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Implications of lymphoscintigraphy in oncologic practice:Principles and differences vis-a-vis other imaging modalities
Implications of Lymphoscintigraphy in Oncologic Practice: Principles and Differences Vis-a-Vis Other Imaging Modalities Millard N. Croll, Luther W. Brady, and Simin Dadparvar The prompt availability of interstitial lymphoscintigraphy and its utilization offer significant advantages over other techniques. Computed tomography represents a highly sensitive technique that suffers from lack of specificity in detecting small lesions. The expense and accessibility of machine time limit its usefulness as a routine survey procedure. Radiographic lymphangiography represents a tedious and
difficult process necessitating identification of lymphatic channels for injection of the contrast material for visualization of the lymph nodes in the region being evaluated. With these demonstrated difficulties, the lymph node scanning technique has emerged as a simple, reliable, and reproducible technique for evaluation of multiple lymph node groups.
NE OF THE GREATEST difficulties fac-
reported by Sherman and Ter-Pogossian in 1953, 2 some three years after they had reported the utilization experimentally of radioactive colloidal gold in the treatment of pelvic cancer? Their report was followed by Hultborn 4 in early 1955 and by Seaman 5 several months later. The technique was not widely utilized until the excellent work of zum Winkel and Scheer from the German Cancer Research Center at Heidelberg in 1965.6 Most of the work at that time was directed toward visualization of the pelvic and periaortic lymph node chains. In 1966, Rossi 7 and Schenck s separately reported the visualization of the parasternal lymph node drainage groups. In 1968,9 the authors reported the clinical evaluation of the technique with colloidal t98Au used primarily in abdominal lymph node scanning and compared those studies with Ethiodol lymphangiograms. The authors again in 196910 reported the utilization of the technique to visualize the parasternal lymph node chains as a prognostic evaluation study in carcinoma of the breast. The following year we published a continued evaluation of the anatomy of the internal mammary lymph node scans as done with radioactive colloidal 198Au. Many publications followed, and in 1977 Ege ~2reported on the use of internal mammary lymphoscintigraphy in the evaluation of patients with carcinoma of the breast. The Ege data represented a study of 1072 patients. The study makes a major contribution since the data are comparable to the results of surgical excision and histologic examination of the internal mammary lymph node chains. Unlike surgical extirpation, the technique is simple, can be repeated, and provides a significant, noninvasive means for individual patient assessment. The data also indi-
O ing the clinician is the early detection of neoplastic involvement of inaccessible lymph nodes in patients with malignant disease. Ethiodol lymphangiography, as first described by Kinmouth, ~ has gained wide acceptance and is extremely useful in determining pelvic and retroperitoneal lymph node involvement. However, this procedure is tedious and time consuming, and its accuracy varies widely from institution to institution depending upon the skill and interest of the diagnostic radiologist. Radioactive colloidal 198Auhas been used for visualization of the pelvic and retroperitoneal lymph nodes for more than 15 yr. Visualization of the internal mammary lymph node chains with 99mTCantimony sulfide colloid is of more recent origin. Lymphoscintigraphy is a safe, reproducible and noninvasive technique utilizing radionuclides to image regional lymph node drainage systems. Current imaging techniques have evolved over the past 30 yr stimulated by the recognition of the critical relationship of lymph node metastases to ultimate prognosis in many varieties of malignant tumors. The diagnostic potential of the interstitial injection of a radioactive colloid was first From the Department of Radiation Therapy and Nuclear Medicine, The Hahnemann University, Philadelphia, PA. Supported by Grants CA-12478 and CA-12252 from the National Cancer Institute and by the Alperin Foundation. Address reprint requests to Millard N. Croll, M.D., Professor, Dept. of Radiation Therapy and Nuclear Medicine, The Hahnemann University for the Health Sciences, Philadelphia, PA 19102. 9 1983 by Grune & Stratton, Inc. 0001-2998/83/1301-0003501.00/0 4
Seminars in Nuclear Medicine, Vol. Xlll, No. 1 (January), 1983
LYMPHOSCINTIGRAPHY IN ONCOLOGY
cate that 99mTCantimony sulfide colloid, with a particle size of 4-11 m/z, has provided scintigraphic images that are of diagnostic quality within 3 hr after the injection, comparable to those earlier obtained with colloidal 198Au. In the last 6 yr, there has been a proliferation of scientific reports demonstrating various applications of lymphoscintigraphy, much of which has been directed towards visualization of the internal mammary node chains. PRINCIPLES OF LYMPHOSCINTIGRAPHY
