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Targeting Area in Metastatic Lymph Nodes in Lung Cancer for Endobronchial Ultrasonography-guided Transbronchial Needle Aspiration

Kurimoto, Noriaki MD FCCP*; Osada, Hiroaki MD*; Miyazawa, Teruomi MD, FCCP; Nishisaka, Takashi MD, PhD; Murayama, Masaki MD, PhD§

doi: 10.1097/LBR.0b013e31817ec366
Original Investigations
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Study Objective Location of the tumor tissue within the metastatic lymph nodes from lung cancer should be determined to improve the results of endobronchial ultrasound-guided transbronchial needle aspiration.

Methods We histopathologically investigated 128 metastatic lymph nodes (LNs), that were less than or equal to 20 mm in short axis, and classified these as follows. Type I was minimal invasive metastasis, including type Ia (marginal metastasis occupying <25% of the LN) and type Ib (marginal invasive metastasis occupying <50% of the LN). Type II was invasive metastasis occupying 50% to 90% of the LN and type III was advanced metastasis occupying >90% of the LN.

Results Among 72 LNs with metastatic adenocarcinoma, types I, II, and III accounted for 32%, 6%, and 62%, respectively. Among 44 LNs with metastatic squamous cell carcinoma, types I, II, and III accounted for 27%, 27%, and 46%, respectively. Ten (22%) out of 45 nodes with adenocarcinoma and 6 (24%) out of 25 nodes with squamous cell carcinoma, greater than 5 mm in short axis, were classified as types Ia and Ib. Types Ia and Ib LNs have no metastasis at the center.

Conclusions In about one-fifth to one-fourth of metastatic LNs, greater than equal to 5 mm and less than or equal to 20 mm in diameter, of adenocarcinoma and squamous cell carcinoma, these metastases can only be detected in biopsy specimens collected from the marginal area of the LN.

*Department of Surgery, Division of Chest Surgery

Department of Pulmonology, St. Marianna University School of Medicine, Kawasaki

Department of Pathology, Hiroshima Prefectural Hospital, Hiroshima

§Department of Surgery, Iwakuni Minami Hospital, Iwakuni, Japan

Reprints: Noriaki Kurimoto, MD, FCCP, Department of Surgery, Division of Chest Surgery, 2-16-1, Sugao, Miyamae-ku, Kawasaki, Kanagawa Prefecture, 216-8511 Japan (e-mail; n.kurimoto@do7.enjoy.ne.jp).

Received for publication April 17, 2008; accepted April 28, 2008

There is no conflict of interest.

Endobronchial ultrasonography (EBUS) has been performed with a radial probe, which provides cross-sectional images of the tracheobronchial wall and adjacent mediastinal structures. The indications for EBUS include: (1) determining the depth of invasion of tracheobronchial tumors,1,2 (2) visualizing peritracheal and peribronchial lymph nodes and detecting metastases,3,4 and (3) localizing and diagnosing benign or malignant peripheral pulmonary lesions.5,6

A bronchoscope combined with a convex ultrasound probe (7.5 MHz, BF-UC260F; Olympus Optical Co Ltd, Tokyo, Japan) has been developed for transbronchial needle aspiration (TBNA). Scanning with this convex probe inside the endobronchial tree provides longitudinal images of the mediastinal structures and allows real-time monitoring for needle aspiration of target lymph nodes adjacent to the tracheobronchial tree (Fig. 1). Although, the target lymph nodes can be visualized clearly by scanning with convex probe, it remains unclear where tumor cells reside in those nodes. If this question could be answered, it would be helpful for the operator to target the area of pathology in each lymph node during the procedure of TBNA.

FIGURE 1.

FIGURE 1.

In the present study, we histopathologically examined the localization of tumor tissue within the metastatic mediastinal and hilar lymph nodes harvested from lung cancer patients.

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MATERIALS AND METHODS

One hundred twenty-eight mediastinal and hilar metastatic lymph nodes, which were less than or equal to 20 mm in the short axis were harvested from lung cancer patients undergoing resection between April 2001 and March 2007 at our institution. We classified lymph nodes by their short axis, as it is the most common criterion used for the radiographic staging of lung cancer. Harvested lymph nodes were fixed in formalin. The specimens were cut into thin slices to prepare histologic sections with the largest cross-sectional area. As EBUS-TBNA is usually performed at the largest cross-sectional area of the lymph node, we evaluated pathology of the largest cross-sectional area of the lymph node.

