because this is a sensitive nerve, the impairment caused will consist of hyposthesia of the skin that covers the axilla and medial face of the arm. The thoracicus longus nerve runs laterally along the thoracic wall and is usually detached from its bed when the fascia of the serratus anterior muscle is removed, such that the nerve adheres to the dissection product. If this situation is not noticed, it may result in sectioning of the nerve and consequent denervation of the serratus anterior muscle, which causes posterior displacement of the scapula (“winged scapula”) (Romrell & Bland). The thoracodorsalis nerve may suffer injury if the subscapulares vessels are damaged or ligated. The subscapulares superior and inferior nerves become damaged when the fascia of the subscapularis muscle is extracted and the field of dissection extends posteriorly to the axillaris vein, or over the latissimus dorsi muscle superolaterally (subscapularis inferior nerve). Ligation of the thoracoacromialis artery beyond its emergence from the clavipectoral fascia will cause sectioning of the pectoralis lateralis nerve. Injury to the pectoralis medialis nerve occurs when the pectoralis minor muscle is extracted, or when the space between the pectoral muscles is extensively dissected.

Anatomy of the breasts.

1. Anatomical description. The breasts have a conical shape and are located, one on each side, within the subcutaneous layer of the thoracic wall, anteriorly to the pectoralis major muscle. They extend superiorly as far as the level of the second rib, inferiorly as far as the level of the sixth or seventh ribs, laterally as far as the anterior axillary line (sometimes as far as the middle axillary line) and medially they reach the lateral margin of the sternum. Posteriorly, they make contact with the fascia of the pectoralis major, serratus anterior and obliquus externus muscles and the most cranial portion of the rectus abdominis muscle (Netter, 1996; Romrell & Bland).

Its base is circular and measures around 10 to 12 cm, but its volume is very variable. The weight of a non-lactating breast ranges from 150 to 225g, while a lactating breast may exceed 500g in weight. The breasts of nulliparous women have a hemispherical shape, while those of multiparous women are broader and pendulant. With aging, the breast volume decreases and the breast becomes less firm, flatter and pendulant (Romrell & Bland).

Three portions are distinguished anatomically: the gland itself (glandula mammaria), the mammary papilla (papilla mammariae) and the areola (areola mammae). The mammary gland is formed by fifteen to twenty lobes (lobi glandulae mammariae) that are arranged radially and delimited by septa of conjunctive tissue and adipose tissue in the subcutaneous layer.

The mammary parenchyma is more abundant in the upper half of the gland, especially in the superolateral quadrant. The mammary tissue frequently extends beyond the apparent outline of the breast, projecting towards the axilla as an axillary process (sometimes called tail of Spence [SBA]). The principal duct of each lobe, the lactiferous duct (ductus lactiferi), opens separately into the mammary papilla. In turn, the lobe is formed by smaller functional units, the lobules (lobuli), from which ducts converge towards the main duct of the lobe (Lockhart et al.; Williams et al.).

The subcutaneous layer (tela subcutanea) completely surrounds the gland, except in the region of the papilla (Williams et al.; Netter). It needs to be clarified that the subcutaneous layer was in the past named the superficial fascia (Hollinshead & Rosse, 1991). The part of this layer located immediately in front of the fascia of the pectoralismajor muscle was erroneously called the deep layer of the superficial fascia (Romrell & Bland). In the subcutaneous layer, fascicles of conjunctive tissue are observed to permeate the lobes and lobules, particularly in the upper part of the gland, which cross the breast anteroposteriorly, extending from the dermis to the part of the subcutaneous layer next to the fascia of the pectoralis major muscle. These fascicles are known as the suspensory (or Cooper’s [SBA]) ligaments of the breast (suspensoria mammaria ligament). Neoplasms of the breast may affect them and cause localized retraction of the overlying skin (Netter; Romrell & Bland).

Although not officially recognized by the present anatomical terminology (SBA), the space located between the deep part of the subcutaneous layer and the muscular fascia of the pectoralis major muscle is known as the retromammary bursa, submammary serous bursa or also Chassaignac’s bursa (Netter; Romrell & Bland). It is easily identified during mastectomy. This space contributes towards the mobility of the breast on the thoracic wall.

The mammary papilla represents the apex of the cone and contains the opening for all the lactiferous ducts from the lobes. Close to the apex of the papilla, each duct presents a distal saclike dilatation known as the lactiferous sinus (sinus lactiferi) (Williams et al.; Netter; Romrell & Bland) (Fig. 7). It is worth emphasizing that, although the term nipple is habitually utilized in clinical practice (Netter), it is recommended that the expression mammary papilla should be utilized in the anatomical terminology (SBA).

The areola is a slightly raised disc-shaped area of variable size surrounding the papilla. Initially, it has a rosy hue, but becomes irreversibly pigmented (chestnut brown) from the second month of gestation. On its surface, it presents granular and pointlike elevations known as areolar tubercles (tubercula areolares) or Montgomery’s tubercles (Netter; Romrell & Bland). These correspond to the anatomical representation of glands with intermediate histological structure between sudoriparous and mammary glands, the areolar glands (glandulae areolares) (Fawcett, 1994).

2. Vascularization. The mammary irrigation is done by means of medial and lateral mammary branches of vessels (rami mammarii mediales and laterales) (Romrell & Bland) . The mammarii mediales branches originate from penetrating branches of the thoracica interna artery (a branch of the subclavia artery), which emerges from the second, third and fourth intercostal spaces (Williams et al.). In the past, this artery was named the internal mammary artery (Lockhart et al.; Hollinshead & Rosse), but this name should no longer be used. The mammarii laterales branches have multiple origins, namely: 1) thoracica superior artery (a branch of the first portion of the axillaris artery); 2) thoracica lateral artery (a branch of the second portion of the axillaris artery); 3) pectorales branches of the thoracoacromialis artery (a branch of the second portion of the axillaris artery); 4) penetrating branches of the intercostales posteriores arteries of the second, third and fourth spaces. The mammarii laterales branches predominantly originate from the thoracica lateral artery (formerly called the external mammary artery) (Williams et al.; Hollinshead & Rosse).

The venous drainage from the mammary gland is done by veins that generally accompany the arteries. Medially, the veins drain to the thoracica interna vein (a tributary of the brachiocephalica vein), and laterally to the axillaris vein. Drainage is also done by the intercostales posteriores veins. Those of the second and third intercostal spaces drain to the intercostalis suprema vein, which in the right side is a tributary of the arch of the azygos vein and on the left side, of the left brachiocephalica vein. Those of the fourth space drain to the azygos vein (on the right side) and hemiazygos vein (on the left side) (Lockhart et al.; Williams et al.; Romrell & Bland; Drake et al.). The superficial (cutaneous) mammary veins are presented profusely anastomosed and easily visible during gestation, the Haller’s vascular network (Netter). Around the mammary papilla, the veins form an anastomotic venous plexus of circular shape, known as the venous circle (Netter), a term that is not applied in the anatomical terminology (SBA).

3. Lymphatic drainage. Four intercommunicating lymphatic plexuses in the breast are described: one located in the dermis (cutaneous plexus), one in the superficial subcutaneous region (subcutaneous plexus), one in the fascia of the pectoralis major muscle (fascial plexus) and the last in the mammary gland, involving the lobes and ducts (glandular plexus). This last one communicates by means of lymphatic vessels that accompany the lactiferous ducts with a region of the subcutaneous plexus located immediately below the areola that is known as the subareolar plexus (or Sappey’s plexus). The fascial plexus establishes communication with the subcutaneous plexus by means of the lymphatic vessels along the fibrous fascicles of the stroma (Williams et al.; Romrell & Bland).

The deep and superficial (cutaneous) lymphatic drainage is performed by the lateral and medial efferent lymphatic vessels, to lymph nodes respectively in the axilla and along the thoracicae internae vessels (Fig. 5). The medial efferent vessels of one breast may anastomose with those of the contralateral breast, thus establishing intermammary lymphatic anastomoses (intermammary communication). This explains the occasional metastatic involvement of contralateral axillares lymph nodes in relation to neoplasm in the other breast (Romrell & Bland; Netter).

The lateral efferent lymphatic vessels initially lead to the pectorales lymph nodes that are located along the thoracicae internae vessels, close to the lower margin of the pectoralis major and minor muscles, and sometimes directly to the lymph nodes along the subscapulares vessels (subscapulares lymph nodes). The lymph vessels may occasionally accompany the intercostales posteriores vessels and lead to the intercostales lymph nodes, which are located close to the heads of the ribs, from where the drainage is to the ductus thoracicus (Lockhart et al.; Williams et al.; Romrell & Bland).

The fascial lymphatic plexus does not have significant participation in the drainage of the breast, but servesasa n alternative route in the event of obstruction of the principal route. The lymph of the fascial plexus drains to efferent vessels that penetrate the pectoralis major and minor muscles and, from there, drain to the apicales nodes of the axilla (Romrell & Bland). On this transpectoral drainage route, also known as Groszman’s route (Netter), an intermediate group of lymph nodes is described (between one and four in total), arranged along the thoracoacromiales vessels and situated between the pectoralis major and minor muscles. These lymph nodes are known as interpectorales lymph nodes «or Rotter’s lymph nodes (SBA)» and are rarely brought into view during surgery or in anatomical specimens

Although there is a belief that the lymph nodes along the thoracicae internae vessels receive the lymph from the medial quadrants, studies have shown that both the axillares lymph nodes and the thoracicae internae lymph nodes receive lymph from all the mammary quadrants, thanks to the widespread lymphatic network. There is, however, clear predominance of drainage to the axilla, and this route corresponds to more than three quarters of the mammary lymphatic drainage. The most cranial part of the breast may have lymphatic drainage directly towards the apicales lymph nodes of the axilla (Romrell & Bland).

The lymph from the breasts may occasionally drain via lymphatic vessels that accompany the lateral cutaneous branches of the intercostales vessels and drain to the intercostales posteriores lymph nodes, which are located close to the heads of the ribs.

From there, the lymph continues to the ductus thoracicus. The lymphatic vessels from the breasts may also occasionally drain to the liver and subdiaphragmatic plexus, by means of the abdominal lymphatic vessels (Gerota’s paramammary route) (Netter; Romrell & Bland).

4. Innervation. The sensitivity of the breast is picked up by means of medial, lateral and superior mammarii branches of nerves (Fig. 9). The medial branches correspond to the anterior cutaneous branch of the intercostales nerves of the second to sixth spaces. The lateral branches correspond to the communicating branch and the anterior division of the lateral cutaneous branch of the same nerves. The only exception is the lateral cutaneous branch of the second intercostalis nerve, named the intercostobrachialis nerve, which runs to the base of the axilla and the superior medial face of the arm. The superior branches run to the most cranial region of the breasts and correspond to the supraclaviculares mediales, intermedii and laterales nerves (branches of the plexus cervicalis). The mammary papilla is plentifully supplied by free and branched nerve ends (Lockhart et al.; Williams et al.; Romrell & Bland; Drake et al.).

Sympathetic fibers reach the breast by means of the abovementioned nerves for vasomotor control, but not for secretion activities, which are controlled by hormonal mechanisms. There are no fibers of parasympathetic nature in the breasts (Fawcett).

Musculature Related to the Breast

The breast lies over the musculature that encases the chest wall. The muscles involved include the pectoralis major, serratus anterior, external oblique, and rectus abdominis fascia. The blood supply that provides circulation to these muscles perforates through to the breast parenchyma, thus also supplying blood to the breast. By maintaining continuity with the underlying musculature, the breast tissue remains richly perfused, thus preventing complications from arising from aesthetic or reconstructive surgery that requires the placement of a breast implant.

Pectoralis majoris

The pectoralis major muscle is a broad muscle that extends from its origin on the medial clavicle and lateral sternum to its insertion on the humerus. The thoracoacromial artery provides its major blood supply, while the intercostal perforators arising from the internal mammary artery provide a segmental blood supply. The medial and lateral anterior thoracic nerves provide innervation for the muscle, entering posteriorly and laterally. The action of the pectoralis major is to flex, adduct, and rotate the arm medially.

The pectoralis major is extremely important in aesthetic and reconstructive breast surgery because it provides muscle coverage for the breast implant. In reconstructive surgery, the pectoralis major muscle covers the implant, providing a decreased risk of exposure of the implant, since the skin and underlying subcutaneous tissues are often thin following mastectomy. The muscle also provides additional tissue between implant and skin, thus decreasing palpability of the implant.

Often, placement of the implant beneath the muscle causes it to be noticeable when the pectoralis is contracted.

In these instances, it may be helpful to release the pectoralis muscle from its inferior and medial attachments to decrease the incidence of noticeable contractions.

In addition, with inferior release of the pectoralis muscle, lower positioning of the implant can be achieved, resulting in a more aesthetically pleasing appearance.

Serratus anterior

The serratus anterior muscle is a broad muscle that runs along the anterolateral chest wall. Its origin is the outer surface of the upper borders of the first through eighth ribs, and its insertion is on the deep surface of the scapula. Its vascular supply is derived equally from the lateral thoracic artery and from branches of the thoracodorsal artery. The long thoracic nerve serves to innervate the serratus anterior, which acts to rotate the scapula, raising the point of the shoulder and drawing the scapula forward toward the body. Transection of the long thoracic nerve is carefully avoided during an axillary lymph node dissection because its loss results in "winging" as the scapula is released from the chest wall and moves upward and outward.

Because the serratus anterior underlies the lateral aspect of the breast, in aesthetic surgery, blunt elevation of the pectoralis major laterally inadvertently elevates a small portion of the serratus muscle. Often the serratus anterior must be elevated sharply to obtain a sufficient muscle layer to provide coverage of the implant.

Rectus abdominis

The rectus abdominis muscle demarcates the inferior border of the breast. It is an elongated muscle that runs from its origin at the crest of the pubis and interpubic ligament to its insertion at the xiphoid process and cartilages of the fifth through seventh ribs. It acts to compress the abdomen and flex the spine. The 7th through 12th intercostal nerves provide sensation to overlying skin and innervate the muscle. Vascularity of the muscle is maintained through a network between the superior and inferior deep epigastric arteries. When placing an implant for breast reconstruction, in attempting to achieve complete coverage with muscle, the rectus fascia must often be elevated to place the implant sufficiently caudal. This dense, thick fascia is often intimately adherent to the ribs below it. Once the fascia is elevated and released, proper positioning and expansion of the implant can proceed.

External oblique

The external oblique muscle is a broad muscle that runs along the anterolateral abdomen and chest wall. Its origin is from the lower 8 ribs, and its insertion is along the anterior half of the iliac crest and the aponeurosis of the linea alba from the xiphoid to the pubis. It acts to compress the abdomen, flex and laterally rotate the spine, and depress the ribs. The 7th through 12th intercostal nerves serve to innervate the external oblique. A segmental blood supply is maintained through the inferior 8 posterior intercostal arteries.

The external oblique muscle abuts the breast on the inferior lateral aspect. Elevated along with the rectus abdominis fascia to provide inferior coverage of the breast implant during reconstructive surgery, its fascia, like the fascia of the rectus abdominis muscle, must be released adequately to provide for proper placement and expansion of the implant. In aesthetic surgery, placement of the implant inferiorly is usually not below these fascial attachments. If the implant is placed behind the fascia, the implant often "rides too high" and may result in a "double bubble" effect, wherein the breast parenchyma slides over and off the implant.