Lymphoscintigraphyis based upon the mechanism of the transport of a radioactive colloid injected into the subcutaneous tissues. If a colloidal substance is injected intravenously, it is localized within the reticuloendothelial system of the liver, spleen and bone marrow. When radioactive colloidal compounds are injected into the intradermal or subcutaneous tissues, however, the flow is through the lymphatic channels to the regional lymph node groups. This is carried out by virtue of phagocytosis in transport as well as by direct transport through the lymphatic channels. The localization of the colloidal particles in the lymph node areas depends upon the lymph node integrity as well as the patency of the lymphatic channels. The flow of the radioactive colloidal material through the lymphatics may be blocked by lymph nodes that are invaded or replaced by tumor. If the colloidal compound is radioactive, such as 198Au colloid or a labeled colloidal compound such as 99mTcantimony sulfide colloid, these substances may be traced and imaging of their distribution may be performed. Agents for lymphatic imaging began with colloidal 198Au,and through development in the field of radiopharmaceuticals as well as instrumentation, the compound of choice at this time has emerged to be 99mTCantimony sulfide colloid. While the initial studies with this technique were performed in the iliopelvic lymph node groups, the widest use for interstitial lymphoscintigraphy has been to study the internal mammary lymphatics in patients with carcinoma of the breast. The fundamental principle relates to the physiological transport and the intralymphatic localization of interstitially injected radiocolloids. This is best demonstrated in the application of the technique to the visualization of the internal mammary lymph node groups in carcinoma of
5
the breast. The parasternal nodes are located at the anterior ends of the intercostal spaces in close proximity to the internal mammary blood vessels. Although variable in number, most of the lymph nodes are in the upper portions of the chains. Afferents are derived from the mammary gland, from the deeper structures of the anterior abdominal wall above the level of the umbilicus, from the upper surface of the liver through a small group of nodes which lie behind the xiphoid process, and from the deeper parts of the anterior portion of the thoracic wall. The parasternal lymph node chain represents a significant drainage area from the breast, and involvement of these lymph nodes with metastatic disease is of great significance clinically. Lymphoscintigrams of this area are derived by injection of the radioactive colloidal material into the posterior rectus sheath bilaterally just below the costal margin and just laterally to the xiphoid process. OTHER RELEVANT MODALITIES
Other noninvasive diagnostic imaging modalities for providing an accurate assessment of the lymphatics are limited. The earliest form of visualization, the lymphangiogram, uses radioopaque contrast material injected into the lymphatic vessels to demonstrate the normal and disrupted lymph node architecture. The study carries with it many limitations. It requires that the lymphatics be cannulated and the availability of lymph node groups which drain suitable, peripheral sites with accessible lymphatic vessels. Therefore, the internal mammary lymph node chains are relatively inaccessible to this particular technique by virtue of the paucity of suitable peripheral lymphatics for cannulization. The radiodensity differentials between the normal and abnormal lymphatics or the abnormal lymphatics and their surrounding structures are frequently not sufficient for diagnosis. The development of computer assisted tomography heralded a major advance in the study of the lymphatic systems. However, the application of this technique is limited still by the resolution of the images. Abnormalities need to be at least 1 cm in size in order to be visualized on the computed tomography scans. The computed tomography scans offer a rather precise morphological demonstration of the anatomy but unfortunately offer little in the way of physiologic information.
6
A review of the literature for comparison of lymphoscintigraphy with computed tomography and lymphangiography reveals little pertinent information. The lymphangiogram has many limitations including the difficulty in performing the study and the total inaccessibility of certain lymph node groups to the technique. Mclvor t3 has recorded that contraction of radiologically normal lymph nodes may occur after lymphangiography. He also reported enlargement of the lymph nodes during the lymphangiography procedure. In a series of patients in which lymphangiography was performed, he demonstrated that on two occasions the size of the lymph node groups could enlarge as much as 20% with a mean increase in volume of 50%. Thus, it is important to realize that there may be an increase in the lymph node size in patients as a consequence of the lymphangiographic procedure and not due to malignant disease. Brown et al. ~4 confirmed what many clinical oncologists have suspected, namely that lymphangiograms for the diagnosis of metastatic carcinoma of the cervix to periaortic lymph node groups can be unreliable. The specificity of the lymphangiographic examination is not accurate enough to be of clinical significance in the detection of these lymph node groups with metastatic disease from cervical cancer. Evaluation of computed tomography reveals different but nonetheless diagnostic discrepancies in the visualization of the lymphatic system. ~5 Since the tomographic measurement of a node looks only at two dimensions, a node enlarged and extending longitudinally may appear to be normal on the computed tomography image. Although the frequency of this discrepancy and its significance in the evaluation of metastases is not fully known, it has been observed in our institution frequently enough to warrant an investigation using both computed tomography and lymphangiography on a selected group of patients. The level of resolution of the computed tomography images also is such that microscopic areas of metastatic disease would be missed. Computed tomography looks only at the morphology, and it depends on nodal enlargement related to tumor involvement. Since it has been amply demonstrated that many nodes are infiltrated or replaced by tumor without change in size, this becomes the most serious diagnostic defect in this modality.