These lymph nodes were classified into 3 types (types I-III) based on the extent of involvement by tumor cells. Then, types I and III nodes were further classified into 2 subtypes (Figs. 2 and 3).

FIGURE 2.

FIGURE 2.

FIGURE 3.

FIGURE 3.

Type I (minimal invasive type): maximum diameter of the metastasis is <50% of the lymph node diameter.

Type Ia (marginal type): metastasis is limited to the marginal area of the lymph node and the maximum diameter of the metastasis is <25% of the lymph node diameter.

Type Ib (marginal invasive type): metastasis involves the marginal area of the lymph node and the maximum diameter of the metastasis is 25% to 50% of the lymph node diameter.

Type II (invasive type): metastasis involves the center of the lymph node and its maximum diameter is 50% to 90% of the lymph node diameter.

Type III (advanced type): maximum diameter of the metastasis is >90% of the lymph node diameter.

Type IIIa (diffuse type): cancer involves almost all of the lymph node, but a few scattered normal areas remain.

Type IIIb (total type): cancer involves the entire lymph node and no normal areas remain.

In addition, the extent of necrosis in the metastatic nodes was investigated in relation to tumor histology, and the sites of necrosis were examined. The lymph nodes were divided into 3 size groups based on their short axis (<5 mm, ≥5 mm, and ≤20 mm), and the nodes in each group were classified by the above criteria.

After obtaining approval from the ethics review board of the Hospital, informed consent was obtained from all patients.

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RESULTS

A total of 128 metastatic lymph nodes (including 72 lymph nodes with adenocarcinoma from 40 patients, 44 lymph nodes with squamous cell carcinoma from 24 patients, and 12 lymph nodes with small cell carcinoma) from 10 patients were studied (Table 1). Figure 3 depicts typical examples of metastatic lymph nodes.

TABLE 1

TABLE 1

Of the 128 metastatic lymph nodes, 49 (38%) had a short axis of <5 mm, 34 (27%) were from 5 to 10 mm, and 45 (35%) were >10 mm. A total of 37 nodes (29%) were classified as type I, 16 nodes (13%) were type II, and 75 nodes (58%) were type III.

Among the 75 lymph nodes classified as type III, which was the most frequent type, 60 (47%) were type IIIb (Table 1).

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Metastatic Adenocarcinoma (Table 2)

Twenty-three (32%) of 72 nodes were classified as type I, 4 (6%) were type II, and 45 (62%) were type III. Among 27 lymph nodes with the short axis of <5 mm, 13 (48%) were classified as type I. Among the 45 lymph nodes with the short axis >5 mm, which are suitable for EBUS-TBNA, 10 nodes (22%) were classified as type Ia or Ib and in these 10 lymph nodes there was no metastasis at the center of the lymph node. Type III was the most common type of metastatic lymph node in adenocarcinoma patients and type IIIa (diffuse tumor cell involvement) was relatively frequent (n=15, 33%). In 128 lymph nodes, histopathologic type of all lymph nodes of type IIIa was adenocarcinoma.

TABLE 2

TABLE 2

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Metastatic Squamous Cell Carcinoma (Table 3)

Twelve (27%) of these 44 nodes were classified as type I, whereas 12 nodes (27%) were type II and 20 nodes (46%) were type III. Thus, type III was the most frequent type of metastatic lymph node for squamous cell carcinoma, but none were classified as type IIIa. Among 19 lymph nodes with the short axis of <5 mm, 6 (32%) were classified as type I. Among 25 lymph nodes with the short axis >5 mm (suitable for EBUS-TBNA), 6 nodes (24%) were classified as type Ia or Ib.

TABLE 3

TABLE 3

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Metastatic Small Cell Carcinoma (Table 4)

Two (17%) of these 12 nodes were classified as type I, none (0%) was type II, and 10 (83%) were type III. There were also no type IIIa nodes as was the case for squamous cell carcinoma. Among 9 lymph nodes with the short axis >5 mm (suitable for EBUS-TBNA), none were classified as type I.

TABLE 4

TABLE 4

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Necrosis

Necrosis was identified pathologically in 22 (17%) of the 128 metastatic lymph nodes, including 4 out of 72 (6%) nodes with adenocarcinoma, 15 out of 44 (34%) nodes with squamous cell carcinoma, and 3 out of 12 (25%) nodes with small cell carcinoma, indicating that necrosis was more common in nodes with squamous cell and small cell carcinoma. In all of the lymph nodes with necrosis, necrotic cells were located far from the blood vessels, whereas viable tumor cells were located around the vessels (Fig. 4).