HISTOLOGY AND PATHOPHYSIOLOGY

The current understanding of breast cancer etiopathogenesis is that invasive cancers arise through a series of molecular alterations at the cell level. These alterations result in breast epithelial cells with immortal features and uncontrolled growth.

Genomic profiling has demonstrated the presence of discrete breast tumor subtypes with distinct natural histories and clinical behavior. The exact number of disease subtypes and molecular alterations from which these subtypes arise remains to be fully elucidated, but these generally align with the presence or absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).

This view of breast cancer–not as a set of stochastic molecular events, but as a limited set of separable diseases of distinct molecular and cellular origins–has altered thinking about breast cancer etiology, type-specific risk factors, and prevention and has had a substantial impact on treatment strategies and breast cancer research.

Evidence from The Cancer Genome Atlas Network (TCGA) confirms the following 4 main breast tumor subtypes, with distinct genetic and epigenetic aberrations.

Luminal A

Luminal B

Basal-like

HER2-positive

It is noteworthy that the basal-like breast tumor subgroup shares a number of molecular characteristics common to serous ovarian tumors, including the types and frequencies of genomic mutations. These data support the evidence that some breast cancers share etiologic factors with ovarian cancer. Most compelling are the data showing that patients with basal-type breast cancers show treatment responsiveness similar to that of ovarian cancer patients.

The various types of breast cancers are listed below by percentage of cases:

Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor and has a tendency to metastasize via lymphatics; this lesion accounts for 75% of breast cancers

Over the past 25 years, the incidence of lobular carcinoma in situ (LCIS) has doubled, reaching a current level of 2.8 per 100,000 women; the peak incidence is in women aged 40-50 years

Infiltrating lobular carcinoma accounts for fewer than 15% of invasive breast cancers

Medullary carcinoma accounts for about 5% of cases and generally occurs in younger women

Mucinous (colloid) carcinoma is seen in fewer than 5% of invasive breast cancer cases

Tubular carcinoma of the breast accounts for 1-2% of all breast cancers

Papillary carcinoma is usually seen in women older than 60 years and accounts for approximately 1-2% of all breast cancers

Metaplastic breast cancer accounts for fewer than 1% of breast cancer cases, tends to occur in older women (average age of onset in the sixth decade), and has a higher incidence in blacks

Mammary Paget disease accounts for 1-4% of all breast cancers and has a peak incidence in the sixth decade of life (mean age, 57 years)

Histology

Breast cancers usually are epithelial tumors of ductal or lobular origin. The following features are all important in deciding on a course of treatment for any breast tumor:

Size; Status of surgical margin; Presence or absence of estrogen receptor (ER) and progesterone receptor (PR); Nuclear and histologic grade; Proliferation; Vascular invasion; Tumor necrosis; Quantity of intraductal component; HER2 status.

Histologic grade

Histologic grade is the best predictor of disease prognosis in carcinoma in situ, but it is dependent on the grading system used, such as the Van Nuys classification (high-grade, low-grade comedo, low-grade noncomedo). The grading of invasive carcinoma is also important as a prognostic indicator, with higher grades indicating a worse prognosis.

Table 2. Grading System in Invasive Breast Cancer

Ductal carcinoma in situ

DCIS is broadly divided into 2 subtypes: comedo (ie, cribriform, micropapillary, and solid; see the first image below) and noncomedo (see the second image below). The likelihood of progression or local recurrence, as well as the prognosis, varies in accordance with the DCIS subtype present.

Table 3. Ductal Carcinoma in Situ Subtypes

Lobular carcinoma in situ

Lobular carcinoma in situ (LCIS) arises from the terminal duct apparatus and shows a rather diffuse distribution throughout the breast, which explains its presentation as a nonpalpable mass in most cases. Over the past 25 years, the incidence of LCIS has doubled, currently standing at 2.8 per 100,000 women. The peak incidence is in women aged 40-50 years.

Infiltrating ductal carcinoma

Infiltrating ductal carcinoma is the most commonly diagnosed breast tumor (accounting for 75% of breast cancers) and has a tendency to metastasize via lymphatic vessels. This lesion has no specific histologic characteristics other than invasion through the basement membrane. DCIS is a frequently associated finding on pathologic examination.

Infiltrating lobular carcinoma

Infiltrating lobular carcinoma has a much lower incidence than infiltrating ductal carcinoma, accounting for 15-20% of invasive breast cancers. Histologically, it is characterized by the "single-file" arrangement of small tumor cells. Like ductal carcinoma, infiltrating lobular carcinoma typically metastasizes to axillary lymph nodes first. However, it also has a tendency to be multifocal and have discontinuous areas of involvement, making mammographic and even MRI staging imprecise.

Medullary carcinoma

Medullary carcinoma is relatively uncommon (5%) and generally occurs in younger women. Most patients present with a bulky palpable mass and axillary lymphadenopathy. Diagnosis of this type of breast cancer depends on the following histologic triad:

Sheets of anaplastic tumor cells with scant stroma

Moderate or marked stromal lymphoid infiltrate

Histologic circumscription or a pushing border

DCIS may be observed in the surrounding normal tissues. Medullary carcinomas are typically high-grade lesions that are negative for ER, PR, and HER2 and that commonly demonstrate mutation of TP53.

Mucinous carcinoma

Mucinous (colloid) carcinoma is another rare histologic type, seen in fewer than 5% of invasive breast cancer cases. It usually presents during the seventh decade of life as a palpable mass or appears mammographically as a poorly defined tumor with rare calcifications.

Mucin production is the histologic hallmark. There are 2 main types of lesions, A and B, with AB lesions possessing features of both. Type A mucinous carcinoma represents the classic variety, with larger quantities of extracellular mucin, whereas type B is a distinct variant with endocrine differentiation.

DCIS is not a frequent occurrence in this setting, though it may be found. Most cases are ER- and PR-positive, but HER2 overexpression is rare. Additionally, these carcinomas predominantly express glycoproteins MUC2 and MUC6.

Tubular carcinoma

Tubular carcinoma of the breast is an uncommon histologic type, accounting

for only 1-2% of all breast cancers. Characteristic features of this type include

a single layer of epithelial cells with low-grade nuclei and apical cytoplasmic snoutings arranged in well-formed tubules and glands.

Tubular components make up more than 90% of pure tubular carcinomas and at least 75% of mixed tubular carcinomas. This type of breast cancer has a low incidence of lymph node involvement and a very high overall survival rate. Because of its favorable prognosis, patients are often treated with only breast-conserving surgery and local radiation therapy.

Papillary carcinoma

Papillary carcinoma of the breast encompasses a spectrum of histologic subtypes. There are 2 common types: cystic (noninvasive form) and micropapillary ductal carcinoma (invasive form). This form of breast cancer is usually seen in women older than 60 years and accounts for approximately 1-2% of all breast cancers. Papillary carcinomas are centrally located in the breast and can present as bloody nipple discharge. They are strongly ER- and PR-positive.

Cystic papillary carcinoma has a

low mitotic activity, which results

in a more indolent course and a good prognosis.

However, invasive micropapillary ductal carcinoma has a more aggressive phenotype similar to that of infiltrating ductal carcinoma, even though about 70% of cases are ER-positive.

Metaplastic breast cancer

Metaplastic breast cancer (MBC) accounts for fewer than 1% of breast cancer cases. It tends to occur in older women (average age of onset in the sixth decade) and has a higher incidence in blacks. It is characterized by a combination of adenocarcinoma plus mesenchymal and epithelial components.

A wide variety of histologic patterns includes the following:

Spindle-cell carcinoma

Carcinosarcoma

Squamous cell carcinoma of ductal origin

Adenosquamous carcinoma

Carcinoma with pseudosarcomatous metaplasia

Matrix-producing carcinoma

This diverse group of malignancies is identified as a single entity on the basis of a similarity in clinical behavior. Compared with infiltrating ductal carcinoma, MBC tumors are larger, faster-growing, commonly node-negative, and typically negative for ER, PR, and HER2.

Mammary Paget disease

Mammary Paget disease is relatively rare, accounting for 1-4% of all breast cancers. The peak incidence is seen in the sixth decade of life. This adenocarcinoma is localized within the epidermis of the nipple-areola complex and is composed of the histologic hallmark Paget cells within the basement membrane. Paget cells are large, pale epithelial cells with hyperchromatic, atypical nuclei, dispersed between the keratinocytes singly or as a cluster of cells.

Lesions are predominantly unilateral, developing insidiously as a scaly, fissured, oozing, or erythematous nipple-areola complex. Retraction or ulceration of the nipple is often noted, along with symptoms of itching, tingling, burning, or pain. In situ or invasive breast cancer is found in approximately 85% of patients with Paget disease. Thus, all diagnosed patients require a careful breast examination and mammographic evaluation, with additional imaging, including breast MRI, if the mammogram is negative.

Breast cancer staging

The American Joint Committee on Cancer (AJCC) staging system groups patients into four stages according to the TNM system, which is based on tumor size (T), lymph node status (N), and distant metastasis (M).

TNM Staging System for Breast Cancer

Primary tumor (T)

Tumor size definitions are as follows:

Tx – Primary tumor cannot be assessed

T0 – No evidence of primary tumor

Tis – DCIS

Tis – LCIS

Tis – Paget disease of the nipple with no tumor (Paget disease associated with a tumor is classified according to the size of the tumor)

T1 – Tumor ≤2 cm in greatest diameter

T1mic – Microinvasion ≤0.1 cm in greatest diameter

T1a – Tumor >0.1 but not >0.5 cm in greatest diameter

T1b – Tumor >0.5 but not >1 cm in greatest diameter

T1c – Tumor >1 cm but not >2 cm in greatest diameter

T2 – Tumor >2 cm but not >5 cm in greatest diameter

T3 – Tumor >5 cm in greatest diameter

T4 – Tumor of any size, with direct extension to (a) the chest wall or (b) skin only, as described below

T4a – Extension to the chest wall, not including the pectoralis

T4b – Edema (including peau d’orange) or ulceration of the skin of the breast or satellite skin nodules confined to the same breast

T4c – Both T4a and T4b

T4d – Inflammatory disease

Regional lymph nodes (N)

Clinical regional lymph node definitions are as follows:

Nx – Regional lymph nodes cannot be assessed (eg, previously removed)

N0 – No regional lymph node metastasis

N1 – Metastasis in movable ipsilateral axillary lymph node(s)

N2 – Metastasis in ipsilateral axillary lymph node(s) fixed or matted, or in clinically apparent ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasis

N2a – Metastasis in ipsilateral axillary lymph nodes fixed to one another or to other structures

N2b – Metastasis only in clinically apparent ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph nodes

N3 – Metastasis in ipsilateral infraclavicular or supraclavicular lymph node(s) with or without axillary lymph node involvement, or clinically apparent ipsilateral internal mammary lymph node(s) and in the presence of axillary lymph node

N3a – Metastasis in ipsilateral infraclavicular lymph node(s)

N3b – Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)

N3c – Metastasis in ipsilateral supraclavicular lymph node(s)

Distant metastasis

Metastases are defined as follows:

Mx – Distant metastasis cannot be assessed

M0 – No distant metastasis

M1 – Distant metastasis

The 5-year survival rates are highly correlated with tumor stage, as follows:

Stage 0, 99-100%; Stage I, 95-100%; Stage II, 86%; Stage III, 57%; Stage IV, 20%.

Lymph node assessment

Evaluation of lymph node involvement by means of sentinel lymph node biopsy or axillary lymph node dissection (ALND) has also been considered necessary for staging and prognosis.

A 2014 update on sentinel lymph node biopsy for patients with early-stage breast cancer by the American Society of Clinical Oncology (ASCO) advises that sentinel lymph node biopsy may be offered to the following patients :

Women with operable breast cancer and multicentric tumors

Women with DCIS who will be undergoing mastectomy

Women who previously underwent breast and/or axillary surgery

Women who received preoperative/neoadjuvant systemic therapy

According to the ASCO guidelines, sentinel lymph node biopsy should not be performed in patients with any of the following:

Large or locally advanced invasive breast cancer (tumor size T3/T4)

Inflammatory breast cancer

DCIS (when breast-conserving surgery is planned)

Pregnancy

ASCO recommendations regarding ALND in patients who have undergone sentinel lymph node biopsy are as follows:

ALND should not be performed in women with no sentinel lymph node (SLN) metastases

In most cases, ALND should not be performed in women with one to two metastatic SLNs who are planning to undergo breast-conserving surgery with whole-breast radiotherapy

ALND should be offered to women with SLN metastases who will be undergoing mastectomy

The 2014 National Comprehensive Cancer Network (NCCN) breast cancer guidelines state that lymph node dissection is optional in the following cases :

Strongly favorable tumors

When no result would affect the choice of adjuvant systemic therapy

Elderly patients

Patients with comorbid conditions

Additional testing

The 2014 NCCN guidelines recommend the following laboratory studies for all asymptomatic women with early-stage breast cancer (stages I and II):

Complete blood count (CBC) with differential

Liver function tests (LFTs) and alkaline phosphatase

In addition, imaging studies (eg, chest x-ray, chest CT, or CT of the abdomen and pelvis) can be considered for women with stage III (locally advanced or inflammatory breast cancer) or symptomatic disease. Tumor markers (carcinoembryonic antigen [CEA] and CA15.3 or CA27.29) may also be obtained in these patients.

HER2 testing

Although several methods for HER2 testing have been developed, approximately 20% of current HER2 testing may be inaccurate; accordingly, the American Society of Clinical Oncology (ASCO) and CAP have recommended guidelines to ensure the accuracy of HER2 testing. Breast cancer specimens should initially undergo HER2 testing by a validated immunohistochemistry (IHC) assay (eg, HercepTest; Dako, Glostrup, Denmark) for HER2 protein expression.

The scoring method for HER2 expression is based on the cell membrane staining pattern and is as follows:

3+ – Positive for HER2 protein expression; uniform intense membrane staining of more than 30% of invasive tumor cells

2+ – Equivocal for HER2 protein expression; complete membrane staining that is either nonuniform or weak in intensity but has circumferential distribution in at least 10% of cells, or uniform intense membrane staining in 30% or less of tumor cells

1+ – Weak or incomplete membrane staining in any tumor cells

0 – Negative for HER2 protein expression; no staining

Breast cancer specimens with equivocal IHC results should undergo validation with a HER2 gene amplification method, such as fluorescence in situ hybridization (FISH). More centers are relying on FISH alone for determining HER2 status.

In general, FISH testing is thought to be more reliable than IHC, but it is more expensive. Equivocal IHC results can be seen in 15% of invasive breast cancers, whereas equivocal HER2 FISH results are seen in fewer than 3% of invasive breast cancer specimens and those that had previously been considered HER2 positive. Discordant results (IHC 3+/FISH negative or IHC < 3+/FISH positive) have been observed in approximately 4% of specimens. Currently, no data support excluding this group from treatment with trastuzumab.

