The most common site of regional involvement of breast cancer is within the axillary lymph nodes. Along with size of the primary carcinoma, the presence of metastatic disease to the axillary lymph nodes is the most important indicator of clinical outcome. Studies of 10-year survival rates have demonstrated that prognosis is directly related to the number of lymph nodes involved.1–3As shown in results obtained in the American College of Surgeons’
survey, with greater number of nodes involved, there is a progressive decline in survival (Table 5.1). When 1 to 2 nodes are involved, 5-year survival is 62% to 63%, whereas when 5 nodes are involved, survival declines to 47%. With more than 10 nodes involved, survival decreases to 29%.
Because knowledge of involvement of lymph nodes is important for staging and treatment planning for patients, techniques to assess the status of these nodes are important.
Additionally, removal of axillary nodes may decrease axillary recurrence of tumor. As axillary recurrence can significantly compromise quality of life with lymphedema and pain, surgical removal or radiation of these involved nodes can be helpful in decreasing the likelihood of this complication.
1. Anatomy
The axillary lymph nodes are divided into three levels that are defined by their relationships to the pectoralis minor muscle: Level I nodes are inferior and lateral to the pec- toralis minor muscle; level II nodes are deep to this muscle, and level III nodes are superior and medial to the pec- toralis minor (Figure 5.1). The majority of breast cancers spread into these axillary nodes with a small percentage of medially located tumors spreading into the internal mammary lymph nodes. This nodal chain is located
parasternally, deep to intercostal muscles, adjacent to the internal mammary vessels.
Metastatic invasion of axillary lymph nodes generally develops in an orderly, progressive pattern, with the nodes of level I first affected, followed by levels II and III.
Because of this pattern, as higher levels of the nodal chain are involved, the number of involved lymph nodes increases, and the prognosis worsens. Rarely, there is involvement of higher levels without involvement of lower level lymph nodes. Large series have shown that these skip metastases only occur only in approximately 3% to 4% of cases.4,5Therefore, if the nodes of level I are free of disease, there is minimal chance of metastatic involvement of lymph nodes in levels II and III.
2. Pathophysiology of Metastatic Disease to Lymph Nodes
Tumor cells usually enter lymph nodes via afferent lym- phatics, passing into the marginal sinus, then into the cortex where they first establish themselves. A focus of tumor cells less than 2 mm in diameter on histopathologic analy- sis is classified as a micrometastasis. Current imaging methods are not able to accurately detect micrometastatic disease. However, as the tumor cells continue to grow within the lymph node, imaging can detect metastatic foci.
With this larger tumor burden, the node enlarges, and eventually tumor growth obliterates the fatty hilum. Tumor cells can ultimately break through the cortex leading to extracapsular and extranodal extension and flow into the efferent nodal vessels, at which point they spread into adjacent lymph nodes.6With extension of tumor into the pericapsular fat, the contour of the node can become spiculated. This extension suggests a more biologically aggressive tumor, especially in women with three or fewer nodes involved.
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The Axilla
Joo Young Melissa Lee and D. David Dershaw
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3. Imaging Methods
3.1. Surgical, Mammographic, and Sonographic Evaluation of Axillary Lymph Nodes
Until recently, imaging of lymph nodes has not played a significant role in staging breast cancer due to the inabil- ity to detect micrometastatic involvement. In the past, the gold standard for detecting metastatic involvement of axillary lymph nodes was axillary lymph node dissection, which was often associated with significant morbidity.
Despite the ability of axillary dissection to help in loco- regional control, it has not been shown to have any impact on the overall survival of the patient.7
Increasingly, sentinel lymph node biopsy has become an alternative procedure to evaluate involvement of lymph nodes. Sentinel lymph node imaging uses radio- nuclide particles and/or a visual tracer to detect the first lymph node draining the tumor site.8 If histopathologic analysis shows tumor involvement, then a full axillary dissection can be performed. This information is also valuable in determining the need for hormonal therapy or chemotherapy.
Although the assessment is often nonspecific, mammog- raphy and sonography can aid in the identification of pathologic lymph nodes. On mammography, abnormal lymph nodes can be identified when they are dense, rounded, or spiculated.9On sonography, abnormal lymph nodes lose their hypoechoic cortex and become more rounded, and the fatty echogenic hilum can be obliterated.
