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Review Article

Lymphatic Drainage Patterns of Thoracic Malignancies

Cordera, Fernando MD; Scott, Walter MD

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doi: 10.1097/01.laboratory.0000188333.98507.6a
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Abstract

The understanding of lymphatic drainage patterns is important for adequate staging of the different malignancies that involve the thorax: lung cancer, mesothelioma, esophageal cancer, and lymphoma. To evaluate patients for metastatic disease, it is important to carefully evaluate the specific nodal stations that drain each of these malignancies according to their primary site. The size of lymph nodes may suggest the presence of metastatic disease; however, pathologic confirmation may be required to confirm the diagnosis. Currently, computed tomography (CT) is the primary imaging modality used to assess thoracic malignancies. It is a useful tool not only to establish the diagnosis and to stage tumors, but also to identify lymph nodes for sampling, planning treatment, evaluating response to treatment, and estimating prognosis. Recently, fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), alone or used in combination with CT, has become an important tool in the evaluation of thoracic lymph nodes involved with metastatic disease. Some authors consider magnetic resonance (MR) equivalent to CT for staging thoracic malignancies, and recently it has been shown that the administration of gadolinium contrast material may further improve its staging accuracy.1 Finally, endoscopic ultrasonography (EUS) has also proven to be useful in staging patients with thoracic malignancies. A recent study evaluated CT, PET, and EUS in 33 patients who were subsequently operated on. With respect to the correct prediction of mediastinal lymph node stage, the sensitivities of CT, PET, and EUS were 57%, 73%, and 94%, respectively. Specificities were 74%, 83%, and 71%. Accuracies were 67%, 79%, and 82%. Results of PET could be improved when combined with CT (sensitivity, 81%; specificity, 94%; accuracy, 88%). The specificity of EUS (71%) was improved to 100% by fine needle aspiration cytology, which gave a tissue diagnosis, including tumor type, without complications.2

Understanding lymphatic drainage according to nodal stations of the different tumors is critical for the appropriate diagnosis, staging, and treatment of patients with thoracic malignancies.

To appropriately evaluate a thoracic CT, certain factors should be considered:

  1. Normal mediastinal lymph nodes are often visualized and are localized around the distal trachea, carina, and main bronchi.3
  2. Most studies use the short-axis diameter of a lymph node, because this is the most reproducible measurement.4
  3. The average size of normal lymph nodes varies depending on their region with normal subcarinal nodes measuring up to 11 mm in short-axis diameter and normal paratracheal up to 7 mm.4-6
  4. Generally, a paratracheal, hilar, subcarinal, paraesophageal, paraaortic, or subaortic lymph nodes are considered abnormal if the short-axis diameter is greater than or equal to 10 mm.5,7
  5. Peridiaphragmatic nodes are considered enlarged if greater than 5 mm in short-axis diameter.6
  6. No size criteria are available for internal mammary, retrocrural, and extrapleural nodes, and detection of these nodes should be considered abnormal.8
  7. Finally, benign processes such as granulomas may cause nodal enlargement and normal-sized lymph nodes may contain metastatic disease. Therefore, the size criteria must be interpreted cautiously. By assessing the metabolic activity rather than the size of lymph nodes, FDG PET can detect metastatic involvement more accurately than CT.9,10 Although PET has poor resolution, the new CT and FDG PET fusion imaging helps overcome this problem.

The American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC) have developed the International Lymph Node Classification to define lymph node stations in the hilum and mediastinum that are relevant to the staging of lung cancer.11 These stations can be applied to other thoracic tumors; however, additional lymph node regions in the thorax not included in this classification may also be involved by metastatic disease (Tables 1 and 2) (Fig. 1).

T1-21
TABLE 1:
Lymph Node Stations
T2-21
TABLE 2:
Other Abbreviations Used in Figures
F1-21
FIGURE 1:
Lung cancer lymph node map A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.

