Lymphatic Drainage of the Breast
The lymphatic system plays an essential role in systemic immunity, fluid homeostasis, and returning tissue fluid and macromolecules to the circulation. Lymphatic drainage plays a significant role in the pathology and treatment of breast cancer; globally the most frequently diagnosed malignancy and leading cause of death due to cancer in women.
Malignant cells traveling within the lymphatic system are a common mechanism of tumor metastasis, and examination of lymphatic tissue is essential for cancer prognosis and staging. Advances in lymph node harvesting have improved survival and reduced morbidity from breast cancer treatment. Moreover, lymphatic vessel disruption, a common side effect of breast cancer therapy, can result in significant morbidity.
The lymphatic system is comprised of:
It is a unidirectional low-pressure network of vessels that run parallel to blood vessels and are found in all regions of the body except the central nervous system and bone marrow.
Like blood plasma, lymph contains interstitial fluid, proteins, clotting factors and leukocytes. Though most of the blood exchanged in a capillary network reenters venous circulation, about 10% is extruded into the interstitial space and must be returned to maintain fluid balance. Lymphatic capillaries contain a single-layer endothelium with loose junctions in the basement membrane that facilitate the entry of cells, macromolecules, and fluid.
Like veins, lymphatic vessels contain valves and have a smooth muscle endothelial layer which creates a pressure gradient that is further maintained through skeletal muscle contraction, respiratory movement, and gravity. Lymphatic capillaries drain into pre-collectors which sequentially drain into collecting vessels and lymph nodes. Efferents from lymph nodes coalesce into larger vessels and regional lymphatic trunks.
Finally, the right upper torso, including right arm and breast, drain into the right lymphatic duct which empties into the right subclavian vein. The rest of the body, including the left arm and breast, lower extremities, and gastrointestinal tract, drain into the thoracic duct which empties into the left subclavian vein.
Lymph nodes are encapsulated bean-shaped structures distributed along the lymphatic system that filter lymph of microorganisms and tumor cells. An ideal location for antigen presentation, lymph nodes are essential for cellular immunity. Three paired lymph node basins, the cervical, axillary and inguinal nodes are located at the neck, axillae, and groin respectively.
Afferent lymphatic collectors drain into sinuses between germinal centers within the node. These germinal centers contain phagocytic cells, such as macrophages, which accumulate foreign material, including the radiolabeled colloids and dyes used to localize lymph nodes during breast cancer treatment.
Lymphatic Drainage of the Breast
Functional Drainage of the Breast
Most (75-90%) of the lymphatic drainage of the breast is to the ipsilateral (same side) axillary nodes. Nearly all lymphatics of the breast drain along a subdermal plane into the axillae, typically collecting in a single sentinel lymph node at the lateral border of the pectoralis major muscle.
Superficial lymphatics of the nipple and areola collect in a dense network of pre-collectors known as the Sappey subareolar plexus. Lymphatics in the breast parenchyma originate in the interlobular tissue and within the walls of the lactiferous ducts. A variable degree of deep breast tissue, particularly of the medial breast, may collect into lymphatic vessels that perforate the deep fascia to drain into internal mammary nodes. Lymphatics may also pass through tiny interval nodes within the breast parenchyma. Sporadic drainage to the subscapular, subclavicular, supraclavicular, or contralateral internal mammary nodes can occur.
Axillary Lymph Nodes
The axillary lymph node chain may be divided into six groups:
The Apical Axillary Group
Also known as the subclavicular group, they contain 8-12 nodes between the superior border of the pectoralis minor muscle and the clavicle, lateral to the first rib. This group receives drainage from all other levels of axillary nodes and drains into the subclavian trunk, which flows into the thoracic duct on the left and the right lymphatic trunk on the right side of the body.
The Brachial Group
Also known as the axillary vein or lateral group, they consist of 4-6 nodes medial and posterior to the axillary vein and receive the majority of drainage from the upper extremity and drains into the apical axillary group.
The Central Group
Lying deep to the pectoralis minor muscle within adipose tissue of the axilla, they contain about 4-5 nodes and receive drainage from the breast, the brachial group, the pectoral group, and the subscapular group.
The Subscapular Group
Also known as the posterior or scapular group, they consist of 5-7 nodes on the lateral edge of the scapula, anterior to the subscapularis muscle; they receive drainage from the posterior neck, shoulder, and trunk.
The Interpectoral Group
Also known as Rotter’s nodes, they consist of 1-4 nodes between the pectoralis major and minor muscles and receive lymph drainage directly from the breast, draining into the apical axillary and pectoral group.