Newer methodologies for establishing HER2 status, including reverse transcriptase–polymerase chain reaction (RT-PCR) and chromogenic in situ hybridization (CISH), have been developed. The HER2 CISH PharmDX Kit (Dako Denmark A/S, Glostrup, Denmark) was approved by the FDA in November 2011. The interpretation for HER2 FISH testing (ratio of HER2 to chromosome 17 centromere [HER2/CEP17] and gene copy number) is as follows:

Positive HER2 amplification – HER2:CEP17 ratio is greater than 2.2 or HER2gene copy is greater than 6.0

Equivocal HER2 amplification – HER2:CEP17 ratio of 1.8-2.2 or HER2 gene copy of 4.0-6.0

Negative HER2 amplification – HER2:CEP17 ratio is less than 1.8 or HER2gene copy of less than 4.0

Molecular profiling assays

The Onco type Dx assay (Genomic Health, Inc, Redwood City, CA) has been approved by the US Food and Drug Administration (FDA) for women with early-stage ER-positive, node-negative breast cancer treated with tamoxifen, where the recurrence score (RS) correlated with both relapse-free interval and overall survival. This assay is an RT-PCR–based assay of 21 genes (16 cancer genes and 5 reference genes) performed on paraffin-embedded breast tumor tissue.

By using a formula based on the expression of these genes, an RS can be calculated that correlates with the likelihood of distant recurrence at 10 years. Breast tumor RSs and risk levels are as follows:

< 18, low risk

18-30, intermediate risk

>30, high risk

Furthermore, in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 and B-20 studies, the Onco type Dx assay was shown retrospectively to predict benefit from chemotherapy and hormonal therapy in hormone-sensitive, node-negative tumors. Similarly, among women with 1- to 3-node-positive, hormone receptor-positive disease, the Onco type Dx recurrence score was a significant predictor of recurrence, with a 21% decrease in recurrence risk for each 10-point drop in RS.

Women with a low RS showed a significantly greater improvement in disease-free survival (DFS) with the addition of tamoxifen; no additional benefit was derived from the addition of chemotherapy. In contrast, women with a high RS had a significant improvement in DFS with the addition of chemotherapy to hormonal therapy (tamoxifen).

The MammaPrint assay (Agendia, The Netherlands) is a genetic test that measures the activity of 70 genes to determine the 5- to 10-year relapse risk for women diagnosed with early breast cancer. It was approved for use by the FDA in 2007 and is an alternative platform to Oncotype DX. MammaPrint test results are reported as either a low-risk or a high-risk RS:

A low-risk score means that the cancer has a 10% risk of coming back within 10 years without any additional treatments after surgery

A high-risk score means that the cancer has a 29% risk of coming back within 10 years without any additional treatments after surgery

POSITIVE AND DIFFERENTIAL DIAGNOSIS

Signs and symptoms

Early breast cancers may be asymptomatic, and pain and discomfort are typically not present. If a lump is discovered, the following may indicate the possible presence of breast cancer:

Change in breast size or shape

Skin dimpling or skin changes

Recent nipple inversion or skin change, or nipple abnormalities

Single-duct discharge, particularly if blood-stained

Axillary lump

History

Many early breast carcinomas are asymptomatic, particularly if they were discovered during a breast-screening program. Larger tumors may present as a painless mass. Pain or discomfort is not usually a symptom of breast cancer; only 5% of patients with a malignant mass present with breast pain.

Often, the purpose of the history is not diagnosis but risk assessment. A family history of breast cancer in a first-degree relative is the most widely recognized breast cancer risk factor.

The US Preventive Services Task Force (USPSTF) has updated its 2005 guidelines on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women. The current USPSTF recommendations are as follows:

Women who have family members with breast, ovarian, tubal, or peritoneal cancer should be screened to identify a family history that may be associated with an increased risk for mutations in the breast cancer susceptibility genes BRCA1 or BRCA2

Women who have positive screening results should receive genetic counseling and then BRCA testing if warranted

Women without a family history associated with an increased risk for mutations should not receive routine genetic counseling or BRCA testing

Physical Examination

If the patient has not noticed a lump, then signs and symptoms indicating the possible presence of breast cancer may include the following:

Change in breast size or shape

Skin dimpling or skin changes (eg, thickening, swelling, or redness)

Recent nipple inversion or skin change or other nipple abnormalities (eg, ulceration, retraction, or spontaneous bloody discharge)

Nipple discharge, particularly if bloodstained

Axillary lump

To detect subtle changes in breast contour and skin tethering, the examination must include an assessment of the breasts with the patient upright with arms raised. The following findings should raise concern:

Lump or contour change; Skin tethering; Nipple inversion; Dilated veins; Ulceration; Mammary Paget disease;Edema or peau d’orange.

The nature of palpable lumps is often difficult to determine clinically, but the following features should raise concern:

Hardness; Irregularity; Focal nodularity; Asymmetry with the other breast; Fixation to skin or muscle (assess fixation to muscle by moving the lump in the line of the pectoral muscle fibers with the patient bracing her arms against her hips)

A complete examination includes assessment of the axillae and supraclavicular fossae, examination of the chest and sites of skeletal pain, and abdominal and neurologic examinations. The clinician should be alert to symptoms of metastatic spread, such as the following:

Breathing difficulties; Bone pain; Symptoms of hypercalcemia; Abdominal distention; Jaundice;Localizing neurologic signs; Altered cognitive function; Headache

The clinical evaluation should include a thorough assessment of specific risk factors for breast cancer. Numerous risk factors have been found to increase a woman’s risk of developing breast cancer The common denominator for many of them is their effect on the level and duration of exposure to endogenous estrogen.

Evidence from the Cancer Genome Atlas Network showed that the 4 main breast cancer subtypes (hER2-enriched, luminal A, luminal B and basal-like) are caused by different subsets of genetic and epigenetic aberrations

Risk factors

Factors that increase the risk of breast cancer include the following:

Advanced age

Family history of cancer in a first-degree relative – Family history of ovarian cancer at < 50 years, 1 first-degree relative with breast cancer, ≥2 first-degree-relatives with breast cancer

Personal history – Positive BRCA1/BRCA2 mutation, breast biopsy with atypical hyperplasia, breast biopsy with lobular or ductal carcinoma in situ

Reproductive history – Early menarche (< 12 years), late menopause, late age of first term pregnancy (>30 years) or nulliparity

Use of estrogen-progesterone hormone replacement therapy (HRT)

Current or recent oral contraceptive use

Lifestyle factors – Adult weight gain, sedentary lifestyle, alcohol consumption

Risk models used in breast cancer include (1) BRCA probability tools and (2) models for predicting absolute risk of developing breast cancer over time.

BRCA probability tools include the following:

BRCAPRO model; Myriad I and II; Manchester; Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA); Ontario Family History Assessment Tool (FHAT)

Breast cancer risk prediction tools include the following:

Gail model; Gail model 2 (used as the basis for eligibility for a number of the breast cancer prevention trials); Women’s Contraceptive and Reproductive Experiences (CARE) model (developed to address concerns regarding applicability of the Gail model to black women)

Epidemiologic studies have identified many risk factors that increase the chance of a woman developing breast cancer. Many of these factors form the basis of breast cancer risk assessment tools. The common denominator for many of these risk factors is their effect on the level and duration of exposure to endogenous estrogen.

For example, early menarche, nulliparity, and late menopause increase lifetime exposure to estrogen in premenopausal women, whereas obesity and hormone replacement therapy (HRT) increase estrogen levels in postmenopausal women. The increased risk in obese women is probably due to adipose conversion of androgens to estrogens.

A study by Goss et al found that exemestane significantly reduced invasive breast cancers among postmenopausal women who had a moderately increased risk of breast cancer.

A study by Bouchardy et al examined the risk of second breast cancer after a first primary estrogen receptor (ER)-negative breast cancer. The results indicated that the risk of second ER-negative breast cancer is high after a first ER-negative tumor; this is particular the case among women with a strong family history.

Age is the most significant risk factor for breast cancer, with breast cancer being rare in women younger than 25 years. Incidence increases with increasing age, with a plateau in women aged 50-55 years.

A family history of breast cancer in a first-degree relative is the most widely recognized breast cancer risk factor. The lifetime risk is up to 4 times higher if a mother and sister are affected; the risk is approximately 5 times greater in women with 2 or more first-degree relatives with breast cancer; and it is also greater among women with a single first-degree relative, particularly if they were diagnosed at an early age (50 y or younger).

A family history of ovarian cancer in a first-degree relative, especially if the disease occurred at an early age (<50 y), has been associated with a doubling of breast cancer risk.

The family history characteristics that suggest increased risk of cancer are summarized as follows:

One or more relatives with breast or ovarian cancer

Breast cancer occurring in an affected relative younger than 50 years

Male relatives with breast cancer

BRCA1 and BRCA2 mutations

Ataxia-telangiectasia heterozygotes (4 times’ increased risk)

Ashkenazi Jewish descent (2 times’ greater risk)

Although 20-30% of women with breast cancer have at least one relative with a history of breast cancer, only 5-10% of women with breast cancer have an identifiable hereditary predisposition. BRCA1 and BRCA2 mutations are responsible for 3-8% of all cases of breast cancer and 15-20% of familial cases. Rare mutations are seen in the PTEN, TP53, MLH1, MLH2, and STK11 genes.

Evidence from the Cancer Genome Atlas Network showed that the four main breast cancer subtypes (hER2-enriched, luminal A, luminal B and basal-like) are caused by different subsets of genetic and epigenetic aberrations. Interestingly, breast basal-like tumors shared a number of molecular characteristics common to ovarian cancer such as the types and frequencies of genomic mutations, suggesting a related etiology and potentially similar responsiveness to some of the same therapies.

The BRCA1 and BRCA2 gene mutations, on chromosomes 17 and 13, respectively, account for the majority of autosomal dominant inherited breast cancers. Both genes are believed to be tumor suppressor genes whose products are involved with maintaining DNA integrity and transcriptional regulation. Mutation rates may vary by ethnic and racial groups.

For BRCA1 mutations, the highest rates occur among Ashkenazi Jewish women (8.3%), followed by Hispanic women (3.5%), non-Hispanic white women (2.2%), black women (1.3%), and Asian women (0.5%). Moreover, 95% of Ashkenazi Jews with a BRCA gene mutation will have 1 of the 3 founder mutations (185delAG, 538insC in BRCA1; 6174delT in BRCA2). Women who inherit a mutation in theBRCA1 or BRCA2 gene have an estimated 50-80% lifetime risk of developing breast cancer.

Specifically, BRCA1 mutations are seen in 7% of families with multiple breast cancers and 40% of families with breast and ovarian cancer. Women with a BRCA1mutation have a 40% lifetime risk of developing ovarian cancer. Breast cancers that develop in BRCA1 mutation carriers are more likely to be high grade, as well as estrogen receptor (ER) negative, progesterone receptor (PR) negative, and HER2-negative (triple negative) or basal-like subtype. BRCA1 mutations are also associated with a higher risk of colon cancer and prostate cancer.

BRCA2 mutations are identified in 10-20% of families at high risk for breast and ovarian cancers and in only 2.7% of women with early-onset breast cancer. Women with a BRCA2 mutation have an approximately 10% lifetime risk of ovarian cancer.

BRCA2 mutation carriers who develop breast cancer are more likely to have a high-grade, ER-positive, PR-positive, and HER2-negative cancer (luminal type). BRCA2is also a risk factor for male breast cancer. Other cancers associated with BRCA2mutations include prostate, pancreatic, fallopian tube, bladder, non-Hodgkin lymphoma, and basal cell carcinoma.

Li-Fraumeni syndrome, caused by TP53 mutations , is responsible for approximately 1% of cases of familial breast cancer. Bilateral breast cancer is noted in up to 25% of patients. Li-Fraumeni syndrome is also associated with multiple cancers, including the SBLLA syndrome (sarcoma, breast and brain tumors, leukemia, and laryngeal and lung cancer). Cancer susceptibility is transmitted in an autosomal dominant pattern, with a 90% lifetime risk of breast cancer.

Cowden disease is a rare genetic syndrome caused by PTEN mutations. It is associated with intestinal hamartoma, cutaneous lesions, and thyroid cancer. There is about a 30% prevalence rate of breast cancer in women with this disease.

Benign mammary abnormalities (eg, fibroadenomas, fibrocystic lesions, ductal epithelial hyperplasia, and nipple malformations) are also common.

Other rare genetic disorders, such as Peutz-Jeghers syndrome and hereditary nonpolyposis colorectal carcinoma (HNPCC), are associated with an increased risk of breast cancer. The table below lists genetically determined breast cancer syndromes.

A study by Mangoni et al found an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in patients with breast cancer. The authors propose a hypothesis that mismatch repair mechanisms may be involved in the cellular response to radiotherapy and that genetic polymorphisms warrant further study as candidates for predicting acute radiosensitivity.

Neoplastic and Benign Risk Factors

Neoplastic conditions that increase the risk of breast cancer include the following:

Previous breast cancer; Ovarian cancer; Endometrial cancer; Ductal carcinoma in situ (DCIS); Lobular carcinoma in situ (LCIS)

Benign breast conditions that increase the risk of breast cancer include the following:

Hyperplasia (unless mild); Complex fibroadenoma; Radial scar; Papillomatosis; Sclerosing adenosis; Microglandular adenosis

Cervical cancer is associated with a decreased risk of breast cancer.

Exogenous hormones

One of the most widely studied risk factors in breast cancer is the use of exogenous hormones in the form of oral contraceptives (OCs) and hormone replacement therapy (HRT).

The overall evidence suggests a modest increased risk among current users of oral contraceptives. Risk is increased 1.24 times for 10 years’ use, normalizing 10 years after discontinuation; the progesterone-only pill is not associated with increased risk.

Consistent epidemiologic data support an increased risk of breast cancer incidence and mortality with the use of postmenopausal HRT. Risk is increased 1.35 times for 5 or more years of HRT use, normalizing 5 years from discontinuing. Risk is directly associated with length of exposure, with the greatest risk observed for the development of hormonally responsive lobular, mixed ductal-lobular, and tubular cancers.

Factors that increase the number of menstrual cycles also increase the risk of breast cancer, probably due to increased endogenous estrogen exposure. Such factors include nulliparity, first full pregnancy when older than 30 years, menarche when younger than 13 years (2 times the risk), menopause when older than 50 years, and not breastfeeding.

Conversely, late menarche, anovulation, and early menopause (spontaneous or induced) are protective, owing to their effect on lowering endogenous estrogen levels or shortening the duration of estrogenic exposure.

Other exogenous factors affecting the risk of breast cancer include the following:

Diethylstilbestrol use

Alcohol consumption, probably through increasing estrogen levels

Irradiation, particularly in the first decade of life

Exposure to dichlorodiphenyldichloroethylene (DDE), a metabolite of the insecticide dichlorodiphenyltrichloroethane (DDT)

Long-term use of calcium channel blockers

A study by Chen et al found that low levels of alcohol consumption were associated with a small increase in breast cancer risk; cumulative alcohol intake throughout adult life was the most consistent measure. Alcohol intake that occurred early and late in adult life was independently associated with risk.