FIGURE 4.

FIGURE 4.

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DISCUSSION

While puncturing the target using image-guided needle biopsy, it is easier to puncture the center area than the marginal area. But according to this study, if the previous puncturing into the center of the lymph node by EBUS-TBNA was negative on-site cytologic evaluation, the operator should puncture the needle into the marginal area of the lymph node. Of lymph nodes which were less than or equal to 20 mm in the short axis, 49 out of 72 (68%) lymph nodes with adenocarcinoma, 32 out of 44 (73%) nodes with squamous cell carcinoma, and 10 out of 12 (83%) nodes with small cell carcinoma were classified as type II or type III, that is, metastasis involving the center of the lymph node. This finding indicates that biopsy of the center of a lymph node will detect metastatic cancer in 68% to 83% of lymph nodes. However, types Ia and Ib lymph nodes have no metastasis at the center, so the collection of specimens from the marginal area of types Ia and Ib lymph nodes increases possibility of diagnosis. Among the metastatic lymph nodes having a short axis >5 mm that are suitable for EBUS-TBNA, we found that 10 out of 45 (22%) nodes with adenocarcinoma, 6 out of 25 (24%) nodes with squamous cell carcinoma, and 0 out of 9 (0%) nodes with small cell carcinoma were classified as types Ia and Ib.

The flow of lymph into lymph nodes occurs via channels that drain predominantly into the subcapsular sinusoids and thence to the parenchymal sinusoids.6 This flow pattern is responsible for the observation that small metastases of breast cancer identified on hematoxylin and eosin sections are usually located in the subcapsular sinusoids. Viale et al7 reported that metastases were largely found in the subcapsular zone where the afferent lymphatics enter lymph nodes. Cserni8 studied the location of metastases in the sentinel lymph nodes of breast cancer patients. Forty sentinel nodes from 36 patients with operable primary breast cancer were identified by lymphatic mapping with patent blue dye. In 23 (72%) sentinel nodes of 32 node-positive patients, metastases were more likely to be localized or more voluminous on the inflow side of the lymphatics draining from the tumor. However, there have been no previous reports about the site of involvement of mediastinal and hilar lymph nodes in lung cancer patients, as well as no reports on diagnostic imaging of mediastinal and hilar lymph node metastasis in lung cancer patients. We believe this study is a lead for these questions.

During aspiration biopsy, it is important to avoid necrotic areas of tumor in lymph nodes. In this study, pathologic examination revealed that necrosis was more frequent in metastatic lymph nodes with squamous cell carcinoma (34%) and small cell carcinoma (25%) than in nodes with adenocarcinoma (6%). The necrosis of neoplasms is probably related at least partly to deficient blood supply.9,10 Histologic examination of all the lymph nodes with necrosis showed that necrotic cells were located far from the blood vessels, whereas viable tumor cells were located adjacent to the vessels. As the convex probe bronchoscope also allows the use of Doppler mode, it not only provides images of the peribronchial great vessels but also images of vessels lying within the lymph nodes. Since viable tumor cells were detected around blood vessels lymph nodes with necrotic areas, use of Doppler imaging to detect nodal vessels and biopsy of perivascular tissue may possibly increase the rate of diagnosis, particularly when metastasis of squamous cell carcinoma or small cell carcinoma is suspected.

Some pulmonary adenocarcinomas have dysconhesive zones with large numbers of single cells that infiltrate the interstium.11 Among all of 128 lymph nodes, 15 lymph nodes with adenocarcinoma were classified in type IIIa. The latter type (diffuse type) might be a characteristic of adenocarcinoma.

It is very difficult to detect metastatic area in a lymph node on images of EBUS using by the convex probe. In the future, we hope new techniques, for example using the contrast agent, harmonic imaging,12 and other new imaging advancements; will aid to overcome this challenge.

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CONCLUSIONS

In 22% to 24% of metastatic lymph nodes, greater than or equal to 5 mm and less than or equal to 20 mm in diameter, of adenocarcinoma and squamous cell carcinoma, metastases did not involve the center of the node. So these metastases can only be detected in biopsy specimens collected from the marginal zone during EBUS-TBNA.

To avoid necrotic areas of the lymph node, it is recommended to target the perivascular areas within the metastatic lymph nodes.

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REFERENCES

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Keywords:

endobronchial ultrasonography; transbronchial needle aspiration; EBUS-TBNA; metastasis; location

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