This review describes the lymphatic drainage pathways of different thoracic malignancies. The role and limitations of imaging techniques, especially CT, are evaluated.

LUNG CANCER

Lung cancer is currently the most common cause of cancer mortality in the United States and throughout the world. The American Cancer Society estimates that lung cancer will be responsible for approximately 163,500 deaths in the United States during 2005, in comparison with 127,500 deaths from the combined mortality of colorectal, breast, and prostate cancer.12

Four major cell types make up 88% of all primary lung neoplasms. The behavior of these tumors varies according to their histology. Thus, for major treatment decisions, these tumors are classified as a small cell carcinoma or as one of the nonsmall cell varieties (squamous, adenocarcinoma, large cell carcinoma, bronchoalveolar carcinoma, and other). At presentation, small cell carcinomas usually have already spread such that surgery is unlikely to be curative, and they are managed primarily by chemotherapy with or without radiotherapy. Small cell carcinomas constitute 20% to 25% of all bronchogenic carcinomas and are classified by a simple 2-stage system:

  1. Limited-stage disease (approximately 30% of patients) when disease is confined to one hemithorax and regional lymph nodes, including mediastinal, contralateral hilar, and usually ipsilateral supraclavicular nodes.
  2. Extensive-stage disease (70% of patients) when disease extends beyond those boundaries.

In contrast, nonsmall cell lung carcinomas (NSCLC) localized at the time of presentation may be cured with either surgery or radiotherapy. NSCLC constitute the majority of patients with bronchogenic carcinomas.12 At presentation, approximately one third of patients have disease localized enough for a curative attempt with surgery or radiotherapy, one third have distant metastatic disease, and one third have local or regional disease that may or may not be amenable to a curative attempt. These tumors constitute the majority of patients with lung cancer and appropriate staging dictates the therapeutic approach. The lung cancer section of this review focuses on NSCLC.

The lungs have a rich lymphatic supply that consists of a pleural and parenchymal network.13 The pleural lymphatics course over the parietal and visceral pleural surfaces and drain into the medial aspect of the lung near the hilum, where they anastomose with the parenchymal lymphatics. The parenchymal lymphatics are located in the interlobular septal and bronchovascular bundles. Multiple lymphatic channels anastomose with each other before draining sequentially into the intralobular, interlobular, lobar, and finally, the hilar nodes. Most parenchymal tumors drain to the hilar nodes and subsequently into the mediastinum; however, pathways to the mediastinum are variable and are related to the lobe of origin (Fig. 2).14,15 Lesions of the right upper lobe predominantly drain into the right paratracheal (station 2R) and anterior mediastinal (station 6) nodes (anterior mediastinal nodes include some pretracheal and preaortic nodes). Right middle and lower lobe tumors predominantly drain into the subcarinal (station 7) nodes and subsequently into the right paratracheal (stations 2R and 4R) and anterior mediastinal (station 6) nodes. Left upper lobe tumors drain to the subaortic (station 5) (also called aortopulmonary window nodes) and anterior mediastinal (station 6) nodes. The left lower lobe tumors drain to the subcarinal (station 7) and subaortic (station 5) nodes.

F2-21
FIGURE 2:
Lymphatic drainage of lung cancer according to the lobe of origin.

Exceptions

The spread of tumor from pulmonary nodes to the hilum and mediastinum is usually ipsilateral. However, contralateral spread does occur. Contralateral spread has been reported in approximately 4% to 5% for right-sided tumors, 9% for left upper lobe tumors, and up to 28% for left lower lobe tumors.16 Thus, almost one third of left lower lobe lesions can spread to lymph nodes in the right side of the mediastinum (Fig. 1).