In addition, the incidence of breast cancer is increased in individuals in higher socioeconomic classes. However, breast cancer survival rates are lower in women from lower socioeconomic classes.

Breast cancer risk assessment models

Several groups have made concerted efforts to develop multivariate methods to derive a breast cancer risk assessment tool using sets of risk factors (genetic and other) that are informative for estimating the risk of breast cancer. Two types of risk models have been developed that are clinically relevant: those that estimate a woman’s absolute risk of developing breast cancer over time and those that determine the likelihood that an individual is a carrier of a BRCA1, BRCA2, or an unknown gene mutation (ie, BRCA1/2 probability models).

The BRCAPRO model, the most commonly used BRCA probability tool, identifies approximately 50% of mutation-negative families but fails to screen 10% of mutation carriers.

Other probability tools include the following:

Myriad I and II; Manchester; Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA); Ontario Family History Assessment Tool (FHAT)

All these tools were developed by using mutation rates in Ashkenazi Jewish families and families of European descent. However, they have been validated in black and Hispanic populations.

Improvements in risk prediction and clinical tools are likely to emerge in the next few years with the addition of factors such as the following:

Breast density; Mammographic density change across examinations; Use of HRT; Weight;

Age at birth of first live child; Number of first-degree relatives with breast cancer.

Danish researchers have developed a model for forecasting the development of breast cancer several years before diagnosis. The model includes a total of 176 variables that comprise lifestyle and phenotype information, years of hormone replacement therapy, and metabolic profiling of plasma samples with nuclear magnetic resonance. These are used to develop a biocontour, which predict breast cancer in the ensuing 2–5 years with sensitivity and specificity well above 80%.

Going forward, it is likely that there will be specific models for risks of premenopausal versus postmenopausal cancers and for specific breast cancer subtypes (luminal vs basal).

Diagnostic Considerations

The differential diagnosis includes the following:

Circumscribed breast lesions – Benign breast disease (eg, fibroadenomas and cysts), breast cancer, breast lymphoma, and metastasis to the breast from other primary sites (eg, neuroendocrine or extramedullary acute myeloid leukemia)

Skin thickening – Inflammatory carcinoma and mastitis

Stellate lesions – Breast cancer, traumatic fat necrosis, a radial scar, and a hyalinized fibroadenoma

Dilated ducts with or without nipple discharge – Papilloma, ductal carcinoma, duct ectasia, and fibrocystic disease

Differential Diagnoses

Breast Abscess and Masses

Breast Fibroadenoma Imaging

Approach Considerations

Breast cancer evaluation should be an ordered inquiry that begins with symptoms and a general clinical history. This is followed by a sequence that has become formalized as triple assessment, which includes the following components:

Clinical examination

Imaging (usually mammography, ultrasonography, or both)

Needle biopsy

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This approach naturally lends itself to a gradually increasing degree of invasiveness, so that a diagnosis can be obtained with the minimum degree of invasiveness and, consequently, the minimum amount of discomfort to the patient. Because the more invasive investigations also tend to be the most expensive, this approach is usually the most economical.

The aims of evaluation of a breast lesion are to judge whether surgery is required and, if so, to plan the most appropriate surgery. The ultimate goal of surgery is to achieve the most appropriate degree of breast conservation while minimizing the need for reoperation.

Breast cancer is often first detected as an abnormality on a mammogram before it is felt by the patient or healthcare provider. Mammographic features suggestive of malignancy include asymmetry, microcalcifications, and a mass or architectural distortion. If any of these features are identified, diagnostic mammography along with breast ultrasonography should be performed before a biopsy is obtained. In certain cases, breast magnetic resonance imaging (MRI) may be warranted.

Breast cancer screening

Whereas early detection has been advocated as a primary defense against the development of life-threatening breast cancer, questions have been raised in the past few years regarding the age at which to initiate, the modality to use, the interval between screenings, whether to screen older women, and even the impact on breast cancer related deaths.

It is widely believed that breast tumors that are smaller or nonpalpable and that present with a favorable tumor marker profile are more treatable when detected early.

A number of screening modalities exist for breast cancer, including clinical breast examination, mammography, ultrasonography, and MRI.

Mammography

Mammography is a low-dose x-ray−based modality used to image the breast. It is currently the best available population-based method for detecting breast cancer at an early stage. Mammography is used both for screening to detect a cancer and for diagnostic workup of patients after a tumor is detected. Screening mammography is performed in asymptomatic women, whereas diagnostic mammography is performed in symptomatic women (ie, when a breast lump or nipple discharge is present or when an abnormality is found during screening mammography).

Mammography is sensitive to microcalcifications that develop in breast tumors with sensitivity at less than 100 µm. Mammography often detects a lesion before it is palpable by clinical breast examination and, on average, 1 to 2 years before noted by breast self-examination.

Recent advances in mammography include the development of digital mammography and the increased use of computer-aided diagnosis (CAD) systems. CAD systems have been developed to help the radiologist identify mammographic abnormalities.

Digital mammography allows the image to be recorded and stored. With computer technology, digital mammogram images can be magnified and the image modified to improve evaluation of specific areas in question. Digital images can be transmitted electronically, decreasing the time to second opinion without the risk of losing the film.

The 2015 ACS recommendations for women at average risk of breast cancer are as follows:

Women should begin regular screening mammography at age 45 years (strong recommendation)

Women aged 45-54 years should be screened annually (qualified recommendation)

Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation)

Women should have the opportunity to begin annual screening at 40-44 years of age (qualified recommendation)

Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation)

Clinical breast examination is not recommended for breast cancer screening in average-risk women at any age

Similarly, a 2015 review by the American College of Physicians (ACP) recommends the following strategies as the least intensive and having the highest value for asymptomatic women at average risk and in good health[91] :

Women 40-49 years of age: Discuss benefits and harms; if the patient requests screening, order biennial mammography

Women 50-74 years of age: Encourage mammography every 2 years

For women of any age, the ACP does not recommend the following low-value screening strategies :

Annual mammography

MRI

Tomosynthesis

Regular systematic breast examination

Diagnostic mammography

Diagnostic mammography is more expensive than screening mammography. It is used to determine the exact size and location of breast abnormalities and to image the surrounding tissue and lymph nodes. Women with breast implants or a personal history of breast cancer may require the additional views used in diagnostic mammography as part of their routine screening examination.

A ductogram (or galactogram) is sometimes helpful for determining the cause of nipple discharge. In this specialized examination, a fine plastic tube is placed into the opening of the duct in the nipple. A small amount of contrast medium is injected, which outlines the shape of the duct on a mammogram and shows whether a mass is present inside the duct.

Ultrasonography

Ultrasonography has become a widely available and useful adjunct to mammography in the clinical setting. It is generally employed to assist the clinical examination of a suspicious lesion detected on mammography or physical examination. As a screening tool, ultrasonography is limited by a number of factors, most notably its failure to detect microcalcifications and its poor specificity (34%).

Originally, ultrasonography was used primarily as a relatively inexpensive and effective method of differentiating cystic breast masses, which did not require sampling, from solid breast masses, which were usually examined with biopsy; in many cases, the results of these biopsies were benign. However, it is now well established that ultrasonography also provides valuable information about the nature and extent of solid masses and other breast lesions and can often provide useful information regarding the staging of the axilla.

This imaging technique is also useful in the guidance of biopsies and therapeutic procedures; research is currently under way to evaluate its role in cancer screening.

Magnetic resonance imaging

In an effort to overcome the limitations of mammography and ultrasonography, MRI has been explored as a modality for detecting breast cancer in women at high risk and in younger women. A combination of T1, T2, and 3-D contrast-enhanced MRI techniques has been found to possess high sensitivity (approximating 86-100% in combination with mammography and clinical breast examination) to malignant changes in the breast.

Indications for MRI

The high cost and limited availability of MRI, as well as the difficulties inherent in performing and interpreting the studies with high false-positive rates, necessitate that the use of this modality be carefully considered before it is recommended in a patient. The following are current indications for MRI:

Characterization of an indeterminate lesion after a full assessment with physical examination, mammography, and ultrasonography

Detection of occult breast carcinoma in a patient with carcinoma in an axillary lymph node

Evaluation of suspected multifocal or bilateral tumor

Evaluation of invasive lobular carcinoma, which has a high incidence of multifocality

Evaluation of suspected extensive high-grade intraductal carcinoma

Detection of occult primary breast carcinoma in the presence of metastatic adenocarcinoma of unknown origin

Monitoring of the response to neoadjuvant chemotherapy

Detection of recurrent breast cancer

Contraindications for MRI

Conversely, in a number of situations, MRI is contraindicated, usually because of physical constraints that prevent adequate patient positioning. Additional contraindications include the following:

Contraindication to gadolinium-based contrast media (eg, allergy or pregnancy)

Patient’s inability to lie prone

Marked kyphosis or kyphoscoliosis

Marked obesity

Extremely large breasts

Severe claustrophobia

Relative contraindications also exist. These are essentially based on the high sensitivity but limited specificity of the technique. MRI may not be useful for the following:

Cancer-phobic patients at average or low risk of disease for breast cancer, because of the psychological stress associated with false-positive findings

Assessment of mammographically detected microcalcifications

Nuclear imaging

The following 3 radiotracers are commonly used for breast imaging or scintimammography in either clinical practice or research:

Technetium-99m ( 99m Tc)-sestamibi (for myocardial perfusion imaging); this was the first radiopharmaceutical agent to be approved by the US Food and Drug Administration (FDA) for use in scintimammography

99m Tc-tetrofosmin (also for myocardial perfusion imaging)

99m Tc-methylene diphosphonate (MDP; for bone scintigraphy)

Scintimammography is not indicated as a screening procedure for the detection of breast cancer. However, it may play a role in various specific clinical indications, as in cases of nondiagnostic or difficult mammography and in the evaluation of high-risk patients, tumor response to chemotherapy, and metastatic involvement of axillary lymph nodes.

Positron Emission Tomography

Using a wide range of labeled metabolites (eg, fluorinated glucose [18 FDG]), positron emission tomography (PET) can detect changes in metabolic activity, vascularization, oxygen consumption, and tumor receptor status.

When PET is combined with computed tomography (CT) to assist in anatomic localization (PET-CT), scans can identify axillary and nonaxillary (eg, internal mammary or supraclavicular) lymph node metastasis for the purposes of staging locally advanced and inflammatory breast cancer before initiation of neoadjuvant therapy and restaging high-risk patients for local or distant recurrences.

Breast Biopsy

Percutaneous vacuum-assisted large-gauge core-needle biopsy (VACNB) with image guidance is the recommended diagnostic approach for newly diagnosed breast tumors. Core biopsies can minimize the need for operative intervention (and subsequent scarring, and provide accurate pathologic diagnosis for appropriate management.

Excisional biopsy, as the initial operative approach, has been shown to increase the rate of positive margins. Open excisional biopsy is reserved for lesions where the diagnosis remains equivocal despite imaging and core biopsy assessment or for benign lesions that the patient chooses to have removed. Because wide clearance of the lesion is usually not the goal in diagnostic biopsies, unnecessary distortion of the breast is thereby avoided. Ongoing audit is essential to help reduce an excessive benign-to-malignant biopsy ratio.

BREAST CANCER TREATMENT PROTOCOLS

Localized Disease

Stage 0, I, II or IIIA (T3N1M0)

In the United States and other developed nations where screening is performed, most patients present with localized breast cancer that is detected by a screening mammogram; less commonly, patients present with a palpable mass that is either self-detected or detected by a health care provider.

Stage 0 (lobular carcinoma in situ [LCIS])

Management options include the following:

Surveillance alone (ie, mammography)

Surveillance plus raloxifene (for postmenopausal women)

Tamoxifen (for women of any menopausal status)

Bilateral prophylactic mastectomy (usually in patients who are very concerned about breast cancer risk and have either a strong family history or mammographically dense breasts that impair surveillance)

If LCIS is detected on stereotactic biopsy, wide excision is indicated. In 10-20% of cases, this may reveal invasive cancer or ductal carcinoma in situ (DCIS) that requires additional local or systemic therapy

Surgical excision to negative margins is not indicated; however, LCIS is associated with about a 5% 5-y risk and a 20-30% lifetime risk of developing invasive breast cancer, which may be ipsilateral or contralateral and may be ductal or lobular in origin

Stage 0 (ductal carcinoma in situ [DCIS])

Primary treatment options include the following:

Lumpectomy without axillary dissection plus whole-breast radiation therapy (RT); use of radiation boost (photons, brachytherapy, or electron beam) to the tumor bed is recommended, especially in patients ≥ 50y or

Total mastectomy, with or without sentinel node biopsy (SNB) and with or without breast reconstruction or

Lumpectomy without lymph node surgery and without radiation therapy (lower-level evidence)

Considerations include the following:

Although axillary dissection or SNB is often not performed, SNB may be done in some cases if an initial core biopsy showed DCIS, because more extensive sampling may show invasive carcinoma

In the absence of risk factors for recurrence (palpable mass, larger size, higher grade, close or involved margins, age < 50 y), some patients may not receive RT

Consider risk-reduction therapy with tamoxifen for 5 years for patients treated with lumpectomy and RT, especially those with estrogen receptor (ER)–positive DCIS

Stage I, IIA, IIB, or IIIA (T3N1M0)

Treatment consists of the following:

Surgery; RT in most cases; Adjuvant chemotherapy, endocrine therapy, or biologic therapy in some cases.

Surgical treatment is with excision or mastectomy plus axillary dissection, SNB, or SNB followed by axillary dissection.

RT is used in patients who undergo wide excision or, in selected cases, after mastectomy; treatment fields are determined by axillary node status. RT should follow chemotherapy if chemotherapy is indicated. Patients undergoing lumpectomy with surgical axillary staging

RT recommendations are as follows:

If patients have four or more positive axillary nodes, whole-breast RT, with or without boost to the tumor bed, is recommended; RT to the infraclavicular and supraclavicular areas should also be considered

Patients with one to three positive axillary nodes should also receive whole-breast RT, with or without boost to the tumor bed; RT to the infraclavicular and supraclavicular areas should also be considered, as should RT to internal mammary nodes

Patients with negative axillary nodes should receive RT to the whole breast, with or without boost to the tumor bed; partial breast irradiation (PBI) may be considered in selected patients

Patients undergoing total mastectomy with surgical axillary staging, with or without reconstruction

RT recommendations are as follows:

Patients with four or more positive axillary nodes should receive postchemotherapy RT to the chest wall plus the infraclavicular and supraclavicular areas; consider RT to internal mammary nodes

For patients with one to three positive axillary nodes, consider postchemotherapy RT to the chest wall, with or without infraclavicular and supraclavicular nodes; consider RT to internal mammary nodes

For patients with negative axillary nodes and tumor >5 cm or positive margins, consider RT to the chest wall, with or without infraclavicular and supraclavicular nodes; consider RT to internal mammary nodes

For patients with negative axillary nodes, tumor ≤5 cm, and margins < 1 mm, postchemotherapy RT to the chest wall is recommended

For patients who have negative axillary nodes, tumor ≤5 cm, and margins ≥1 mm, no RT is needed

Preoperative chemotherapy for large clinical stage IIA, IIB, or IIIA (T3N1M0) tumors

Stage I, IIA, IIB, or IIIA (T3N1M0)

Treatment considerations are as follows:

Anti-HER2/neu–directed therapy (eg, trastuzumab) is indicated for use in combination with chemotherapy in patients with HER2/neu-positive disease; HER2/neu overexpression occurs in about 15-20% of cases of localized breast cancer, is associated with a higher risk of recurrence, and identifies patients who benefit from adjuvant anti-HER2/neu directed therapy

The only anti-HER2/neu – directed therapy is currently shown to reduce the risk of recurrence is trastuzumab

In the only studies that evaluated trastuzumab, patients were randomly assigned to receive chemotherapy alone or in combination with trastuzumab[9]

There is suggestion that overlapping trastuzumab therapy with taxane therapy is more effective than a strategy of completing all chemotherapy first and then administering trastuzumab

Trastuzumab cannot be given concurrently with anthracyclines, because of the high risk of cardiac toxicity

Stage I, IIA, IIB, or IIIA (T3N1M0)

First-generation regimens

First-generation regimens are considered less effective than second- or third-generation regimens but do play a role in selected situations; CMF represents a reasonable alternative for patients who have contraindications to anthracycline (cardiac disease) and/or taxane therapy; AC would be a reasonable consideration for patients with contraindications to taxane therapy (eg, neuropathy).