CROLL, BRADY, AND DADPARVAR
Some of these deficiencies can be covered by lymphoscintigraphy. The radionuclide causes no change in the size or character of the lymph nodes. Replacement of the lymph node in part or in whole by tumor will cause obstruction and subsequent abnormality in the localization of the radioactive material producing a positive result. A retrospective analysis was made, at our institution, of 871 abnormal lymph node scans performed in 757 patients. Of this group, 180 patients subsequently had lymphangiography. Table 1 is a comparison of the ethiodol lymphangiographic results with those of colloidal 198Auin lymph node scanning. It is evident that the number of patients with negative lymph node scans who underwent lymphangiography is quite small. The best correlation between the two studies is in the group of patients with lymphomas and Hodgkin's disease who had positive lymph node scans. More meaningful, however, is Table 2, in which colloidal t98Au lymph node scanning is compared to the results of lymph node biopsies obtained from one or more visualized areas. Again, it is quite evident that the number of patients with negative lymph node scans who underwent biopsy procedures is quite small. Good correlation is seen in the group of patients with lymphoma and Hodgkin's disease who had positive lymph node scans, with an accuracy rate of 88%. A very poor correlation is seen in the group of patients with the established diagnosis of carcinoma of the cervix between the positive lymph node scan and biopsy results. This is believed to be related to the large number of patients who had inflammatory or hyperplastic Table 1. Lymph Scan Versus Lymphangiogram Lymphoma Positive lymph scan Positive lymphangiogram Positive lymph scan Negative lymphangiogram Percent agreement with positive scans Negative lymph scan Negative lymphangiogram Negative lymph scan Positive lymphangiogram Percent agreement with negative scans Total patients
Cervix Other Total
65
18
28
111
16
10
14
40
80% 11
64% 5
66% 4
74% 20
6
0
3
9
64% 98
100% 33
57% 49
68% 180
LYMPHOSCINTIGRAPHY IN ONCOLOGY
7
Table 2. Lymph Scan Versus Lymph Node Biopsy Lyrnphoma Positive lymph scan Positive biopsy Positive lymph scan Negative biopsy Percent agreement with positive scan Negative scan Negative biopsy Negative scan Positive biopsy Percent agreement with negative scans Total patients
Cervix Others Total
57
23
43
123
8
25
16
49
88% 4
48% 10
73% 7
72% 21
3
1
3
7
57% 72
91% 59
70% 69
85% 200
changes in the primary lymph node groups. In the heterogenous group designated as "others" there is a 70% accuracy in the positive scan group and 70% accuracy if the scan is negative. Both radioactive colloidal lymph node scanning and lymphangiographic procedures have deficiencies. Information concerning the size and internal abnormality of the lymph nodes is often not obtained with the radioisotope procedure. This information may be necessary when defining a radiation therapy field or when contemplating a lymph node dissection. Isotopic studies are quite useful in patients with lymphoma and Hodgkin's disease as an aid in the interpretation of the all-too-frequent equivocal lymphangiogram. A suspicious area on the lymphangiographic study may show as a very notable obstruction on the colloid study. The colloid study must be performed prior to the Ethiodol lymphangiogram since reactive changes in the lymph nodes from the ethiodol lymphangiogram are sufficient to cause a positive isotopic study. Repeat lymph node scans are also useful in following patients with lymphoma or Hodgkin's disease after radiation therapy because the study can be repeated without difficulty. In patients with other malignant diseases in whom lymphangiography is contraindicated because of sensitivity to iodine or marked pulmonary disease, useful information can be obtained with the radioactive lymph node scan. We have found this study to be quite reproducible, and changes from a baseline study invariably signify progressive disease. We continue to have enthusiasm for t h e radioactive colloidal lymph node scans and find them to be useful adjuncts to lymphangiography
in patients with lymphoma and Hodgkin's disease where evaluation of the pelvic and periaortic lymph node groups plays an important part in the evaluation of the patient as well as in those individuals who have contraindications to lymphangiography. The utilization of the radioactive colloidal compounds in the evaluation of the status of clinically inaccessible parasternal lymph nodes is essential. This particular study using radiocolloids in evaluation of the parasternal lymph node groups would be helpful not only in the better selection of early cases for definitive treatment but might eliminate unnecessary operations for the unsuitable patient. It would also shed some light on the prognosis of the patient at the time of presentation for treatment. The technique for evaluation of the parasternal lymph node groups is now well established as has been demonstrated by Kazem et al. 9'1~ and Ege. ~2 For the interpretation of the parasternal lymph node scan, one should be aware of the typical normal pattern as well as the atypical normal anatomic variations. There are conflicting reports in the literature about existence of communicating collaterals between contralateral parasternal lymph node groups. Hultborn et al. 4 demonstrated radioactivity accumulation in the parasternal lymph nodes on the same side after the injection of 198Aucolloid in the breast substance. But they were unable to detect any localized uptake in the contralateral parasternal regions, Turner-Warwick, ~6 