The Pectoral Group
Also known as the anterior or external mammary group, they contain 5-6 nodes along the lateral thoracic vessels at the inferior border of the pectoralis minor and superior border of the pectoralis major. They receive drainage from the lateral aspect of the breast and abdominal wall, and drain into the central group.
The Infraclavicular group
Also known as the deltopectoral group, while not part of the axillary chain, lie in the region bordered by the clavicle, deltoid and pectoralis major muscles. Surrounding the cephalic vein, this group receives drainage from the forearm and hand.
The Internal mammary nodes
Also known as the parasternal group, these nodes travel along the internal mammary artery and vein within the intercostal spaces and deep to the parietal pleura. Perforating lymphatics accompany perforating branches of the internal mammary artery through the deep fascia and pectoralis muscles. Variations in blood supply to the breast via these perforators explain why, in all quadrants of the breast, cancer has the potential to metastasize via internal mammary lymphatics, especially in the deep medial aspect of the breast.
Globally, breast cancer affects 1 in 8 women in their lifetime. In the US alone, over 250,000 new cases of breast cancer are diagnosed, and over 40,000 deaths are attributed to breast cancer each year. An overall 90% 5-year survival rate can be attributed to early detection due to cancer screening and advances in adjuvant treatment.
Women with localized cancer, not involving lymph nodes (early stage breast cancer), have an estimated 99% 5-year survival. Survival drops to 85% with lymph-node involvement (locally advanced breast cancer), and 27% with distant metastasis. Breast cancer in men is less common, comprising about 1% of breast cancers diagnosed in developed countries and 1% of cancers diagnosed in men. Though typically presenting at a later stage, male breast cancer carries a similar prognosis to female breast cancer.
Factors such as early menarche, late menopause, exposure to hormone replacement therapy, and nulliparity must be considered due to the risk of increased estrogen exposure. Family history of breast cancer or ovarian cancer, particularly in patients with a BRCA gene mutation, is a significant risk factor. Women with a BRCA1 gene mutation have a 60% risk of developing breast cancer by the age of 70. Routine screening mammography for women over age 50 has resulted in a 25% reduction in breast cancer mortality in countries with these screening programs.
As many as 20% of women who develop breast cancer have a family history of breast cancer in a first-degree relative. Of those with a family history, up to 20% of those have a germline mutation that increases breast cancer susceptibility (as well as other forms of malignancy), most with a BRCA1 or BRCA2 mutation. Genetic screening and counseling should be performed in women diagnosed with breast cancer at age 50 or less, or have a relative diagnosed with breast cancer at age 50 or less. Women who develop more than one primary breast cancer, women with invasive ovarian cancer in self or a relative, men with breast cancer, also meet criteria for genetic testing.
In countries with screening mammography programs, breast cancer is most frequently detected by abnormal mammogram results . Microcalcifications within a soft tissue mass are radiologic findings that indicate invasive cancer. Breast cancer may also present with a breast mass, classically a single firm, immobile, and irregular mass. Palpable lymph nodes, skin or nipple retraction, and skin changes, may be present in more advanced stages of the disease. Histological examination is obtained by core needle biopsy, fine needle aspiration, or surgical removal, and is essential to make the diagnosis.
About 25% of breast neoplasms present as ductal carcinoma in situ (DCIS), where malignancy is limited to the breast duct. With it’s potential to progress to infiltrating ductal carcinoma (IDC), the most common form of breast cancer, DCIS is treated aggressively. The remaining 30% of invasive neoplasms present as invasive lobular carcinoma, mixed ductal/lobular carcinoma, and rare inflammatory, papillary, mucinous, Paget’s disease, among others. Molecular subtypes, grade of tumor, and hormone receptor status such as, estrogen receptor, progesterone receptor, and HER2 receptor play a key role in prognosis and selection of treatment and therapy.
Due to the lack of developed lobules in the normal male breast, invasive ductal carcinoma accounts for 90% of breast cancer diagnosed in men. Male breast cancer usually presents at a later stage, presumably because of lack of awareness and little to no screening protocols. The workup and evaluation of male breast cancer is identical to the workup in women, involving diagnostic imaging, histological evaluation, analysis of hormone receptor subtype, and evaluation of axillary lymph nodes. Up to 15% of men who develop breast cancer have a BRCA mutation; therefore all men with breast cancer should receive BRCA testing and genetic counseling.
Staging breast cancer in men and women classifies prognosis and guides treatment. The TNM classification is used, based on:
- the size and invasiveness of the tumor (T)
- involvement of regional lymph nodes (N)
- presence or absence of metastatic disease (M)
Stage I cancer involves a tumor-size ≤ 20mm (T1) and no lymph node (N0) or metastatic disease (M0). Stage II cancer involves tumors > 20mm (T2-3) and/or involvement of 1-3 lymph nodes (N1). Stage III cancer involves tumors of any size involving the chest wall or skin (T4), and/or involvement of ≥ 4 lymph nodes, or palpable nodes (N2-3). Stage IV involves any metastatic disease.