Second-generation regimens

Second-generation regimens have been shown to be more effective than other regimens with which they were compared, which in some studies included first-generation regimens such as CMF. Some of these regimens may be appropriate for patients who desire less prolonged regimens. There is geographic variation in the use of these regimens: DC and AC-P are more commonly used in the United States, and epirubicin-containing regimens are more commonly used in Europe.

Third-generation regimens

Third-generation regimens have been shown to be more effective than some second-generation regimens and include both taxanes and anthracyclines.

Adjuvant endocrine therapy, ER/PR+ Localized Disease

General considerations

Patients with invasive breast cancer that is ER or PR positive should be considered for adjuvant endocrine therapy. Options for endocrine therapy in breast cancer patients include the following:

Tamoxifen; Aromatase inhibitors (AIs); Luteinizing hormone–releasing hormone (LHRH) analogues; Oophorectomy may produce additional benefit.

Selection considerations are as follows:

Selection of agents depends on menopausal status and concern about side-effect profile (eg, thrombosis with tamoxifen, bone loss with AIs)

Tamoxifen has been shown to reduce the risk of recurrence by about 40% and the risk of death by about 30%, is effective in both premenopausal and postmenopausal women, and may be used either alone or after chemotherapy

Acute toxicities of tamoxifen include hot flushes and gynecologic symptoms; long-term toxicities are thrombosis and uterine cancer

AIs are effective for postmenopausal women, reducing the risk of recurrence by approximately 20% compared with tamoxifen

Nonsteroidal AIs (anastrozole, letrozole) and steroidal AIs (exemestane) exhibit comparable efficacy and side effects

Acute toxicities of AIs include arthralgias, hot flushes, and gynecologic symptoms; osteoporosis is a long-term adverse effect

Regimens for premenopausal patients

Regimens are as follows:

Tamoxifen 20 mg PO daily for 5 y [25] or

Tamoxifen 20 mg PO daily for 2-5 y, followed by an AI for a total of up to 10 y of endocrine therapy; this regimen is typically used for patients who are premenopausal at diagnosis and become postmenopausal during therapy; it has been shown to be more effective than a 5-y course of tamoxifen [26]

Ovarian suppression with LHRH analogues, added to tamoxifen or an AI, is associated with a modest effect; this approach is being evaluated in ongoing trials

Localy advanced disease

Stage III

Considerations are as follows:

Patients with stage III disease are divided into those who are candidates for operative treatment and those who are not

Patients with stage IIIA breast cancer are further divided into those with T3N1M0 disease and those with TanyN2M0 disease; for treatment of patients with operable T3N1M0 disease, see Treatment recommendations for localized disease, above

Therapeutic options for locally advanced disease are similar to those for localized disease but include consideration of preoperative (neoadjuvant) chemotherapy followed by local surgical therapy

In general, all planned chemotherapy should be given preoperatively to optimize the potential for inducing a pathologic complete response (pCR), which has been shown to be associated with improved outcomes (90% of higher disease-free survival [DFS] rates)

Preoperative systemic chemotherapy is indicated for all patients with inflammatory breast carcinoma, ipsilateral supraclavicular adenopathy, bulky axillary adenopathy, extension to the skin or chest wall, or a large (>5 cm) primary tumor; patients who do not meet these criteria but would benefit from tumor cytoreduction before surgery to facilitate breast conservation should be considered for such treatment

Radiopaque clips should be placed in the tumor bed before the start of preoperative therapy, and breast imaging should be repeated after therapy in any such patients for whom breast conservation is being considered

RT to the breast or chest wall is indicated for any patient who received preoperative systemic chemotherapy

Treatment recommendations for inoperable noninflammatory locally advanced disease (stage IIIA except T3N1M0)

Treatment includes chemotherapy, with or without a taxane

Treatment recommendations for HER2/neu+ locally advanced disease

In patients with HER2/neu-positive disease, concurrent trastuzumab with chemotherapy improves the pCR rate.

Metastatic or Recurrent Disease (Stage IV)

Local-only recurrence

Recommended therapy depends on the initial treatment given, as follows :

Patients whose initial treatment was lumpectomy and radiation therapy (RT) should undergo total mastectomy with axillary lymph node staging if level I/II axillary dissection was not previously done

Patients whose initial treatment was mastectomy plus level I/II axillary dissection and RT should undergo surgical resection if possible

Patients whose initial treatment was mastectomy with no prior RT should undergo surgical resection if possible, along with RT if possible to the chest wall and supraclavicular and infraclavicular nodes

Regional-only or local-regional recurrence

Recommendations vary by site of recurrence, as follows:

For axillary recurrence, treatment is surgical resection if possible, plus RT if possible to the chest wall, supraclavicular and infraclavicular nodes, and axilla

For supraclavicular recurrence, treatment is RT if possible to the chest wall and supraclavicular and infraclavicular nodes

For internal mammary node recurrence, treatment is RT if possible to the chest wall, supraclavicular and infraclavicular nodes, and internal mammary nodes

Bone disease

Local irradiation should be considered for patients with localized bony disease that is symptomatic or at risk for producing a catastrophic complication (eg, spinal cord compression or pathologic fracture).

If expected survival is at least 3 mo and renal function is adequate, any of the following may be given (all with calcium and vitamin D supplementation) on a 3-wk to 5-wk schedule in conjunction with chemotherapy or endocrine therapy

Systemic disease

Treatments for systemic disease are used to prolong survival and improve quality of life. Considerations in treatment selection are as follows:

In patients with ER and/or PR expression who have no or minimal disease symptoms and bone-only disease or a low disease burden, endocrine therapy is always preferred to other therapeutic options because of its favorable toxicity profile relative to other alternatives

Chemotherapy is used in patients with resistance to endocrine therapy or ER/PR-negative disease and a moderate or high disease burden

Single-agent sequential cytotoxic therapy is preferred; combination cytotoxic therapy is associated with a higher response rate, but it is also more toxic and confers no survival benefit

Endocrine therapy in premenopausal women

Recommended treatment is ovarian suppression plus endocrine therapy with tamoxifen or an AI. Gonadotropin-releasing hormone (GRH) analogues may be used to suppress ovarian estrogen production

Treatment considerations are as follows:

Exercise caution when using GRH analogues in combination with AIs because of inconsistent inhibition of estrogen production.

Oophorectomy is preferred because it induces permanent menopause and does not necessitate repeated injections

Tamoxifen or AIs are used in the same doses and schedules commonly employed for adjuvant therapy

Selected patients who have had prolonged response or periods of stability on AIs may be switched to one of the following: progestational agents (megestrol acetate 40 mg PO QID) or  androgens ( fluoxymesterone 10-40 mg PO in divided doses) or  estradiol (10 mg PO TID)

In patients whose menopausal status is uncertain (eg, because of hysterectomy or chemotherapy-induced amenorrhea), confirmation of menopausal status may require documentation of an elevated serum follicle-stimulating hormone (FSH) level and a low estradiol level

BREAST CANCER SURGERY

General considerations

Primary surgery usually includes either a mastectomy or lumpectomy with wide excision to cancer-free margins of excision (usually 1-10 mm)

Patients with invasive disease also receive axillary surgery; if nodes are clinically positive, this comprises axillary dissection; if nodes are clinically negative, SNB is performed

SNB involves identification of ≥ 1 lymph nodes in the draining lymph node basin by injecting, into the breast, isosulfan blue dye that may be visualized, technetium-labeled sulfur colloid that may be detected by a handheld probe, or both; the success rate in identifying sentinel nodes varies by experience but is usually 90-95% in experienced hands and is associated with a false negative rate ≤ 5-10%

Although axillary dissection had been the standard of care for patients with a positive SNB, studies have indicated comparable local and systemic control rates without axillary dissection for patients who also receive radiation and systemic chemotherapy

Completion of axillary dissection is recommended for patients who will not be receiving adjuvant chemotherapy or for those who have had a mastectomy and would otherwise not receive RT

Breast cancer in the elderly

Infirm elderly patients who are not suitable candidates for surgery may be managed with endocrine therapy alone if the tumor is ER/PR positive

Ipsilateral breast, chest wall, or locoregional recurrence

Patients with localized recurrence should undergo a thorough evaluation for metastatic disease, including a careful history and physical examination, bone scan, and computed tomography (CT) of the chest and abdomen; clinically unsuspected metastases are not uncommon; the tumor should be resected with an attempt to establish adequate tumor-free margins, whenever feasible

RT should also be administered to the chest wall and regional lymphatics, although this may be problematic for those who have previously undergone chest wall irradiation in the adjuvant setting

Systemic therapy should also be considered in order to decrease the likelihood of subsequent recurrence

Oligometastatic disease

Surgery may be able to achieve prolonged disease control in selected patients with oligometastatic disease, especially those with solitary lung metastases

Patients with single cerebral metastases may benefit from surgical resection, even if there are other sites of systemic metastases

Resection of bone metastases is generally reserved for patients with or at high risk for pathologic fracture and is generally followed by local irradiation

Resection or ablation of liver metastases may also be indicated in some cases

Lumpectomy margins

The following consensus guideline, released by the Society of Surgical Oncology and the American Society for Radiation Oncology, addresses margins for breast-conserving surgery with whole-breast irradiation (WBI) in stages I and II invasive breast cancer

Positive margins are associated with at least a 2-fold increase in ipsilateral breast tumor recurrence (IBTR)

Negative margins optimize IBTR; this risk is not significantly lowered by wider margin widths

IBTR rates are reduced with the use of systemic therapy; in patients who do not receive adjuvant systemic therapy, margins wider than no ink on tumor are not needed

Biologic subtypes do not indicate the need for margins wider than no ink on tumor

Margin width should not determine the choice of WBI delivery technique, fractionation, and boost dose.

Wider negative margins than no ink on tumor are not indicated for patients with invasive lobular cancer; classic lobular carcinoma in situ (LCIS) at the margin is not an indication for reexcision; the significance of pleomorphic LCIS at the margin is not clear

Young age is associated with an increased risk for IBTR after breast-conserving therapy, an increased risk for local relapse on the chest wall after mastectomy, and adverse biologic and pathologic features; an increased margin width does not nullify the increased risk for IBTR in young patients

An extensive intraductal component (EIC) identifies patients who may have a large residual ductal carcinoma in situ (DCIS) burden after lumpectomy; when margins are negative, there is no evidence of an association between an increased risk for IBTR and EIC

Postlumpectomy radiation therapy

The purpose of radiation therapy after breast-conserving surgery is to eradicate local subclinical residual disease while reducing local recurrence rates by approximately 75%. On the basis of results from several randomized controlled studies, irradiation of the intact breast is considered standard of care, even in the lowest-risk disease with the most favorable prognostic features.

There are 2 general approaches used to deliver radiation therapy: conventional external-beam radiotherapy (EBRT) and partial-breast irradiation (PBI). Whole-breast radiotherapy (WBRT) consists of EBRT delivered to the breast at a dose of 50-55 Gy over 5-6 weeks. This is often followed by a boost dose specifically directed to the area in the breast where the tumor was removed.

Common side effects of radiation therapy include fatigue, breast pain, swelling, and skin desquamation. Late toxicity (lasting ≥6 months after treatment) may include persistent breast edema, pain, fibrosis, and skin hyperpigmentation. Rare side effects include rib fractures, pulmonary fibrosis, cardiac disease (left breast treatment), and secondary malignancies such as radiation-induced sarcoma (0.5%).

PBI is employed in early-stage breast cancer after breast-conserving surgery as a way of delivering larger fraction sizes while maintaining a low risk of late effects. Techniques that can deliver this therapy include interstitial brachytherapy (multiple catheters placed through the breast) and intracavitary brachytherapy (a balloon catheter inserted into the lumpectomy site [ie, MammoSite]).

The American Society of Breast Surgeons (ASBrS) recommends the following selection criteria when patients are being considered for treatment with accelerated PBI:

Age ≥45 years; Invasive ductal carcinoma or ductal carcinoma in situ (DCIS); Total tumor size (invasive and DCIS) ≤3 cm; Negative microscopic surgical margins of excision; ALN- or SLN-negative.

Potential complications of PBI are catheter placement followed by removal secondary to inadequate skin spacing, infection, seroma, fibrosis, chronic pain, or disease recurrence.

Single-dose radiotherapy

According to 2 major studies, single-dose radiotherapy delivered during or soon after surgery for breast cancer is a viable alternative to conventional EBRT in selected patients who are at low risk for local recurrence.

Postmastectomy radiation therapy

Clinical practice guidelines developed by the American Society of Clinical Oncology (ASCO), along with several prospective, randomized clinical trials, recommend that postmastectomy radiation therapy be performed according to the following criteria[4]:

Positive postmastectomy margins

Primary tumors >5 cm

Involvement of ≥4 lymph nodes

Patients with more than 4 positive lymph nodes should also undergo prophylactic nodal radiation therapy at doses of 45-50 Gy to the axillary and supraclavicular regions. For patients in whom ALND shows no node involvement, axillary radiation therapy is not recommended.

Meta-analyses have shown that postmastectomy radiation therapy combined with regional nodal radiation therapy significantly decreases the rate of local relapse and breast cancer mortality.

The benefit of radiation therapy for women with 1-3 positive ALNs has been uncertain. Adjuvant treatment of breast cancer is designed to treat micrometastatic disease (ie, breast cancer cells that have escaped the breast and regional lymph nodes but which have not yet had an established identifiable metastasis). Treatment is aimed at reducing the risk of future recurrence, thereby reducing breast cancer-related morbidity and mortality. Depending on the model of risk reduction, adjuvant therapy has been estimated to be responsible for 35-72% of the reduction in mortality.

Emerging data suggest that adjuvant therapy with bisphosphonates may prevent disease recurrence and prolong survival. The Early Breast Cancer Trialists' Collaborative Group found that in postmenopausal women with early breast cancer, adjuvant bisphosphonate therapy produced highly significant reductions in recurrence.