Occasionally, mediastinal involvement may occur through direct lymphatic drainage that bypasses the hilar nodes (so-called “skip metastases”).15,17 This occurs more often with adenocarcinomas than with squamous cell carcinomas18 and is seen more commonly with tumors of the upper lobes occurring in up to 25% of cases according to some autopsy studies.17 In rare instances, a direct connection may exist between the pulmonary segments and the thoracic duct; this allows direct passage of tumor into the systemic circulation without mediastinal node involvement.17 In addition, once tumors involve the visceral pleura, tumors may spread through the extensive lymphatic channels of the diaphragmatic pleura that are described later in this article. Thus, such tumors may not follow the usual pattern of lymphatic spread.19

Clinical Relevance

In lung cancer, nodal status determines resectability. According to the TNM classification system for lung cancer20 (Table 3), involvement of ipsilateral peribronchial, hilar, or intrapulmonary nodes (stations 10-14; double digits) is considered N1 disease. These nodes lie within the pleural reflection. Lung cancer with N1 disease is considered resectable in the absence of mediastinal invasion by tumor, a malignant pleural effusion, satellite nodules, or metastases (Fig. L3, Image L3).

F6-21
FIGURE:
L3. Axial views of the mediastinum at the level of the aortopulmonary window. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
T3-21
TABLE 3:
Definition of TNM for Lung Cancer
F9-21
FIGURE:
IMAGE L3. Enhancing low paratracheal nodes (4R) (arrowhead), subaortic nodes (5) (straight arrows), and low left (contralateral) paratracheal nodes (4L) (curved arrow). *Primary tumor; therefore, level 5 and level 4L are N3 lymph nodes. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.

Ipsilateral mediastinal or subcarinal (stations 1-9; single digit) node involvement is classified as N2 disease. These nodes lie outside the pleural reflection. Treatment of N2 disease usually consists of a combination of radiation and chemotherapy therapy with or without surgery (Fig. L1, Image L1).

F4-21
FIGURE:
L1. Axial views of the mediastinum at the level of the aortopulmonary window. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F7-21
FIGURE:
IMAGE L1. Seven-millimeter diameter subaortic node (station 5) (arrow), which lies lateral to a calcified ligamentum arteriosum (arrowhead) = N2. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.

Contralateral mediastinal or hilar node involvement and disease in the supraclavicular nodes are classified as N3 disease. This is advanced disease, and patients are not considered surgical candidates (Fig. L2, Image L2).

F5-21
FIGURE:
L2. Axial views of the mediastinum at the level of the aortopulmonary window. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F8-21
FIGURE:
IMAGE L2. Three-centimeter ipsilateral hilar node (station 10) = N1. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.

Distinction between the different nodal stations around the right tracheobronchial angle can be difficult with CT, because the parietal pleural reflection may not be visible.21 As a general guideline, N1 nodes lie within the confines of the pleural reflection and are therefore intrapulmonary, and N2 nodes lie outside the pleural reflection and are considered mediastinal. The pleural reflection begins at the origin of the right upper lobe bronchus. Lymph nodes proximal to this bronchus should be considered mediastinal in location.

Although radiologic imaging is very useful in the detection of lymph node involvement, lymph node size does not always predict the presence or absence of metastases and tissue diagnosis is often required. Adequate detection by CT directs the interventional radiologist, bronchoscopist, or the surgeon to sample lymph nodes preoperatively or intraoperatively to determine the most appropriate therapeutic approach.

ESOPHAGEAL CANCER

Anatomically, the esophagus is divided into cervical and thoracic portions. The cervical esophagus begins at the level of the lower margin of the cricoid cartilage and ends at the thoracic inlet. The thoracic esophagus extends from the thoracic inlet to the gastroesophageal junction and is divided into 3 regions.22 The upper thoracic portion extends from the thoracic inlet (at the level of the suprasternal notch) to the carina. The midthoracic portion extends from the carina to just above the gastroesophageal junction. The lower esophagus includes the intraabdominal esophagus and the gastroesophageal junction.