utilizing a similar technique, reported no significant drainage of lymph from the breast to the contralateral nodes under normal conditions. Trivellini et al. 17 conducted similar experiments and concluded that their results demonstrated beyond doubt the drainage of the breast to the contralateral lymph node groups. This view was confirmed by Schenck et al. 8 We have demonstrated on occasion communicating collaterals between contralateral parasternal lymph node groups. Another anatomic variation is the complete fusion of the two parasternal chains into one single tract. This solitary channel may be centrally located behind the sternum or placed on either side of the sternum. Pathologic lymph nodes fail to pick up the radioactive colloidal compounds and are thus poorly visualized or not at all. Also, obstruction of the lymphatics delays or halts the flow of the
8
CROLL, BRADY, AND DADPARVAR
activity in the normal direction. If the obstruction is of some duration, retrograde collaterals as well as alternative connecting channels are visualized with the activity that gains access to these routes. Extensive parasternal lymph node metastases therefore block and flow of activity in one or both sides. The injected activity visualizes at the site of the injection or possibly, if the collaterals are patent, in the axillary or pectoral nodes or in the hepatic area or the anterior abdominal wall. The technique of the parasternal lymph node scan allows for interpretation of the normal and abnormal patterns. The test is simple, painless, and safe; and its reliability does help in the better selection of suitable causes for definitive treatment techniques directed toward the breast as well as identifying prognosis factors that would be important in the patient's ultimate course. In areas of aggressive treatment techniques, lymph node scanning offers multiple advantages,
the most important of which is the identification of abnormalities in the lymph node groups due to dissemination of the malignant disease that would have significant impact upon ultimate prognosis. The identification of abnormalities within the lymph nodes draining a particular tumor allows for the derivation of more aggressive treatment programs which will result in an improved potential for survival. The technique of lymph node visualization also offers the opportunity for repetitive studies done for evaluation of the patient in follow-up offering earlier evidence of recurrence of disease than can be achieved by many of the diagnostic techniques available at this time. Therefore, the technique for the visualization of the lymph groups using radioactive colloidal compounds has taken its place as an important adjunct in the diagnostic evaluation of patients with malignant disease as well as the follow-up evaluation of patients after treatment.
REFERENCES
1. Kinmouth JB: Lymphangiography in man; method outlining lymphatic trunks at operation. Clin Sci 11:13-20, 1952 2. Sherman AI, Ter-Pogossian M: Lymph node concentration of radioactive colloidal gold following interstitial injection. Cancer 6:1238-1240, 1953 3. Sherman AI, Nolan JF, Allen WM: The experimental application of radioactive colloidal gold in the treatment of pelvic cancer. Am J Roentgen 64:75-85, 1950 4. Hultborn KA, Larsson LG, Ragnhult I: The lymph drainage from the breast to the axillary and parasternal lymph nodes, studied with the aid of colloidal Au-198. Acta Radiol 43:52~4, 1955 5. Seaman WB, Powers WE: Studies on the distribution of radioactive colloidal gold in regional lymph nodes containing cancer. Cancer 8:1044-1046, 1955 6. zum Winkel K, Scheer KE: Scintigraphic and dynamic studies of the lymphatic system with radio-colloids. Minerva Nucl 9:390-398, 1965 7. Rossi R, Ferro O: La visualizzazione della catena mammaria interna con 198Au. Presentazione di una nuova metodica: la linfoscintigrafia. Minerva Med 57:1151-1155, 1966 8. Schenck P: Scintigraphische DarsteUung des parasternalen Lymphysystems. Strahlentherapie 130:504-508, 1966 9. Kazem I, Antoniades J, Brady LW, et al: Clinical
evaluation of lymph node scanning utilizing colloidal goldo 198. Radiology 90:905-911, 1968 10. Kazem I, Brady LW, Croll MN et al: The parasternal lymph node scan as a prognostic test in breast carcinoma. Radiology 92:617-620, 1969 11. Kazem I, Brady LW, Croll MN: The living anatomy of parasternal lymph nodes as seen on the 19Smu Scan. Radioaktive Isotope in Klinik und Forschung, in Vortr~ige am Gasteiner lnternationalen Symposion Brand IX, Urban & Schwartzenberg. Miinchen-Berlin-Wien, 1970, 399-404 12. Ege G: Internal mammary lymphoscintigraphy in breast carcinoma: a study of 1072 patients. Int J Radiat Oncol Biol Phys 2:755-761, 1977 13. Mclvor J: Changes in lymph node size induced by lymphography. Clin Radiol 31:541-544, 1980 14. Brown RC, Buchsbaum H J, Tewfik HH, et al: Accuracy of lymphangiography in the diagnosis of paraaortic lymph node metastases from carcinoma of the cervix. Obstet Gynecol 54:571-575, 1979 15. Haskin P: Personal communication 16. Turner-Warwick RT: The lymphatics of the breast. Br J Surg 46:574-582, 1959 17. Trivellini A, Rossi R: Scintigraphic technique to evaluate the lymphatic drainage of normal and neoplastic breast. Acta Un Int Cancr 20:1834-1835, 1964
difficult process necessitating identification of lymphatic channels for injection of the contrast material for visualization of the lymph nodes in the region being evaluated. With these demonstrated difficulties, the lymph node scanning technique has emerged as a simple, reliable, and reproducible technique for evaluation of multiple lymph node groups.