Ductal carcinoma in situ

Currently, the standard treatment of DCIS is surgical resection with or without radiation. Adjuvant radiation and hormonal therapies are often reserved for younger women, patients undergoing lumpectomy, or those with the comedo subtype.

For the majority of patients with DCIS, other approaches might be considered, such as endocrine therapy with tamoxifen/raloxifene or aromatase inhibitors.

Women at lowest risk might simply be followed with observation and prevention strategies such as diet, exercise, alcohol moderation, and avoidance of postmenopausal hormone therapy with progesterone-containing regimens.

In DCIS, WBRT is delivered over 5-6 weeks after surgery, reducing the local recurrence rate by approximately 60%. Roughly 50% of local recurrences are invasive breast cancer.

Tamoxifen is the only hormonal therapy currently approved for adjuvant therapy in patients treated with breast-conserving surgery and radiation for DCIS. Adjuvant tamoxifen also reduces the risk of contralateral breast cancer.

Lobular carcinoma in situ

Overall, treatment options for lobular carcinoma in situ (LCIS) include observation and close follow-up care with or without tamoxifen and bilateral mastectomy with or without reconstruction. There is no evidence of therapeutic benefit from local excision, axillary dissection, radiotherapy, or chemotherapy. LCIS in the breast of a woman with ductal or lobular cancer does not require further immediate surgery on the opposite breast. Mirror biopsy of the contralateral breast, once advocated for treatment of LCIS, is now mainly of historic interest.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial prospectively studied the efficacy of tamoxifen in the prevention of breast cancer and included patients with LCIS. The researchers found a 55% risk reduction in women treated with tamoxifen.

Originally, the reason for grouping locally advanced breast cancer (LABC) with inflammatory breast cancer (IBC) was the recognition that both diseases had little or no chance of cure from local therapy alone and were therefore considered inoperable. The definition of locally advanced disease has now broadened to include patients who are technically operable but who have large primary tumors (>5 cm).

It is important to recognize, however, that the reasons for using neoadjuvant therapy in women with large primary tumors, in whom the goal is to increase the possibility of breast-conserving surgery, are different from the reasons in women with disease that meets the original criteria of LABC or IBC, for whom the administration of systemic treatment is essential to make definitive local treatment possible with the intent of cure.

Overall, the prognosis is better for women with T3N0 (stage IIB) and T3N1 (stage IIIA) breast cancer than it is for those with classically defined LABC (IIIB, IIIC) or IBC (IIIB, T4d). Disease-free survival (DFS) and overall survival are typically better for stage IIB and IIIA patients; however, the likelihood of achieving a pathologic complete response (pCR) from neoadjuvant treatment, a well-recognized surrogate for long-term outcome, is inversely related to tumor size. Thus, the relative proportions of patients in each category are important.

Inflammatory breast cancer

IBC is a clinical diagnosis that implies presentation with the cardinal signs of inflammation (calor [warmth], rubor [redness], tumor [mass]) involving the breast, although the warmth may be subtle and the mass may not be appreciated as something discrete.

Indeed, even when a localized mass is apparent in IBC, the true extent of the disease (as shown by performing skin biopsies from the surrounding normal-appearing skin) is usually greater than is apparent on physical examination.

IBC was originally described as having an erysipeloid border. However, only a minority of cases have this component of a raised edge. In Western countries, the frequency of IBC is low—1-2% of all breast cancers—but in some parts of the world, such as northern Africa, it is much higher, for reasons that are not known. IBC tends to occur at a younger age than LABC does. Pathologically, IBC was originally associated with the classic finding of involvement of subdermal lymphatic vessels, though this finding is not in itself diagnostic of IBC (it may occur with LABC as a secondary phenomenon).

These tumors are more likely to stain negatively by IHC for ER and PR and somewhat more likely to be positive for HER2 overexpression. In addition, both angiogenesis and lymphangiogenesis appear to be increased by microvessel density or RNA-based gene expression arrays.

Locally advanced breast cancer

LABC is more common in the US than IBC is; by the definition used here, it may account for 10-15% of patients (this drops to about 5% if one uses the older, stricter definition that includes inoperability). Epidemiologically, LABC is associated with lower socioeconomic class and, probably for that reason, with black race in the United States.

LABC encompasses both relatively indolent neglected tumors and those that have grown rapidly as a result of their inherent biology. In most case series, LABC has a better long-term outcome than IBC does, even when only inoperable cases are considered.

Evaluation of lymph nodes and response

Patients with LABC or IBC with clinically positive nodes should undergo a core biopsy before initiating chemotherapy. Those with clinically negative nodes may undergo sentinel lymph node biopsy before they start treatment, or else sentinel node determination may be delayed until after treatment is completed.

Theoretically, it should be preferable to perform sentinel node sampling up front, because chemotherapy might eradicate preexistent disease in the sentinel lymph node and result in a false-negative result, or altered lymphatic drainage in large tumors might affect accuracy of the procedure. However, data from the NSABP B-27 trial suggest that the false-negative rate for sentinel lymph node biopsies performed after neoadjuvant chemotherapy is about 11%, comparable to the false-negative rate for patients undergoing initial resection.

In general, the best single test for evaluating the status of measurable tumor is ultrasonography (preferably done by the same operator). The mass often appears larger on physical examination than on ultrasonography, which can more effectively discriminate hypoechoic masses from surrounding stroma or hematoma. In IBC, magnetic resonance imaging (MRI) may be an important adjunct to response assessment. The role of positron emission tomography (PET) in routine assessment of response must be determined on a case-by-case basis.

No current imaging technique appears to be highly accurate for the prediction of pCR. Thus, the purposes of regular size assessment are as follows:

To exclude continuation of therapy in a patient with a growing tumor (seen in < 5% with the initial treatment)

To suggest when maximal response of grossly evident disease has been achieved (this may be the optimal time to proceed to resection

Marked advances are being made in the treatment of early-stage breast cancer, but many women still develop recurrence and metastasis. In addition, 5-10% of breast cancer patients have metastatic disease at presentation. Although treatments for metastatic breast cancer continue to improve, there remains no cure once distant metastases develop.

Furthermore, although occasional patients with metastatic breast cancer benefit from surgical resection for an isolated recurrence and many require radiation therapy for palliation at a specific site (or definitive treatment of brain metastasis), in general, recurrent or metastatic breast cancer must be approached systemically so that the therapeutic effect reaches all sites of disease. There are two main interventions: hormone therapy and chemotherapy.

Hormone therapy

For patients who have hormone receptor (ER and/or PR)–positive disease without a life-threatening component (eg, massive liver metastases) or systemic symptoms requiring immediate palliation for comfort, in general, hormone manipulation is the initial treatment of choice. Response rates are higher with chemotherapy, but so is the incidence of potentially dangerous toxicity, and there is no evidence that patients live longer as a result of receiving initial chemotherapy.

Chemotherapy

Cytotoxic chemotherapy for metastatic breast cancer initially consisted of single-agent regimens. Combination therapy is currently considered up front, depending on the patient's performance status, because of higher response rates. However, in the setting of advanced disease, the goal in determining a treatment regimen should be to prolong survival while maintaining a good quality of life.

When the patient has life-threatening disease and/or severe symptoms that require quick relief, combinations of cytotoxic agents may be preferable because of their high response rate and early onset of clinical benefit. Randomized trials have shown a survival advantage for the use of a two-drug combination versus a single agent, but this practice has not been widely adopted, because the combination is more toxic and the study designs were flawed in that patients randomized to receive a single agent initially were not crossed over to the other drug component of the initial therapy at the time of relapse.

A second situation, which is becoming increasingly common, is when a cytotoxic chemotherapeutic agent is combined with a targeted agent other than hormone therapy. These targeted agents often have very low response rates when given as monotherapy, but they provide added benefit when given in combination with cytotoxic chemotherapy.

The initial choice of chemotherapy is highly influenced by the patient's personal history of previous drug exposure. For example, if doxorubicin was a component of previous adjuvant therapy, the tumor cells have a higher risk of developing resistance, and there is a relationship between cumulative lifetime total dose of doxorubicin and the risk of potentially fatal cardiomyopathy.

It is important to realize that if 1 year or more has elapsed since completion of adjuvant therapy, a patient's tumor is likely to respond to a previously given drug or combination as though that drug or combination had never been given. Most patients have been exposed to both an anthracycline (ie, doxorubicin) and a taxane (docetaxel or paclitaxel) in the adjuvant setting.

Treatment of breast cancer with a taxane in the metastatic setting after treatment in the adjuvant setting may be difficult because of residual toxicity. Although taxanes are not cardiotoxic, they can produce lingering neuropathy (especially paclitaxel) or problems with edema (docetaxel especially), which makes further administration problematic. Substitution of one taxane for another is possible, depending on the nature of the chronic toxicity.

If the tumor has recurred quickly after administration of adjuvant chemotherapy containing a taxane, then changing the schedule of administration can be effective. At least one third of breast cancer patients with taxane resistance due to administration of every-3-week paclitaxel show a response when the same drug is administered on a weekly schedule at a lower dose.

In addition to taxanes and anthracyclines, a variety of other chemotherapeutic agents can be used as single agents or in combination with taxanes. Capecitabine (Xeloda) is an oral agent that essentially represents a sustained-release formulation of the older antimetabolite fluorouracil (5-FU) and provides the convenience of self-administration.

Drugs such as capecitabine have very little associated myelosuppression, and they are often chosen when the patient's bone marrow has been damaged by previous therapy or when there is a desire to coadminister a myelosuppressive agent for more rapid effect. As a single agent, capecitabine has an ORR of 25-30%, with minimal toxicity. When combined with a taxane, an ORR of 40-50% has been observed, along with a median overall survival benefit of 3-15 months.

Approach Considerations

Surgery is considered primary treatment for early-stage breast cancer; many patients are cured with surgery alone. The goals of breast cancer surgery include complete resection of the primary tumor with negative margins to reduce the risk of local recurrences and pathologic staging of the tumor and axillary lymph nodes (ALNs) to provide necessary prognostic information.

Adjuvant treatment of breast cancer is designed to treat micrometastatic disease (ie, breast cancer cells that have escaped the breast and regional lymph nodes but which have not yet had an established identifiable metastasis). Adjuvant treatment for breast cancer involves radiation therapy and systemic therapy (including a variety of chemotherapeutic, hormonal and biologic agents).

Goals include complete resection of the primary tumor, with negative margins to reduce the risk of local recurrences, and pathologic staging of the tumor and axillary lymph nodes to provide necessary prognostic information. Several different types of operations are available.

This specimen radiograph shows the wire and the localized speculated mass in situ, with a good excision margin.

ASCO updates guidelines on lymph node dissection and biopsy in early stage breast cancer

The American Society of Clinical Oncology (ASCO) has released updated guidelines on the use of lymph node dissection and biopsy for patients with early stage breast cancer.

Recommendations include the following:

Women without sentinel lymph node (SLN) metastases should not undergo axillary lymph node dissection (ALND)

In most cases, ALND should not be performed on women with 1-2 metastatic SLNs who are planning to undergo breast-conserving surgery with whole-breast radiotherapy

ALND should be offered to women with SLN metastases who will be undergoing mastectomy

SLN biopsy may be offered to women who have operable breast cancer and multicentric tumors, women with ductal carcinoma in situ who will be undergoing mastectomy, women who have had previous breast and/or axillary surgery, and women who have been treated with preoperative/neoadjuvant systemic therapy

SLN biopsy should not be performed on women with large or locally advanced invasive breast cancer (tumor size T3/T4), inflammatory breast cancer, or ductal carcinoma in situ (when breast-conserving surgery is planned) or who are pregnant

Breast conserving surgery and mastectomy

Breast conserving surgery (lumpectomy, partial or segmental mastectomy) is defined as complete surgical resection of a primary tumor with a goal of achieving widely negative margins (ideally 1 cm). It may be performed with palpation guidance or with image guidance and is applicable in most patients with stage I or II invasive carcinomas.

Relative contraindications include the following:

Small breast size

Large tumor size (>5 cm)

Collagen vascular disease

Absolute contraindications include the following:

Multifocal disease

History of previous radiation therapy to the area of treatment

Inability to undergo radiation therapy for invasive disease

First or second trimester of pregnancy

Persistent positive margins after attempts at conservation

Options for breast reconstruction after partial mastectomy include the following:

Fasciocutaneous local tissue advancement flaps

Breast parenchymal local flaps

Latissimus dorsi myocutaneous flaps

A total mastectomy involves complete removal of all breast tissue to the clavicle superiorly, the sternum medially, the inframammary crease inferiorly, and the anterior axillary line laterally, with en bloc resection of the pectoralis major fascia. The following variants are performed:

Modified radical mastectomy – A total mastectomy with axillary lymph node dissection (ALND)

Radical mastectomy – A total mastectomy plus en bloc resection of the pectoralis major and ALND

Extended radical mastectomy – A radical mastectomy with resection of the internal mammary lymph nodes

Skin-sparing total mastectomy (SSM)

Nipple-sparing total mastectomy (NSM)

Complications after total mastectomy include the following:

Risk of local recurrence (5-10%); Wound infection; Seroma; Mastectomy skin flap necrosis; Hematoma; Chronic pain; Incisional dog ears; Lymphedema; Fibrosis

Postmastectomy reconstruction may be immediate or delayed. Options are as follows:

Implant-based methods – Expanders and saline or silicone implants

Autologous tissue-based methods – Transverse rectus abdominis myocutaneous (TRAM) flap, latissimus dorsi flap, deep inferior epigastric perforator (DIEP) flap

A combination of the 2 methods

The following complications may be encountered:

Infected or ruptured prosthetic implant; Capsular contracture; Flap necrosis or loss; Fat necrosis; Asymmetry; Scarring.

Sentinel lymph node biopsy and axillary lymph node dissection

Sentinel lymph node (SLN) biopsy is currently preferred for axillary staging, because it offers accuracy equivalent to that of ALND with less morbidity. The American College of

Breast Surgeons (ACBS) states the following:

SLN biopsy is suitable for virtually all patients with clinically node-negative T1-2 invasive breast cancers

Limited data are available regarding the suitability of SLN biopsy for patients with T3 cancers, multifocal/multicentric disease, prior radiation therapy, or prior breast/axillary surgery

SLN biopsy appears to be feasible in patients who have had minimal axillary surgery; the decision to use it in these situations requires individualized surgical judgment and an unequivocally successful mapping procedure

SLN biopsy is also indicated in patients with ductal carcinoma in situ (DCIS) in whom mastectomy is required or invasive disease is suspected

ALND is a complete en bloc removal of the level I and level II lymph nodes; the level III nodes are not removed unless suspicious or palpable adenopathy is present. All nodal tissue defined by the borders of the axillary vein superiorly, the latissimus dorsi laterally, the medial border of the pectoralis minor medially, and the subscapularis posteriorly is removed.

ALND carries a high rate of surgical morbidity, including the following:

Lymphedema (~25%); Shoulder dysfunction; Wound infection; Seroma; Nerve damage Numbness; Chronic pain Brachial plexus injury (rare).