The esophageal lymphatics form a contiguous dense submucosal plexus around the esophagus23,24 (Fig. 3). Generally, the lymphatics of the upper two thirds of the esophagus drain cephalad and the lymphatics of the lower one third caudally toward the abdomen. In addition, esophageal lymphatics also directly communicate with the thoracic duct at multiple levels. As a result of this extensive drainage system, skip metastases are common, and nodal disease can appear at remote sites with no intervening nodal involvement.23 Recent studies suggest that direct drainage from the esophagus to the thoracic duct without nodal relay can occur and, in fact, one study suggests that this communication occurs most often in the dorsal/right quadrant of the esophagus. Esophageal carcinomas that are located in this region may have a higher incidence of cervical lymph nodes involved by metastatic disease.25

F3-21
FIGURE 3:
Esophageal carcinoma lymph node map. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.

Nodal spread of tumors from the upper and middle esophagus often involves paratracheal (stations 2 and 4) lymph nodes. Lower esophageal cancers often spread to the lymph nodes of the lesser curvature of the stomach (stations 17-20), mainly left gastric artery (station 17) and gastrohepatic ligament (station 18) nodes.

The TNM staging system for esophageal cancer (Table 4) reflects the bidirectional longitudinal lymphatic flow along the esophagus. In all patients with esophageal carcinoma, the entire thorax from the thoracic inlet to the upper abdomen should be evaluated because detection and confirmation of regional nodal disease usually dictates the addition of chemoradiation treatment to surgery. Specific regional nodes for tumors of the cervical esophagus include the supraclavicular, internal jugular, upper and lower cervical, and periesophageal nodes. Regional nodes for tumors of the thoracic esophagus are the paratracheal (stations 2 and 4), (Figs. E1, E2, Image E1), periesophageal (station 8), and subcarinal (station 7) nodes (Fig. E3, Image E2). For gastroesophageal junction tumors, the regional nodes include nodes adjacent to the diaphragm (station 15), pericardium (station 16), left gastric artery (station 17), gastrohepatic ligament (station 18), and celiac artery (station 20).20 For all intrathoracic esophageal tumors, supraclavicular (station 1) and celiac axis nodal involvement (station 20) are classified as M1 (distant metastatic disease) and generally preclude surgery (Images E3).20

T4-21
TABLE 4:
Definition of TNM for Esophageal Carcinoma
F10-21
FIGURE E1:
Upper mediastinum at the level of T2. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F11-21
FIGURE E2:
Upper mediastinum at the level of T4. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F12-21
FIGURE E3:
Mediastinum at the level of the aortopulmonary window/tracheal bifurcation. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F13-21
FIGURE:
IMAGE E1. Prominent left anterior scalene/subclavian (ASSCN) nodes (arrow). A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F14-21
FIGURE:
IMAGE E2. Esophageal mass. Prominent subcarinal (station 7) and subaortic (station 5) and periesophageal (station 8) nodes (arrow). A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F15-21
FIGURE:
IMAGE E3. Several gastrohepatic ligament nodes (station 18) (arrow). containing tumor considered M1 for intrathoracic esophageal tumors, but N1 for tumors of the gastroesophageal junction A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.

Like with other tumors, the size of the lymph nodes does not always correlate with metastatic involvement, and strong suspicion of involvement should be confirmed by other methods because management decisions may change with the results. Recently, EUS has shown promising results and may prove to be a useful adjunct for the detection of diseased lymph nodes.26,27

MALIGNANT PLEURAL MESOTHELIOMA

Malignant mesothelioma is an insidious neoplasm with a dismal prognosis. It arises in the parietal and diaphragmatic pleura. The natural spread of mesothelioma is to the lungs through the visceral pleura and by local extension into the chest wall and diaphragm.28

The anterior pleural lymphatics drain into the internal mammary lymph nodes in the upper and middle thorax and the peridiaphragmatic (station 15) lymph nodes in the lower thorax. The posterior pleural lymphatics drain into the extrapleural lymph nodes, which lie in the paraspinal extrapleural fat adjacent to the rib heads.29