NE OF THE GREATEST difficulties fac-
reported by Sherman and Ter-Pogossian in 1953, 2 some three years after they had reported the utilization experimentally of radioactive colloidal gold in the treatment of pelvic cancer? Their report was followed by Hultborn 4 in early 1955 and by Seaman 5 several months later. The technique was not widely utilized until the excellent work of zum Winkel and Scheer from the German Cancer Research Center at Heidelberg in 1965.6 Most of the work at that time was directed toward visualization of the pelvic and periaortic lymph node chains. In 1966, Rossi 7 and Schenck s separately reported the visualization of the parasternal lymph node drainage groups. In 1968,9 the authors reported the clinical evaluation of the technique with colloidal t98Au used primarily in abdominal lymph node scanning and compared those studies with Ethiodol lymphangiograms. The authors again in 196910 reported the utilization of the technique to visualize the parasternal lymph node chains as a prognostic evaluation study in carcinoma of the breast. The following year we published a continued evaluation of the anatomy of the internal mammary lymph node scans as done with radioactive colloidal 198Au. Many publications followed, and in 1977 Ege ~2reported on the use of internal mammary lymphoscintigraphy in the evaluation of patients with carcinoma of the breast. The Ege data represented a study of 1072 patients. The study makes a major contribution since the data are comparable to the results of surgical excision and histologic examination of the internal mammary lymph node chains. Unlike surgical extirpation, the technique is simple, can be repeated, and provides a significant, noninvasive means for individual patient assessment. The data also indi-
O ing the clinician is the early detection of neoplastic involvement of inaccessible lymph nodes in patients with malignant disease. Ethiodol lymphangiography, as first described by Kinmouth, ~ has gained wide acceptance and is extremely useful in determining pelvic and retroperitoneal lymph node involvement. However, this procedure is tedious and time consuming, and its accuracy varies widely from institution to institution depending upon the skill and interest of the diagnostic radiologist. Radioactive colloidal 198Auhas been used for visualization of the pelvic and retroperitoneal lymph nodes for more than 15 yr. Visualization of the internal mammary lymph node chains with 99mTCantimony sulfide colloid is of more recent origin. Lymphoscintigraphy is a safe, reproducible and noninvasive technique utilizing radionuclides to image regional lymph node drainage systems. Current imaging techniques have evolved over the past 30 yr stimulated by the recognition of the critical relationship of lymph node metastases to ultimate prognosis in many varieties of malignant tumors. The diagnostic potential of the interstitial injection of a radioactive colloid was first From the Department of Radiation Therapy and Nuclear Medicine, The Hahnemann University, Philadelphia, PA. Supported by Grants CA-12478 and CA-12252 from the National Cancer Institute and by the Alperin Foundation. Address reprint requests to Millard N. Croll, M.D., Professor, Dept. of Radiation Therapy and Nuclear Medicine, The Hahnemann University for the Health Sciences, Philadelphia, PA 19102. 9 1983 by Grune & Stratton, Inc. 0001-2998/83/1301-0003501.00/0 4
Seminars in Nuclear Medicine, Vol. Xlll, No. 1 (January), 1983
LYMPHOSCINTIGRAPHY IN ONCOLOGY
cate that 99mTCantimony sulfide colloid, with a particle size of 4-11 m/z, has provided scintigraphic images that are of diagnostic quality within 3 hr after the injection, comparable to those earlier obtained with colloidal 198Au. In the last 6 yr, there has been a proliferation of scientific reports demonstrating various applications of lymphoscintigraphy, much of which has been directed towards visualization of the internal mammary node chains. PRINCIPLES OF LYMPHOSCINTIGRAPHY
Lymphoscintigraphyis based upon the mechanism of the transport of a radioactive colloid injected into the subcutaneous tissues. If a colloidal substance is injected intravenously, it is localized within the reticuloendothelial system of the liver, spleen and bone marrow. When radioactive colloidal compounds are injected into the intradermal or subcutaneous tissues, however, the flow is through the lymphatic channels to the regional lymph node groups. This is carried out by virtue of phagocytosis in transport as well as by direct transport through the lymphatic channels. The localization of the colloidal particles in the lymph node areas depends upon the lymph node integrity as well as the patency of the lymphatic channels. The flow of the radioactive colloidal material through the lymphatics may be blocked by lymph nodes that are invaded or replaced by tumor. If the colloidal compound is radioactive, such as 198Au colloid or a labeled colloidal compound such as 99mTcantimony sulfide colloid, these substances may be traced and imaging of their distribution may be performed. Agents for lymphatic imaging began with colloidal 198Au,and through development in the field of radiopharmaceuticals as well as instrumentation, the compound of choice at this time has emerged to be 99mTCantimony sulfide colloid. While the initial studies with this technique were performed in the iliopelvic lymph node groups, the widest use for interstitial lymphoscintigraphy has been to study the internal mammary lymphatics in patients with carcinoma of the breast. The fundamental principle relates to the physiological transport and the intralymphatic localization of interstitially injected radiocolloids. This is best demonstrated in the application of the technique to the visualization of the internal mammary lymph node groups in carcinoma of