While surgery remains the mainstay of breast cancer treatment, chemotherapy, radiation therapy, and hormone therapy serve as essential adjuncts to surgery. Involvement of axillary lymph nodes in breast cancer is the most important prognostic factor and drives subsequent therapy. Prior to 1994, complete removal of the axillary lymph nodes, axillary lymph node dissection (ALND), was necessary to accurately stage breast cancer. This procedure comes with significant morbidity including nerve damage and lymphedema.
Surgically, the axillary lymph node chain may be divided into three groups based on their position relative to the pectoralis minor muscle: Level I nodes lie lateral to the pectoralis minor; Level II nodes are found posterior to the pectoralis minor, and Level III nodes medial to the pectoralis minor. Historically, ALND involved removal of all three levels, which required division or removal of the pectoralis minor muscle. Current therapy reduces morbidity by limiting the removal to Level I and II nodes, without compromising survival.
Sentinel Lymph Node Biopsy
The concept that the presence or absence of malignant cells in the sentinel node (the first lymph node downstream of invasive breast cancer) can reflect the status of tumor involvement in the entire lymph node region markedly reduced the need for ALND and its associated morbidity.
Sentinel lymph node (SLN) biopsy is also employed with other types of malignancy, such as melanoma. The procedure involves pre-operative localization of the SLN by injecting blue dye or radiolabeled colloid around the breast tumor. This permits the surgeon to identify the SLN using a gamma probe or visual confirmation. Often, the two techniques are used together.
Once identified, the SLN is removed and immediately examined by a pathologist while the patient remains under anesthesia. More than one SLN may be removed. If the SLN does not contain malignant cells, it is presumed that the cancer is contained within the breast and ALND is unnecessary. If the SLN contains malignant cells, the surgeon may remove the remaining axillary nodes. Completion of the ALND is not necessary in every case as some patients will undergo additional treatment. In this case, the SLN biopsy still serves a significant role in the staging and prognosis. The procedure is successful in identifying a SLN in more than 97% of cases and accurately predicts the status of the remaining lymph nodes more than 95% of the time.
Systemic treatment is indicated in most circumstances and involves chemotherapy, hormone therapy, radiation, and targeted therapy. Neoadjuvant chemotherapy may be employed prior to surgery to reduce tumor burden and increase the likelihood of complete tumor removal. Radiation therapy is typically used for DCIS, early stage, and locally advanced cancer.
Hormone therapy relies on knowledge of the status of the hormone receptor on the tumor cells. Hormone therapy may be continued for the duration of the patient's ’ life to reduce recurrence risk and risk of new malignancies. Unlike chemotherapy, which affects healthy cells as well, targeted therapy is a pharmaceutical treatment specifically directed to the particular subtype of cancer.
Disruption of primary lymphatic vessels, as in the case of ALND and occasionally SLN biopsy, leads to the accumulation of interstitial fluid in the downstream extremity. In contrast to edema from venous obstruction or venous insufficiency, lymphedema is a low-output failure given that lymphatics are a low-pressure system. Generally, the onset is more insidious and symptoms less severe than edema of venous origin.
An estimated 20% of patients will experience lymphedema following ALND. Multiple factors augment this risk and the severity of the condition: radiation therapy, often accompanying breast cancer treatment, results in an increased risk of lymphedema. Indwelling venous catheters, surgery and malignancy itself increase the risk of venous thrombosis. Cachexia due to chemotherapy and malignancy results in interstitial fluid retention due to hypoalbuminemia. The presence of obesity also increases risk and severity of lymphedema in cancer survivors.
Persistence of lymphedema can cause the accumulation of dermal and subcutaneous fibroadipose tissue. The skin may become dry, firm, and hyperkeratotic, where vesicular skin lesions may develop. A hallmark of lymphedema is peau d’orange skin (thick, pock-marked skin like an orange rind) and the Stemmer sign (the inability to tent the skin at the base of the finger or toe). The swelling can cause pain, paresthesia, numbness, limit range of motion and impair proper function. The dramatic effect on appearance inexorably has consequences to the quality of life of the patient.
Although lymphedema is incurable, management is possible with complex decongestive physiotherapy (CDPT). This labor-intensive approach involves a specific massage technique, skin care, and carefully fitted elastic compression garments. However, when applied correctly, CDPT dramatically increases lymphatic transport, delays the development of interstitial fibrosis, and improves symptoms.