When abnormal lymph nodes are identified on sonogra- phy, fine needle aspiration under sonographic guidance can be performed for definitive cytologic evaluation. This can be very useful as inflammatory, reactive, and metastatic adenopathy can have an identical mammographic and sonographic pattern. The usefulness of mammography has been limited to the evaluation of level I nodes. Level II and III nodes can be imaged sonographically, but the utility of this technique for screening of these nodal levels has very limited experience.
Other cross-sectional imaging modalities can be valu- able in assessing the axilla. Computed tomography (CT) can image all levels, but its application is limited by its high radiation doses and thus it would be unusual to use CT for axillary screening. Positron emission tomography (PET) shows a high sensitivity in detecting axillary metastases.
However, its specificity is lower. Published sensitivities have ranged from 80% to 95%, while specificities have been reported from 66% to 95%.10,11
4. Magnetic Resonance Imaging of Lymph Nodes
Contrast-enhanced magnetic resonance imaging (MRI) of the breast is becoming an integral part of evaluating extent of disease in patients with known breast carcinoma. Con- trast-enhanced MRI can identify breast tumors due to their increased tumor vascularity and increased tumor cap- illary permeability. The same characteristics make it possi- ble to image lymph nodes, which are also intensely vascular and thus can be well seen on contrast-enhanced MRIs. On standard MRI of the breasts, intramammary lymph nodes can be detected as some level I lymph nodes are included in the examination. However, the entire axilla is not fully included in these images as standard breast coils often do not adequately cover this area.
Figure 5.1. Anatomy of lymph nodes within the axilla: Level I nodes are located inferior and lateral to the pectoralis minor muscle (PMM), level II nodes are located deep to the PMM, and level III nodes are superior and medial to the PMM.
Table 5.1. Five-Year Results Related to the Number of Pathologically Positive Lymph Nodes
No. of Positive Axillary No. of Survival Recurrence
Nodes Patients (%) (%)
0 12,299 72 19
1 2,012 63 33
2 1,338 62 40
3 842 59 43
4 615 52 44
5 478 47 54
6–10 1,261 41 63
11–15 562 29 72
16–20 301 29 75
⭓21 225 22 82
Source: Data from Nemoto T, et al. Management and survival of female breast cancer: results of a national survey by the American College of Surgeons. Cancer 1980;45:2915–2924.
5. Identifying Metastatic Disease
On MRI, normal lymph nodes demonstrate characteristics identical to those seen on other imaging studies: well- circumscribed, reniform masses with a fatty hilum (Figure 5.2). Precontrast T1-weighted sequences without fat saturation can often demonstrate the fatty hilum.
On T2-weighted sequences, lymph nodes have intermediate-to-high signal intensity. On postcontrast T1-weighted sequences, they show vivid homogenous enhancement or rim enhancement (Figure 5.3). Size is a nondiscriminating characteristic, as normal lymph nodes with large fatty hila can measure up to 5cm and lymph nodes containing metastatic disease are not necessarily enlarged (Figure 5.4).
Malignant lymph nodes have a more rounded contour as tumor cells grow and expand the lymph node. Eccentric enlargement of the lymph node with focal thickening of the cortex and obliteration of the fatty hilus can occur.
They typically demonstrate heterogeneous enhancement (Figure 5.5). However, if tumor has totally replaced the node, diffuse enhancement can also be seen. Lymph nodes
containing metastatic disease are still usually smoothly marginated; however, there also can be gross spiculation and irregularity due to extranodal extension (Figure 5.6).
Malignancies other than breast cancer can spread to the axillary lymph nodes. Lymphomas and leukemias can often cause massive enlargement of lymph nodes. Other common malignancies include lung, melanoma, thyroid, ovarian, and gastrointestinal tumors. These have a similar appearance on MRI to metastatic breast cancer.