5
the breast. The parasternal nodes are located at the anterior ends of the intercostal spaces in close proximity to the internal mammary blood vessels. Although variable in number, most of the lymph nodes are in the upper portions of the chains. Afferents are derived from the mammary gland, from the deeper structures of the anterior abdominal wall above the level of the umbilicus, from the upper surface of the liver through a small group of nodes which lie behind the xiphoid process, and from the deeper parts of the anterior portion of the thoracic wall. The parasternal lymph node chain represents a significant drainage area from the breast, and involvement of these lymph nodes with metastatic disease is of great significance clinically. Lymphoscintigrams of this area are derived by injection of the radioactive colloidal material into the posterior rectus sheath bilaterally just below the costal margin and just laterally to the xiphoid process. OTHER RELEVANT MODALITIES
Other noninvasive diagnostic imaging modalities for providing an accurate assessment of the lymphatics are limited. The earliest form of visualization, the lymphangiogram, uses radioopaque contrast material injected into the lymphatic vessels to demonstrate the normal and disrupted lymph node architecture. The study carries with it many limitations. It requires that the lymphatics be cannulated and the availability of lymph node groups which drain suitable, peripheral sites with accessible lymphatic vessels. Therefore, the internal mammary lymph node chains are relatively inaccessible to this particular technique by virtue of the paucity of suitable peripheral lymphatics for cannulization. The radiodensity differentials between the normal and abnormal lymphatics or the abnormal lymphatics and their surrounding structures are frequently not sufficient for diagnosis. The development of computer assisted tomography heralded a major advance in the study of the lymphatic systems. However, the application of this technique is limited still by the resolution of the images. Abnormalities need to be at least 1 cm in size in order to be visualized on the computed tomography scans. The computed tomography scans offer a rather precise morphological demonstration of the anatomy but unfortunately offer little in the way of physiologic information.
6
A review of the literature for comparison of lymphoscintigraphy with computed tomography and lymphangiography reveals little pertinent information. The lymphangiogram has many limitations including the difficulty in performing the study and the total inaccessibility of certain lymph node groups to the technique. Mclvor t3 has recorded that contraction of radiologically normal lymph nodes may occur after lymphangiography. He also reported enlargement of the lymph nodes during the lymphangiography procedure. In a series of patients in which lymphangiography was performed, he demonstrated that on two occasions the size of the lymph node groups could enlarge as much as 20% with a mean increase in volume of 50%. Thus, it is important to realize that there may be an increase in the lymph node size in patients as a consequence of the lymphangiographic procedure and not due to malignant disease. Brown et al. ~4 confirmed what many clinical oncologists have suspected, namely that lymphangiograms for the diagnosis of metastatic carcinoma of the cervix to periaortic lymph node groups can be unreliable. The specificity of the lymphangiographic examination is not accurate enough to be of clinical significance in the detection of these lymph node groups with metastatic disease from cervical cancer. Evaluation of computed tomography reveals different but nonetheless diagnostic discrepancies in the visualization of the lymphatic system. ~5 Since the tomographic measurement of a node looks only at two dimensions, a node enlarged and extending longitudinally may appear to be normal on the computed tomography image. Although the frequency of this discrepancy and its significance in the evaluation of metastases is not fully known, it has been observed in our institution frequently enough to warrant an investigation using both computed tomography and lymphangiography on a selected group of patients. The level of resolution of the computed tomography images also is such that microscopic areas of metastatic disease would be missed. Computed tomography looks only at the morphology, and it depends on nodal enlargement related to tumor involvement. Since it has been amply demonstrated that many nodes are infiltrated or replaced by tumor without change in size, this becomes the most serious diagnostic defect in this modality.