Postoperative care

Immediate postoperative care involves the following:

Assessment for appropriate wound healing

Evaluation and treatment of postoperative complications, such as seroma, wound infection, bleeding, and nerve damage

Follow-up of the pathologic specimen

Encouragement of early patient mobility and range-of-motion exercises

Recommendations for longer-term follow-up are as follows:

Baseline postoperative mammography of both breasts or of the remaining breast at 6 months

Clinical assessment every 4 months during the first 2 years, every 6 months up to the fifth year, and then annually for the remainder of the patient’s lifetime

Annual mammography and chest radiography

No further workup except as indicated by the development of suggestive symptoms such as bone pain, headache, or abnormal findings on annual routine laboratory chemistry panels

Lumpectomy

Lumpectomy is defined as complete surgical resection of a primary tumor with a goal of achieving widely negative margins (ideally a 1-cm margin around the lesion). It is applicable in most patients with stage I and stage II invasive carcinomas.

Other terms synonymous with lumpectomy include partial mastectomy, segmental mastectomy, and tylectomy. A quadrantectomy is a type of lumpectomy that is defined as complete removal of the entire affected breast quadrant; it is less cosmetically satisfactory than lumpectomy.

Contraindications

Relative contraindications to lumpectomy include small breast size, large tumor size (>5 cm), and collagen vascular disease. Absolute contraindications include the following:

Multifocal disease; History of previous radiation therapy to the area of treatment; Inability to undergo radiation therapy for invasive disease; First or second trimester of pregnancy; Persistent positive margins following attempts at conservation.

Factors that are often considered but should not be deterrents include axillary node involvement and tumor location. Consideration of cosmesis, while important, should never outweigh the clinical priority of obtaining negative surgical margins.

For instance, lesions involving Paget disease of the nipple may be treated with excision of the nipple-areolar complex and reconstruction. Larger lesions in patients with concerns regarding cosmesis may be better served by standard modified radical mastectomy and concurrent reconstruction.

Lumpectomy versus mastectomy

The National Surgical Adjuvant Breast and Bowel Project’s B-06 (NSABP-B06) was a landmark study that established breast-conserving surgery with radiation therapy to be equivalent to modified radical mastectomy. This was a prospective trial in which 2163 breast cancer patients were randomized to modified radical mastectomy (the standard of care at that time), lumpectomy and whole-breast radiation therapy, or lumpectomy without radiation. All patients underwent axillary lymph node dissection.

At 20-year follow-up, no significant difference was seen in overall survival, disease-free survival, or distant disease-free survival among the 3 treatment groups. However, the researchers did find a significant difference in the rate of local recurrence between the 3 treatment arms.

Patients in the group that received therapy with lumpectomy alone without radiation had a significantly higher local recurrence rate (39.2%) than patients undergoing lumpectomy plus radiation therapy (14.3%). Patients who underwent modified radical mastectomy had a 10.2% risk of chest wall recurrence.

Technique

Lumpectomies may be performed with palpation guidance or with image guidance. Variations on the theme of image guidance include the following:

Wire localization of nonpalpable image-detected lesions via ultrasonographic, stereotactic, or MRI guidance (see images below)

Hematoma ultrasonographic guidance by the operating surgeon

Radioactive seed localization; the specimen should be evaluated radiographically to confirm excision of the intended lesion before completion of the operation

This mammogram shows a spiculated mass to be transfixed by the guidewire

Grid technique of localization.

This orthogonal (mediolateral) projection confirms the position of the needle to be placed beyond the cluster of microcalcification.

This specimen radiograph shows the wire and the localized speculated mass in situ, with a good excision margin.

Patients who undergo a lumpectomy for calcifications should always be advised to have a mammogram following their lumpectomy to establish definitively that all calcifications were removed successfully. This mammogram should be performed before the administration of any radiation therapy.

In general, 2 mm or greater is a reasonable definition of a clear margin. Patients with margin widths less than 2 mm are often advised to return to the operating room for reexcision to improve local recurrence rates. The rate of surgical reexcision after lumpectomy ranges from 20-60% in the published literature.

Breast reconstruction after partial mastectomy

Oncoplastic surgery is a rapidly advancing field that uses local tissue rearrangement to reconstruct a partial mastectomy defect. Options include fasciocutaneous local tissue advancement flaps, breast parenchymal local flaps, or latissimus dorsi myocutaneous flaps. The selection of aesthetically appropriate incisions also impacts the overall cosmetic result after lumpectomy.

Silverstein and Lagios reported a variety of options for oncoplastic approaches to breast conservation. Kronowitz et al reported that partial mastectomy reconstruction produces superior aesthetic results and lower complication rates when performed before radiation therapy.

Mastectomy

A total mastectomy is defined as complete removal of all breast tissue to the clavicle superiorly, the sternum medially, the inframammary crease inferiorly, and the anterior axillary line laterally, with en bloc resection of the fascia of the pectoralis major.

The nipple-areolar complex (NAC) is resected along with a skin paddle to achieve a flat chest wall closure when performing a total mastectomy.

A total mastectomy does not refer to removal of any axillary nodes but may be performed in conjunction with a sentinel or axillary node dissection.

A modified radical mastectomy is defined as a total mastectomy with axillary lymph node dissection. In contrast, a radical mastectomy is defined as a total mastectomy plus en bloc resection of the pectoralis major and axillary lymph node dissection. Extended radical mastectomy refers to a radical mastectomy with resection of the internal mammary lymph nodes. Historically, radical (Halsted) mastectomy was the most commonly performed procedure for breast cancer.

Radical mastectomy defect.

Two modern variations of the total mastectomy include the skin-sparing total mastectomy (SSM) and the nipple-sparing total mastectomy (NSM). These operations refer to surgical approaches designed for patients who elect to have immediate reconstruction.

Both SSM and NSM are minimally invasive surgical approaches that are technically more difficult and, thus, more time-consuming than traditional mastectomy. SSM and NSM result in preservation of the patient's skin envelope and maintain the position of the inframammary fold. However, both SSM and NSM are intended to be complete total mastectomies with the same extent of resection as a traditional total mastectomy.

These operations may not be appropriate for cancers near the skin or nipple. Additionally, SSM or NSM are not appropriate for locally advanced or inflammatory breast cancer. Multiple retrospective single-institution studies have reported excellent results with SSM and NSM. No randomized clinical trials have compared survival results for SSM, NSM, and total mastectomy. One study analyzed breast cancer recurrence data on patients who had undergone mastectomy with immediate reconstruction versus those who had not undergone reconstruction after mastectomy and concluded that neither incidence nor time to detection of recurrent disease was impacted by reconstruction.

However, most surgical oncologists accept that as long as SSM and total mastectomy are performed carefully and patients are selected carefully, these are reasonable oncologic choices for prophylactic mastectomy and for the treatment of selected early stage breast cancers.

A relative contraindication to modified radical mastectomy is locally advanced cancer requiring neoadjuvant therapy before surgical intervention.

Mastectomy complications

Complications after total mastectomy include the following:

Risk of local recurrence (5-10%); Wound infection; Seroma; Mastectomy skin flap necrosis; Hematoma; Chronic pain; Incisional dog ears; Lymphedema; Fibrosis

Preoperative preparation of the patient for breast surgery should include attention to psychosocial as well as surgical issues. Patients may have unexpressed concerns regarding risk of recurrence, need for adjuvant radiation or chemotherapy, surveillance, length of rehabilitation, and particularly cosmesis. In discussing treatment options, it is important not to neglect the options of immediate versus delayed reconstruction and/or augmentation.

From a surgical standpoint, routine preoperative laboratory testing should be performed based on the patient's age, presence of symptoms, and comorbid conditions. Preoperative administration of a first-generation cephalosporin is a common practice, albeit with no proven benefit.

The keys to successful surgery of the breast include a thorough knowledge of anatomy, accurate assessment of the extent of disease, and recognition of the potential for future operations.

All biopsy incisions should be placed carefully with consideration for the placement of a future mastectomy incision. For instance, a radial incision in the upper inner quadrant does not incorporate into an elliptical mastectomy scar with the same ease as a horizontal or curvilinear incision. However, clearly, adequate surgical margins should never be compromised for the sake of cosmesis. Circumareolar incisions are cosmetically favorable and generally adequate for most central parenchymal lesions.

The axillary incision, if done separately, can be made in a curvilinear or S-shaped fashion based on surgeon preference. Dissection begins with incision of the clavipectoral fascia and identification of the lateral border of the pectoralis minor and the inferior border of the axillary vein. The vein then is traced laterally to the thoracodorsal complex. Once this has been identified with careful preservation of the nerve, attention is turned directly medially to the chest wall where the long thoracic nerve descends to the serratus.

Often, several branches of the intercostobrachial nerve can be identified superficially during axillary dissection. These can be divided if preservation means compromise of the extent of dissection. level I and II lymphatic tissue is resected with a combination of blunt and careful sharp dissection. Use of electrocautery should be avoided during deep dissection. Hemoclips or sutures are used to divide small vessels or lymphatics to reduce the risk of seroma and/or hematoma formation. Next, an axillary drain, if placed, is brought through a separate stab incision inferiorly.

For a mastectomy, the standard elliptical incision includes the nipple-areolar complex and extends from the lateral border of the sternum to the latissimus dorsi. An umbilical tape or suture may be helpful in measuring the upper and lower sides of the ellipse to ensure even lengths and avoid dog ears, particularly at the lateral corner.

Cat's paw retractors or rakes are used to elevate the skin edges, and flaps are raised superiorly and inferiorly using electrocautery. Ideally, the thickness of the flaps should be approximately 1.0 cm.

This relatively avascular plane is readily identifiable with adequate flap traction perpendicular to the chest wall. The breast parenchyma is removed from medial to lateral either sharply or with electrocautery in continuity with the pectoral fascia. Care should be taken to ligate or cauterize any major perforating vessels. The axillary dissection then should proceed as described above through the same incision.

Some authors routinely place 2 drains through separate stab incisions inferior and lateral just above the inframammary fold. One is placed in the axilla and the other in the parenchymal defect. Fine subcuticular suture is used to close the skin.

In a randomized, double-blinded, parallel-group, placebo-controlled study of 66 women who had undergone ambulatory breast tumor resection, Abdallah et al found that multilevel, ultrasonographically guided paravertebral blocks and total intravenous anesthesia improved the quality of recovery and postoperative analgesia and expedited discharge in comparison with inhalational gas- and opioid-based general anesthesia.

Breast reconstruction after mastectomy may be performed in the immediate or the delayed setting. Most patients undergoing mastectomy for prophylaxis or early stage breast cancer are candidates for reconstruction.

Immediate reconstruction, when feasible, generally provides superior cosmetic results, because a skin-sparing total mastectomy (SSM) or nipple-sparing total mastectomy (NSM) may be offered to selected patients, resulting in preservation of the native skin envelope and inframammary crease. However, when postmastectomy radiation is likely or a reconstructive surgeon is unavailable, delayed reconstruction following all adjuvant therapies may be recommended.

Reconstruction may be performed using implant-based methods, autologous tissue-based (termed flaps) methods, or a combination of the two. Implant-based approaches include tissue expanders and saline or silicone implants. Tissue-based approaches include the transverse rectus abdominis myocutaneous (TRAM) flap, latissimus dorsi flap, and the deep inferior epigastric perforator (DIEP) flap.

Although federal law protects the rights of patients to have reconstruction by mandating that insurance companies support the procedure, most patients undergoing mastectomy do not undergo breast reconstruction. Reasons for this include provider biases, patient preferences, and lack of available specialty services.

Patients and physicians should have realistic expectations for breast reconstruction. Although excellent results may be achieved, often multiple operations are required for revisions, symmetry procedures, and nipple reconstruction. Complications related to reconstruction include an infected prosthetic implant, implant rupture, capsular contracture, flap necrosis, flap loss, fat necrosis, asymmetry, and scarring.

Patients diagnosed with breast cancer who are not known carriers of a deleterious BRCA mutation are predicted to have a 0.7% annual risk of contralateral breast cancer. Patients who are known BRCA mutation carriers have a 3% annual risk of a contralateral breast cancer.

The decision for contralateral prophylactic mastectomy (CPM) is a personal decision for the patient and is impacted by cancer stage, patient’s desire for symmetry, comorbidities, histologic risk factors, family history, potential difficult surveillance, and degree of risk aversion.

Patients with locally advanced breast cancers should be discouraged from a contralateral prophylactic mastectomy, as potential surgical complications could compromise their oncologic treatments.Mastopexy and reduction mammoplasty for the contralateral breast are potential alternatives to contralateral prophylactic mastectomy as symmetry procedures.

One study sought to identify factors predictive of high-risk lesions and/or occult contralateral breast cancer in women undergoing CPM for newly diagnosed breast cancer. The study found that while the diagnosis of multifocality/multicentricity invasive index cancer was the only factor associated with occult malignancy, patient age and progesterone receptor positivity of the index cancer were associated with finding either malignancy or a high-risk lesion in the CPM. The findings suggest that because lack of standardized definitions and differences in pathologic evaluation may limit the use of this data in the preoperative setting, the use of CPM in an average-risk woman with newly diagnosed breast cancer is not supported.

Sentinel Lymph Node Biopsy

Sentinel lymph node (SLN) biopsy is a minimally invasive procedure designed to stage the axilla in breast cancer patients who have clinically negative nodes. Sentinel nodes are the first node or first group of nodes that drain from the breast to the axilla.

SLN biopsy has become the preferred SLN technique for axillary staging, because it offers accuracy equivalent to that of axillary lymph node dissection with less morbidity. According to the American College of Breast Surgeons (ACBS), SLN biopsy is suitable for virtually all clinically node-negative T1-2 invasive breast cancers. Limited data are available regarding the suitability of SLN biopsy for patients with the following conditions :

T3 cancers; Multifocal/multicentric disease; Prior radiation therapy; Prior breast/axillary surgery.

SLN biopsy appears to be feasible in patients who have had minimal axillary surgery, especially previous SLN surgery and radiotherapy. The ACBS advises that the decision to use SLN biopsy in these situations requires individualized surgical judgment and an unequivocally successful mapping procedure.

SLN biopsy is also indicated in patients with ductal carcinoma in situ (DCIS) in whom mastectomy is required or in whom invasive disease is suspected. The role of SLN biopsy in patients who have had neoadjuvant therapy remains controversial and is currently under study.

There is no role for SLN biopsy in inflammatory breast cancer.

SLN biopsy technique

The best results with SLN biopsy are achieved with the combination of careful intraoperative digital examination and lymphatic mapping. The latter technique involves injecting radioisotope (technetium-99m sulfur colloid) alone or radioisotope plus a patent blue dye (Lymphazurin or methylene blue) into the tissues of the breast.

Several techniques of injection are available, including subareolar, peritumoral, intradermal, or intraparenchymal. The technique of injection may not be as important as the skill and experience of the surgeon with the chosen technique and with SLN identification in general.

With SLN dissection, typically 1-3 lymph nodes are removed and tested for nodal metastasis with hematoxylin and eosin (H&E) stain and immunohistochemistry (IHC) with an anticytokeratin cocktail.