The diaphragm, which has a rich lymphatic network that communicates between the thorax and peritoneum, is often involved by mesothelioma. The anterior and lateral diaphragm lymphatics drain into the internal mammary and anterior peridiaphragmatic (station 15) lymph nodes. The posterior diaphragm lymphatics drain into the paraaortic (station 5) lymph nodes and nodes of the posterior mediastinum (station 3). Posterior mediastinal lymphatics drain superiorly and communicate with the middle mediastinum lymphatics. They may also drain inferiorly and involve the lymphatics of the gastrohepatic ligament (station 18) and celiac axis (station 20).30

Several staging systems are available for pleural mesothelioma. The UICC first proposed a staging system in 1990 based on the TNM standard used for many other tumors, which was modified in 1995 by the International Mesothelioma Interest Group (IMIG).31 This staging system, was adopted by the AJCC/UICC for their TNM staging system in 200232 (Table 5).

T5-21
TABLE 5:
Definition of TNM for Pleural Mesothelioma (IMIG Staging System)

In this classification, N1 disease includes involvement of ipsilateral hilar or bronchopulmonary nodes (hilar, interlobar, lobar, segmental, and subsegmental nodes) (stations 10-14). N2 disease includes subcarinal (station 7) and ipsilateral mediastinal (stations 2-9) nodes, including the internal mammary nodes (Figs. M2, M3). N3 disease includes contralateral mediastinal or internal mammary nodes and all supraclavicular (station 1) (Fig. M1) nodes. The staging system is of limited value, because most patients present with advanced disease. However, there is a subset of patients who benefit from surgery and follow-up chemotherapy.31 These patients have epithelial histology and no evidence of extrapleural nodes, defined as mediastinal (stations 2-9) or peridiaphragmatic (station 15) nodes. Detection of these lymph nodes at CT could change the management of this group of patients (Image M3).

F16-21
FIGURE:
M1. Axial views of the mediastinum at the level of T2. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F17-21
FIGURE:
M2. Mediastinum at the level of the aortopulmonary window/tracheal bifurcation. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F18-21
FIGURE:
M3. Mediastinum at the level of the coronary sinus (CS). A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F19-21
FIGURE:
IMAGE M1. Tumor extension into left anterior chest wall and pericardium. Four-millimeter diameter extrapleural lymph node in the left supraclavicular region (station 1) (arrow). T4, N3 = unresectable. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
FU1-21
FIGURE:
IMAGE M2. Tumor extension into left anterior chest wall and pericardium. Four-millimeter diameter lymph node in the left extrapleural space (arrow). T4, N3 = unresectable. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
FU2-21
FIGURE:
IMAGE M3. Cluster of enhancing left peridiaphragmatic (PDN) nodes (arrow). A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.

LYMPHOMA

Lymphomas are neoplastic transformations of normal lymphoid cells, which reside predominantly in lymphoid tissues. They are morphologically subdivided into 2 major categories: non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Further subdivisions depend on the histologic type. Several classifications have been described. In 1995, the Society for Hematopathology and the European Association of Hematopathologists jointly developed a classification of hematologic neoplasms for the World Health Organization, which is currently the most widely used classification (Table 6).33

T6-21
TABLE 6:
Staging for Lymphoma

It is difficult to differentiate Hodgkin disease from non-Hodgkin lymphoma on the basis of nodal distribution alone; however, certain guidelines may be useful to make this differentiation: patients with HL often have intrathoracic involvement. At their initial presentation, more than 80% of patients will have disease in thoracic lymph nodes.34 HL frequently involves the anterior mediastinal (station 6) and paratracheal (stations 2 and 4) regions and tends to spread to contiguous nodal groups (Figs. LY1-LY3, Images LY1, L2). The subcarinal (station 7), peridiaphragmatic (station 15), periesophageal (station 8), and internal mammary nodes are involved in decreasing order of frequency. In most patients, 2 or more nodal groups are involved at initial presentation. Isolated hilar involvement is rare and should suggest an alternative diagnosis (Image LY2).