CROLL, BRADY, AND DADPARVAR
Some of these deficiencies can be covered by lymphoscintigraphy. The radionuclide causes no change in the size or character of the lymph nodes. Replacement of the lymph node in part or in whole by tumor will cause obstruction and subsequent abnormality in the localization of the radioactive material producing a positive result. A retrospective analysis was made, at our institution, of 871 abnormal lymph node scans performed in 757 patients. Of this group, 180 patients subsequently had lymphangiography. Table 1 is a comparison of the ethiodol lymphangiographic results with those of colloidal 198Auin lymph node scanning. It is evident that the number of patients with negative lymph node scans who underwent lymphangiography is quite small. The best correlation between the two studies is in the group of patients with lymphomas and Hodgkin's disease who had positive lymph node scans. More meaningful, however, is Table 2, in which colloidal t98Au lymph node scanning is compared to the results of lymph node biopsies obtained from one or more visualized areas. Again, it is quite evident that the number of patients with negative lymph node scans who underwent biopsy procedures is quite small. Good correlation is seen in the group of patients with lymphoma and Hodgkin's disease who had positive lymph node scans, with an accuracy rate of 88%. A very poor correlation is seen in the group of patients with the established diagnosis of carcinoma of the cervix between the positive lymph node scan and biopsy results. This is believed to be related to the large number of patients who had inflammatory or hyperplastic Table 1. Lymph Scan Versus Lymphangiogram Lymphoma Positive lymph scan Positive lymphangiogram Positive lymph scan Negative lymphangiogram Percent agreement with positive scans Negative lymph scan Negative lymphangiogram Negative lymph scan Positive lymphangiogram Percent agreement with negative scans Total patients
Cervix Other Total
65
18
28
111
16
10
14
40
80% 11
64% 5
66% 4
74% 20
6
0
3
9
64% 98
100% 33
57% 49
68% 180
LYMPHOSCINTIGRAPHY IN ONCOLOGY
7
Table 2. Lymph Scan Versus Lymph Node Biopsy Lyrnphoma Positive lymph scan Positive biopsy Positive lymph scan Negative biopsy Percent agreement with positive scan Negative scan Negative biopsy Negative scan Positive biopsy Percent agreement with negative scans Total patients
Cervix Others Total
57
23
43
123
8
25
16
49
88% 4
48% 10
73% 7
72% 21
3
1
3
7
57% 72
91% 59
70% 69
85% 200
changes in the primary lymph node groups. In the heterogenous group designated as "others" there is a 70% accuracy in the positive scan group and 70% accuracy if the scan is negative. Both radioactive colloidal lymph node scanning and lymphangiographic procedures have deficiencies. Information concerning the size and internal abnormality of the lymph nodes is often not obtained with the radioisotope procedure. This information may be necessary when defining a radiation therapy field or when contemplating a lymph node dissection. Isotopic studies are quite useful in patients with lymphoma and Hodgkin's disease as an aid in the interpretation of the all-too-frequent equivocal lymphangiogram. A suspicious area on the lymphangiographic study may show as a very notable obstruction on the colloid study. The colloid study must be performed prior to the Ethiodol lymphangiogram since reactive changes in the lymph nodes from the ethiodol lymphangiogram are sufficient to cause a positive isotopic study. Repeat lymph node scans are also useful in following patients with lymphoma or Hodgkin's disease after radiation therapy because the study can be repeated without difficulty. In patients with other malignant diseases in whom lymphangiography is contraindicated because of sensitivity to iodine or marked pulmonary disease, useful information can be obtained with the radioactive lymph node scan. We have found this study to be quite reproducible, and changes from a baseline study invariably signify progressive disease. We continue to have enthusiasm for t h e radioactive colloidal lymph node scans and find them to be useful adjuncts to lymphangiography
in patients with lymphoma and Hodgkin's disease where evaluation of the pelvic and periaortic lymph node groups plays an important part in the evaluation of the patient as well as in those individuals who have contraindications to lymphangiography. The utilization of the radioactive colloidal compounds in the evaluation of the status of clinically inaccessible parasternal lymph nodes is essential. This particular study using radiocolloids in evaluation of the parasternal lymph node groups would be helpful not only in the better selection of early cases for definitive treatment but might eliminate unnecessary operations for the unsuitable patient. It would also shed some light on the prognosis of the patient at the time of presentation for treatment. The technique for evaluation of the parasternal lymph node groups is now well established as has been demonstrated by Kazem et al. 9'1~ and Ege. ~2 For the interpretation of the parasternal lymph node scan, one should be aware of the typical normal pattern as well as the atypical normal anatomic variations. There are conflicting reports in the literature about existence of communicating collaterals between contralateral parasternal lymph node groups. Hultborn et al. 4 demonstrated radioactivity accumulation in the parasternal lymph nodes on