Studies have attempted to further distinguish benign from malignant lymph nodes on MRI. Mumtaz et al.12 classified nodes as abnormal when they enhanced with gadolinium, their size was greater than 5mm, and their signal intensity was higher than soft tissue on short inver- sion time recovery images. With these criteria, they pro- duced a sensitivity of 90% and specificity of 82%. Kvistad et al.13used dynamic enhancement features to distinguish between normal and abnormal lymph nodes. They charac- terized lymph nodes as being pathologic when their signal intensity increases >100% during the first postcontrast image. With this threshold, they obtained a sensitivity of 83% and specificity of 90%, with an accuracy of 88%.
In another study Murray et al.14 examined lymph node enhancement using a region of interest method and calcu- lated the nodal area. With an enhancement index of >21%
and a nodal area of >0.4cm2, they achieved a sensitivity of 100%, a specificity of 56%, a positive predictive value of 38%, and a negative predictive value of 100%.
Unfortunately, other causes of nodal enlargement can present with patterns identical to that seen with malignant adenopathy. Inflammatory conditions such as rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, and sarcoidosis can cause axillary adenopathy and be indistinguishable from that found with metastatic disease.
Gallardo et al.15 demonstrated that nonmalignant lymph nodes can also rapidly enhance. Biopsy was needed to differentiate hyperplasia from malignant disease in this study.
5.1. Internal Mammary Lymph Nodes
Only a small percentage of cancers drain into the internal mammary lymph nodes. Due to their infrequent involve- ment, they are not routinely staged. In addition, studies have shown that dissection or irradiation of internal mammary nodes does not improve overall survival.16It is, however, an independent additional indicator for a worse prognosis, and therefore when suspected, sampling may be performed on select patients. On MRI, internal mammary lymph node metastasis can be identified along the internal mammary artery and vein in the intercostal space. A rela- tively recent study has shown that when they measure 5mm in diameter or more, metastatic involvement should be suspected.17
Figure 5.2. Sagittal fat-suppressed T1-weighted sequence that demonstrates a normal crescentic-shaped axillary lymph node with a fatty hilum (arrow).
A
B C
Figure 5.3. The appearance of normal lymph nodes on various sequences. (A) Sagittal non–fat-suppressed T1-weighted sequence:
intermediate-to-high signal intensity consistent with a fatty hilum.
(B) Sagittal fat-suppressed T2-weighted sequence: lymph node has intermediate-to-high signal intensity. (C) Sagittal fat-suppressed postcontrast T1-weighted sequence: homogeneous enhancement of the lymph node.
Figure 5.4. Metastatic breast carcinoma to an intramammary lymph node. Sagittal fat-suppressed postcontrast T1-weighted sequence shows a small intramammary lymph node with loss of the fatty hilum and irregular margins in this patient with known ipsilateral breast carcinoma.
A B
Figure 5.5. Example of metastatic breast carcinoma to axillary lymph nodes. (A) Sagit- tal fat-suppressed postcontrast T1-weighted sequences shows a large irregular enhancing mass (arrow) with a heterogeneously enhancing enlarged axillary lymph nodes (double arrows).
(B) Sagittal fat-suppressed postcontrast T1-weighted se- quence shows multiple irregu- lar heterogeneously enhancing masses.
Figure 5.6. Metastatic breast carcinoma with spiculated axillary adenopathy. Sagittal fat-suppressed postcontrast T1- weighted sequences show spiculated heterogenously enhancing nodes within the axilla from a patient with known ipsilateral infil- trating ductal carcinoma.
6. New Contrast Agents
Our current ability to detect small foci of metastasis to lymph nodes is somewhat limited. Recently, dextran- coated ultrasmall superparamagnetic iron oxide (USPIO) particles have been investigated as an alternative contrast agent to evaluate the lymphatic system. These are small iron oxide particles that are intravenously injected and are taken up by normal functioning lymph nodes and inflamed nodes. The macrophages of normal lymph nodes can phagocytose these particles while the lymph nodes with tumor cells are not able to incorporate them. Due to the ferromagnetic properties of iron oxide, normal lymph nodes show a signal intensity decrease on T2*- and T2- weighted sequences because of the effect of magnetic sus- ceptibility. This makes it possible to differentiate benign from malignant lymph nodes. Michel et al.18used this agent to attempt to predict the status of axillary lymph nodes with promising results, obtaining a sensitivity of 82% and specificity of 100%. Further large-scale studies with this new contrast agent will ultimately determine its role in pre- operative axillary imaging.