F20-21
FIGURE:
LY1. Upper mediastinum at the level of T3. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F21-21
FIGURE:
LY2. Upper mediastinum at the level of T4. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F22-21
FIGURE:
LY3. Mediastinum at the level of the aortopulmonary window/tracheal bifurcation. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F23-21
FIGURE:
IMAGE LY1. Prominent right paratracheal (4R) (white arrow), left internal mammary (IMN) (black arrow), and anterior mediastinal (station 5) (arrowhead) nodes. Three nodal groups above the diaphragm = at least stage II. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.
F24-21
FIGURE:
IMAGE LY2. Prominent right hilar (station 10) (arrow) and subcarinal (station 7) (arrowhead) lymph nodes. Two nodal groups above the diaphragm = a least stage II. A color version of this figure can be accessed using the Article Plus feature on the Journal's Web site: www.bronchology.com.

NHL is a more heterogeneous group of diseases. Thoracic involvement is present in up to 45% of cases.35 The anterior mediastinal (station 6) and paratracheal (stations 2 and 4) nodes are also the most common sites of involvement for NHL. Other common sites, in decreasing order of frequency, are the subcarinal (station 7), hilar (station 10), posterior mediastinal (station 3), and pericardial (station 16) nodes (Image LY3).35

F25-21
FIGURE:
IMAGE LY3. Enlarged pericardial fat nodes (PCF) (black arrow). Soft tissue in the extrapleural space (white arrows) and bilateral pleural effusions are also present. Findings commonly seen with recurrence.

Tumor stage is the most important prognostic factor in lymphoma (Table 5). For both HL and NHL, single-station nodal disease is defined as stage 1. Multiple nodes confined to one body area such as the chest are defined as stage 2, and disease on both sides of the diaphragm is defined as stage 3. Visceral involvement is regarded as stage 4. The grade and bulk of tumor determine whether treatment is with chemotherapy, radiation therapy, or a combination. Accurate determination of the extent of disease is important for radiation therapy planning. Large mediastinal adenopathy or bulky disease is defined as the presence of a mediastinal mass greater than 10 cm in transverse diameter or greater than one third of the thoracic diameter (measured at the level of the diaphragm). Large mediastinal adenopathy is associated with an increased risk of relapse and therefore requires both chemotherapy and radiation therapy, regardless of tumor grade.20

Recurrent disease is common in the pericardial and internal mammary lymph nodes, because these are usually not included in the radiation field. Involvement of the posterior mediastinal (station 3) lymph nodes is associated with pleural, retrocrural, and retroperitoneal disease as well as within the extrapleural space (especially in NHL).36 There is often an associated pleural effusion secondary to malignancy or obstruction of the pleural lymphatics. After treatment, diseased lymph nodes may show irregular or eggshell calcifications at CT.

CONCLUSIONS

Lymphatic drainage of thoracic malignancies varies according to the primary tumor. Careful, orderly evaluation of nodal stations from the primary tumor is important for adequate staging of tumors. The size criterion may serve as a useful guideline; however, inconsistencies occur and pathologic confirmation is critical for true staging. CT and EUS are useful tools to guide the surgeon or interventionalist to the most appropriate approach for nodal sampling. PET, particularly when fused with CT, is becoming a useful tool to determine the presence of disease in lymph nodes that appear normal at CT alone. Appropriate radiologic evaluation is useful not only to diagnose and stage thoracic malignancies, but also to plan treatment, evaluate response to treatments, and estimate prognosis.

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Keywords:

lymphatic drainage; cancer; lung; mesothelioma; esophagus; lymphoma

© 2005 Lippincott Williams & Wilkins, Inc.