SLNs may be checked intraoperatively by imprint touch preparation, frozen section, or real-time polymerase chain reaction (RT-PCR). Intraoperative evaluation allows for immediate axillary lymph node dissection if an SLN is unequivocally positive for nodal metastasis. The American Society of Clinical Oncology (ASCO) guideline recommendations for SLN biopsy in early stage breast cancer include axillary lymph node dissection after detection of a positive SLN. However, isolated tumor cells detected by specialized techniques such as IHC and RT-PCR remain of uncertain significance.

Axillary Lymph Node Dissection

Axillary lymph node dissection for breast cancer is a complete en bloc removal of the level I and level II lymph nodes. level I nodes are lateral to the pectoralis minor, level II nodes are beneath the pectoralis minor, and level III nodes are medial to the pectoralis minor.

The level III nodes are not removed surgically unless there is suspicious or palpable adenopathy present. Skip metastasis to the axillary apex of level III without lower axillary involvement is very rare.

Axillary lymph node dissection removes all nodal tissue defined by the borders of the axillary vein superiorly, the latissimus dorsi muscle laterally, the medial border of the pectoralis minor muscle medially, and the subscapularis muscle posteriorly.

Care is taken to preserve the long thoracic and thoracodorsal nerves along their course through the axilla. Injury to the long thoracic nerve results in a winged scapula, whereas injury to the thoracodorsal nerve compromises internal rotation and abduction of the arm beyond 90°.

The median and lateral pectoral nerves may also be injured during axillary lymph node dissection. The intercostobrachial nerves run directly through the resection specimen and are typically sacrificed, resulting in a predictable pattern of cutaneous numbness in the inner arm region for most patients after this procedure.

Axillary lymph node dissection was previously considered the standard of care for all patients diagnosed with invasive breast cancer. However, axillary lymph node dissection carries a high rate of surgical morbidity, including the following:

Lymphedema (rates of about 25%); Shoulder dysfunction; Wound infection; Seroma; Nerve damage; Numbness; Chronic pain; Brachial plexus injury (rare).

Lymphedema is the abnormal accumulation of protein-rich edema fluid in the upper extremity following axillary lymph node dissection. This occurs because a portion of the lymphatics that drain from the breast to the axilla and those that drain from the arm are shared within the axilla.

Early detection of lymphedema is paramount, as lymphedema is potentially reversible when treated in its earliest stage. Compression garments and physical therapy with lymphatic massage remain the backbone for the treatment of lymphedema.

Patients who have an axillary lymph node dissection should be cautioned about the risk of lymphedema and should take precautions to avoid breaks in the skin or infections in the affected extremity. Lymphedema may develop at any time after lymph node dissection but most commonly occurs within the first 2 years after the surgery.

Risk factors for developing lymphedema include obesity and radiation therapy. Although patients are commonly advised to avoid having blood pressure measurements taken or intravenous catheters placed in the affected arm after axillary lymph node dissection, no level I or level II evidence supports these recommendations.

Postoperative care

Immediate postoperative care involves assessment for appropriate wound healing and evaluation and treatment of postoperative complications, such as seroma, wound infection, bleeding, and nerve damage. Drains are routinely removed when output is less than 30 mL/d. Seromas that develop following drain removal are usually best managed with repeat aspiration. Follow-up of the pathologic specimen should be routine to determine adequacy of margins in the resection of the primary tumor.

Early patient mobility and range of motion exercises should be encouraged postoperatively, although the timing and degree should be tailored to the extent of the procedure performed (ie, lumpectomy vs skin-sparing mastectomy with immediate reconstruction).

Recommendations for surveillance include baseline postoperative mammography of both breasts or of the remaining breast at 6 months and tapered clinical visits. The suggested frequency of clinical assessment during the first 2 years is every 4 months; every 6 months up to the fifth year; then annually for the remainder of the patient's lifetime. Mammography and chest radiographs should also be performed annually. Further workup is not indicated in the absence of suggestive symptoms such as bone pain, headache, or findings on annual routine laboratory chemistry panels.

Postoperative imaging

Women who have had surgery for breast cancer may still require breast cancer screening with mammography. If a woman had a total mastectomy, then the other breast requires yearly follow-up, because there is still a higher risk that cancer will develop in the remaining breast. If the woman had a subcutaneous mastectomy, partial mastectomy, or lumpectomy, then that breast itself requires follow-up mammography.

The first mammogram is best performed 6 months postoperatively to provide a baseline for the new postoperative and postirradiation changes. Thereafter, mammography may be performed every 6-12 months for screening and follow-up.

Monitoring of metastatic disease

Recommendations for monitoring disease response in the metastatic setting vary. In general, monthly evaluations consisting of a history and physical examination to evaluate progression of disease and toxicities are reasonable.

Measurement of tumor markers, such as CEA, CA15.3, and CA27.29, can be used in conjunction with diagnostic imaging, history, and physical examination for monitoring patients on active therapy. CA15.3 and CA27.29 levels correlate with the course of disease in 60-70% of patients, whereas CEA levels correlate in 40% of patients.

However, data are insufficient to recommend the use of CEA, CA15.3, or CA27.29 alone for monitoring response to treatment. Caution should be used in the interpretation of rising CEA, CA15.3, or CA27.29 levels during the first 4-6 weeks of a new therapy; spurious early rises may occur.

Monitoring of radiation-induced heart disease

According to a new consensus statement from the European Association of Cardiovascular Imaging and the American Society of Echocardiography, patients treated with radiotherapy to the chest for Hodgkin's disease, or breast, lung, or esophageal cancer, should have an echocardiogram every 5 to 10 years to detect radiation-induced heart disease (RIHD). The relative risk of RIHD is 2- to 5.9 times higher in patients treated with radiation for breast cancer.

Recommendations of the statement include the following :

Before starting radiotherapy to the chest, patients should have a baseline echocardiogram to evaluate cardiac morphology and function, and identify any abnormalities

After radiotherapy, patients should have a yearly physical exam

Modifiable CVD risk factors should be corrected

Patients who have a cardiac abnormality or are asymptomatic but at high risk of CVD should have an initial transthoracic echocardiogram screening test five years after radiation treatment

Asymptomatic patients who are not at high risk of CVD should have an initial screening echocardiogram 10 years after radiation treatment

After an initial screening electrocardiogram, patients should have an echocardiogram every five years

When the findings from an echocardiogram are equivocal, cardiac computed tomography (CT), cardiac magnetic resonance (CMR), and nuclear cardiology can be used to confirm and evaluate the extent of RIHD

The Society for Integrative Oncology has released clinical practice guidelines on the use of integrative therapies as supportive care in patients treated for breast cancer. Recommendations include the following :

Meditation, yoga, and relaxation with imagery may be useful for alleviating anxiety and mood disorders (grade A evidence)

Stress management, yoga, massage, music therapy, energy conservation, and meditation may reduce stress, improve mood, decrease fatigue, and improve quality of life (grade B evidence)

Acetyl-L-carnitine for the prevention of taxane-induced neuropathy may increase neuropathy and should not be used (grade H [likely harmful])

Evidence of benefit is weak or lacking for many interventions

STUDY SECTION

OBJECTIVE OF THE STUDY

This paper aims to study the surgical treatment of benign and malignant breast tumors during a period of three years. The paper`s objective consists in a presentation of the clinical diagnosis problems and the surgical treatment recived.

MATERIAL AND METHOD

The study section of the paper proposes a retrospective analysis of case-control clinical and therapeutic outcomes for surgical treatment in breast cancer in the Surgical Clinic II of the Emergency County Hospital Constanta.

The evaluation period was from March 1, 2015 – March 1, 2018, including inpatients diagnosed and treated for breast cancer.

Completion of clinical observation sheets and operator protocols have obtained data on:

Patient Sex

Patient Age

Histopathologic diagnosis benign/ malignant

Evolutive stage of the tumor

TNM staging

Type of surgical procedure

Evolution after surgery.

RESULTS

Yearly distribution of inpatients.

Table 8.1

During 2015 – 2018 there have been 15640 inpatients in the surgical department of Constanta County Clinical Emergency Hospital.

Yearly distribution of patients with breast cancer.

Table 8.2

During the same period of time, a number of 346 patients with breast cancer underwent breast conserving surgery or mastectomy. Of the total of inpatients, in 2015 2,52% were operated for breast cancer, 1,52% in 2016, 3,16% in 2017 and 1,65% in 2018.

Repartition of operated patients by sex.

Table 8.3

Out of the total of 346 patients with breast cancer, 96,82% were females.

Repartition of patients by age groups and sex.

Table 8.4

For women, the repartition by age groups shows the maximum incidence to be in the 5th decade, with 30%, followed by the 4th decade with 22,33%, whereas the lowest incidence, with only 2,76% was noted under 20 years age group. For men, there was a similar pattern, the 5th and 4th decade having an incidence of 27,28% each, while no cases were recorded for the under 20 year age group.

Repartition pf patients with mammary gland tumor.

Table 8.5

For the preoperative diagnosis of mammary gland tumor, there can be observed a slightly preference for the left breast, with 50% of the cases.

Repartition of patients with fibrocystic mastosis.

Table 8.6

For the preoperative diagnosis of fibrocystic mastitis, the same higher incidence in the left breast can be observed, with 49% of the cases.

Repartition of patients with mammary neoplasm.

Table 8.7

For the preoperative diagnosis of mammary neoplasm, there was an 85% incidence in the left breast.

Repartition of patients by pre-op diagnosis.

Table 8.8

Out of the total of 346 patients with breast cancer, the biggest majority (87%) were diagnosed with mammary tumor, followed by fibrocystic mastosis with 10%, mammary neoplasm with 2%, mastosis with 1% and Paget disease with just one case.

Repartition of patients who underwent a mastectomy by age groups and sex.

Table 8.9

Out of the total of 320 patients who underwent a mastectomy, 29% were in the 5th decade, while only 2,81% under 20 years of age.

Repartition of pateints who underwent breast conserving surgery.

Repartition of pateints who underwent breast conserving surgery.

Table 8.10

Repartition of patients who underwent BCS by age groups.

Table 8.11

Out of the 18 patients who underwent BCS, 44,44% were in the 5th decade, 22,22% in the 7th, 16,66% in the 6th, 11,11% were over 70 year age group and only 5,55% in the 3rd.

Breast conserving surgery by evolutive stages

Table 8.12

50% of BCS were suitable for stage II of breast cancer, while for stage III only 10%.

Type of Breast conserving surgery.

Tabel 8.13

Lumpectomy and quadrantectomy were the most frequent types of BCS (89%). In all cases, axillary lymphadenectomy was performed and postoperative there were subjected to the evaluation of an oncologist who recommended radiotherapy for all cases and chemotherapy and hormonal therapy according to the status of the axillary ganglia showed on histopathology examination and biological status.

Types of benign lesions.

Table 8.14

The most frequent benign lesions encountered were fibrocystic mastitis (39%), fibroadenoma (26%) and adenomatous hyperplasia (14%).

Malignant lesions. Invasive carcinoma.

Table 8.15

The most frequent types of invasive carcinoma encountered were trabecular and lobular, ductal and trabecular, lobular and cribriform.

Other malignant lesions.

Table 8.16

Other types of malignant lesions were intraductal noninvasive lobular carcinoma (3 cases), alveolar intraductal carcinoma (2 cases), Lobular in situ carcinoma + papillary (2 cases), Paget disease + epidermoid ductal carcinoma ( 1 case) and hemangiopericytosarcoma ( 2 cases)

Repartition of patients by the type of mastectomy they underwent.

Table 8.17

94% of the patients underwent modified radical mastectomy (Madden).

Postoperative complications.

Table 8.18

The most common postoperative complication encountered was breast swelling, with 40%, followed by lymphoedema and wound infection with 15%.

SURGICAL TREATMENT

Mastectomy

Modified radical mastectomy (patey)

Radical mastectomy(halsted)

Extended radical mastectomy

Skin-sparing total mastectomy

Nipple-sparing total mastectomy

Brest conserving surgery

Lumpectomy

Partial mastectomy

Segmental mastectomy

Simple Mastectomy with an Axillary Lymph Node Dissection

Skin sparing mastectomy: Technique

Lumpectomy.

DISCUSSIONS

During 2015 – 2018 there have been 15640 inpatients in the surgical department of Constanta County Clinical Emergency Hospital.

Out of the total of 346 patients with breast cancer, 96,82% were females.

For women, the repartition by age groups shows the maximum incidence to be in the 5th decade, with 30%, followed by the 4th decade with 22,33%, whereas the lowest incidence, with only 2,76% was noted under 20 years age group. For men, there was a similar pattern, the 5th and 4th decade having an incidence of 27,28% each, while no cases were recorded for the under 20 year age group.

Out of the total of 346 patients with breast cancer, the biggest majority (87%) were diagnosed with mammary tumor, followed by fibrocystic mastosis with 10%, mammary neoplasm with 2%, mastosis with 1% and Paget disease with just one case.

Out of the total of 15640 operation during 2015-2018, 11% were in 2015, out of which 5,45% were breast conserving surgery, 12% were in 2016 (out of which 4,85% were BCS), 13% in 2017 ( with 3,53% being BCS) and 14% in 2018, with 5,45% BCS.

Out of the 18 patients who underwent BCS, 44,44% were in the 5th decade, 22,22% in the 7th, 16,66% in the 6th, 11,11% were over 70 year age group and only 5,55% in the 3rd.

Lumpectomy and quadrantectomy were the most frequent types of BCS (89%). In all cases, axillary lymphadenectomy was performed and postoperative there were subjected to the evaluation of an oncologist who recommended radiotherapy for all cases and chemotherapy and hormonal therapy according to the status of the axillary ganglia showed on histopathology examination and biological status.

The most frequent types of invasive carcinoma encountered were trabecular and lobular, ductal and trabecular, lobular and cribriform.

Other types of malignant lesions were intraductal noninvasive lobular carcinoma (3 cases), alveolar intraductal carcinoma (2 cases), Lobular in situ carcinoma + papillary (2 cases), Paget disease + epidermoid ductal carcinoma ( 1 case) and hemangiopericytosarcoma ( 2 cases)

94% of the patients underwent modified radical mastectomy (Madden).

The most common postoperative complication encountered was breast swelling, with 40%, followed by lymphoedema and wound infection with 15%.

CONCLUSIONS

Nowadays, the treatment of breast cancer is a pluridisciplinary complex treatment, which underwent an impressive evolution along the time, partly because of the progress made in understanding the biology of the disease, and secondly due to the increasingly frequent detection of the disease in earlier stages, and also due to the diversification of therapeutic methods, including surgery, radiotherapy, chemotherapy, hormone therapy and immunotherapy, the indications and sequence of these therapeutic procedures varying according to the disease stage, the histological type and tumor grading, the patient’s age and general condition .

The conservative treatment of breast cancer represents a therapeutic alternative to radical surgery and it comprises at least two treatment sequences: a minimal surgical intervention followed by postoperative adjuvant radiotherapy to eradicate any residual disease, with or without chemotherapy and hormonal therapy.

The conservative treatment of breast cancer has elective indication and curative visa in the early stages (I and II), but it can be used, with limited indications and palliative character also in advanced stages (IIIA and IIIB), especially in the case of elderly, sick patients.

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