7. Conclusion
At present, the preferred method for detecting metastatic disease to the axilla is surgical, using identification and biopsy of the sentinel node. Contrast-enhanced MRI currently does not detect metastatic disease with enough sensitivity and specificity to obviate sentinel node biopsy.
Whether MRI will have a role in the detection of metas- tatic disease to the axilla in the future is uncertain. The need to be able to detect micrometastatic disease by an imaging modality will challenge those who are currently involved in investigation of new contrast agents.
References
1. Valagussa P, Bonadonna G, Veronesi V. Patterns of relapse and survival following radial mastectomy. Cancer 1978;41:
1170–1178.
2. Fisher B, Slack NH, Katrych D, et al. Ten-year followup results of patients with carcinoma of the breast in a coopera- tive clinical trial evaluating surgical adjuvant chemotherapy.
Surg Gynecol Obstet. 1975;140:528–534.
3. Ferguson DJ, Meier P, Karrison T, et al. Staging of breast cancer and survival rates: an assessment based on 50 years of
experience with radial mastectomy. JAMA. 1982;248: 1337–
1341.
4. Veronesi U, Rilke F, Luini A, et al. Distribution of axillary node metastases by level of invasion: an analysis of 539 cases.
Cancer 1987;59:682–687.
5. Rosen PP, Martin LL, Kinne DW, et al. Discontinuous or
“skip” metastases in breast carcinoma: analysis of 1228 axillary dissections. Ann Surg. 1983;197:276–283.
6. Hartveit F, Maehle BO, Halvorsen JF, Tangen M. On the pro- gressive nature of tumour growth in axillary nodes in breast cancer. Oncology 1983;40:309–314.
7. Fisher B, Redmond C, Fisher ER, et al. Ten-year results of randomized trial comparing radical mastecomy and total mastecomy with or without radiation. N Engl J Med. 1985;
312:674–681.
8. Giulano AE, Kirgan DM, Guenther JM, Morton DL. Lym- phatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg. 1994;220:391–401.
9. Dershaw DD, Selland DG, Tan LK, et al. Spiculated axillary adenopathy. Radiology 1996;201:439–442.
10. Adler LP, Faulhaber PF, Schnur KC, et al. Axillary lymph node metastases: screening with (F-18)2-deoxy-2-fluoro-D- Glucose (FDG) PET. Radiology 1997;203:323–327.
11. Rieber A, Schirrmeister H, Gabelmann A, et al. Preopera- tive staging of invasive breast cancer with MR mammogra- phy and/or PET: boon or bunk? Br J Radiol. 2002;75:789–798.
12. Mumtaz H, Hall-Craggs MA, Davidson D, et al. Staging of symptomatic primary breast cancer with MR imaging. AJR Am J Roentgenol. 1997;169:417–424.
13. Kvistad KA, Rydland J, Smethurst B, et al. Axillary lymph node metastases in breast cancer: preoperative detection with dynamic contrast-enhanced MRI. Eur Radiol. 2000;10:
1464–1471.
14. Murray AD, Staff RT, Redpath TW, et al. Dynamic contrasted enhanced MRI of the axilla in women with breast cancer:
comparison with pathology of excised nodes. Br J Radiol.
2002;75:220–228.
15. Gallardo X, Sensits M, Castaner E, et al. Enhancement of intramammary lymph nodes with lymphoid hyperplasia:
a potential pitfall in breast MRI. Eur Radiol. 1998;8: 1662–
1665.
16. Veronesi U, Marubini E, Mariani L, et al. The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomized trial.
Eur J Cancer. 1999;35:1320–1325.
17. Kinoshita T, Odagiri, K, Kazuo A, et al. Evaluation of small internal mammary lymph node metastases in breast cancer by MRI. Radiat Med. 1999;17:189–193.
18. Michel SC, Keller TM, Frohlich JM, et al. Preoperative breast cancer staging: MR imaging of the axilla with ultrasmall superparamagnetic iron oxide enhancement. Radiology 2002;225:527–536.