the same side after the injection of 198Aucolloid in the breast substance. But they were unable to detect any localized uptake in the contralateral parasternal regions, Turner-Warwick, ~6 utilizing a similar technique, reported no significant drainage of lymph from the breast to the contralateral nodes under normal conditions. Trivellini et al. 17 conducted similar experiments and concluded that their results demonstrated beyond doubt the drainage of the breast to the contralateral lymph node groups. This view was confirmed by Schenck et al. 8 We have demonstrated on occasion communicating collaterals between contralateral parasternal lymph node groups. Another anatomic variation is the complete fusion of the two parasternal chains into one single tract. This solitary channel may be centrally located behind the sternum or placed on either side of the sternum. Pathologic lymph nodes fail to pick up the radioactive colloidal compounds and are thus poorly visualized or not at all. Also, obstruction of the lymphatics delays or halts the flow of the
8
CROLL, BRADY, AND DADPARVAR
activity in the normal direction. If the obstruction is of some duration, retrograde collaterals as well as alternative connecting channels are visualized with the activity that gains access to these routes. Extensive parasternal lymph node metastases therefore block and flow of activity in one or both sides. The injected activity visualizes at the site of the injection or possibly, if the collaterals are patent, in the axillary or pectoral nodes or in the hepatic area or the anterior abdominal wall. The technique of the parasternal lymph node scan allows for interpretation of the normal and abnormal patterns. The test is simple, painless, and safe; and its reliability does help in the better selection of suitable causes for definitive treatment techniques directed toward the breast as well as identifying prognosis factors that would be important in the patient's ultimate course. In areas of aggressive treatment techniques, lymph node scanning offers multiple advantages,
the most important of which is the identification of abnormalities in the lymph node groups due to dissemination of the malignant disease that would have significant impact upon ultimate prognosis. The identification of abnormalities within the lymph nodes draining a particular tumor allows for the derivation of more aggressive treatment programs which will result in an improved potential for survival. The technique of lymph node visualization also offers the opportunity for repetitive studies done for evaluation of the patient in follow-up offering earlier evidence of recurrence of disease than can be achieved by many of the diagnostic techniques available at this time. Therefore, the technique for the visualization of the lymph groups using radioactive colloidal compounds has taken its place as an important adjunct in the diagnostic evaluation of patients with malignant disease as well as the follow-up evaluation of patients after treatment.
REFERENCES
1. Kinmouth JB: Lymphangiography in man; method outlining lymphatic trunks at operation. Clin Sci 11:13-20, 1952 2. Sherman AI, Ter-Pogossian M: Lymph node concentration of radioactive colloidal gold following interstitial injection. Cancer 6:1238-1240, 1953 3. Sherman AI, Nolan JF, Allen WM: The experimental application of radioactive colloidal gold in the treatment of pelvic cancer. Am J Roentgen 64:75-85, 1950 4. Hultborn KA, Larsson LG, Ragnhult I: The lymph drainage from the breast to the axillary and parasternal lymph nodes, studied with the aid of colloidal Au-198. Acta Radiol 43:52~4, 1955 5. Seaman WB, Powers WE: Studies on the distribution of radioactive colloidal gold in regional lymph nodes containing cancer. Cancer 8:1044-1046, 1955 6. zum Winkel K, Scheer KE: Scintigraphic and dynamic studies of the lymphatic system with radio-colloids. Minerva Nucl 9:390-398, 1965 7. Rossi R, Ferro O: La visualizzazione della catena mammaria interna con 198Au. Presentazione di una nuova metodica: la linfoscintigrafia. Minerva Med 57:1151-1155, 1966 8. Schenck P: Scintigraphische DarsteUung des parasternalen Lymphysystems. Strahlentherapie 130:504-508, 1966 9. Kazem I, Antoniades J, Brady LW, et al: Clinical
evaluation of lymph node scanning utilizing colloidal goldo 198. Radiology 90:905-911, 1968 10. Kazem I, Brady LW, Croll MN et al: The parasternal lymph node scan as a prognostic test in breast carcinoma. Radiology 92:617-620, 1969 11. Kazem I, Brady LW, Croll MN: The living anatomy of parasternal lymph nodes as seen on the 19Smu Scan. Radioaktive Isotope in Klinik und Forschung, in Vortr~ige am Gasteiner lnternationalen Symposion Brand IX, Urban & Schwartzenberg. Miinchen-Berlin-Wien, 1970, 399-404 12. Ege G: Internal mammary lymphoscintigraphy in breast carcinoma: a study of 1072 patients. Int J Radiat Oncol Biol Phys 2:755-761, 1977 13. Mclvor J: Changes in lymph node size induced by lymphography. Clin Radiol 31:541-544, 1980 14. Brown RC, Buchsbaum H J, Tewfik HH, et al: Accuracy of lymphangiography in the diagnosis of paraaortic lymph node metastases from carcinoma of the cervix. Obstet Gynecol 54:571-575, 1979 15. Haskin P: Personal communication 16. Turner-Warwick RT: The lymphatics of the breast. Br J Surg 46:574-582, 1959 17. Trivellini A, Rossi R: Scintigraphic technique to evaluate the lymphatic drainage of normal and neoplastic breast. Acta Un Int Cancr 20:1834-1835, 1964