0 Special Feature
INTERNAL MAMMARY LYMPHOSCINTIGRAPHY IN BREAST CARCINOMA: A STUDY OF 1072 PATIENTS? GCJNES Head,
Department and Assistant
N.
EGE, M.D.,
of Nuclear Professor,
F.R.C.S.,
D.M.R.T.,
F.F.R.,
F.R.C.P.(C)
Medicine,
The Princess Margaret Hospital, 500 Sherbourne Street, Toronto, Ontario, M4X 1K9, Canada Department of Radiology, University of Toronto, Ontario, Canada
Data comparable to the results of surgical excision and histological examination of internal mammary nodes can be obtained from parasternal lymphoscintigraphy. Unlike surgical extirpation, the technique is simple, can be repeated, and provides a significant, non-invasive means of individual patient assessment. Preliminary data on the prognostic implications of the abnormal lymphoscintigram indicate relevance of the technique in clinical staging of breast carcinoma and the more rational management of this disease. Parasternal
lymphoscintigraphy,
Radionuclide
lymphoscintigraphy,
INTRODUCTION Prognosis in breast carcinoma remains unaltered, despite aggressive therapeutic approaches; although related directly to the stage of disease, only axillary nodes have been readily accessible for clinical and pathological examination. Since the earlier recognition of the extent of disease will inevitably promote a more rational approach towards management, we have been evaluating radiocolloid lymphoscintigraphy as a means of examining the parasternal lymphatics. The technique, specific radiocolloid requirements, reproducibility and reliability of the method, criteria for interpretation of the lymphoscintigram and normal variability of parasternal lymphatics have been published.’ The technique consists of the bilateral subcostal injection into the posterior rectus sheath of a small volume (0.1-0.2 ml) of radiocolloid of suitable W’“Tc antimony co1loidS with a physical properties. particle size of 4-12 rnp has provided diagnostic quality scintigraphic images within 3 hr after injection. No complications have been encountered in over 3000 studies to date. Matsuo3 utilized the same technique in preoperative evaluation of 106 patients with breast carcinoma. At the time of mastectomy the ipsilateral parasternal lymphatics were removed, examined histologically, and results compared with the preoperative lymphoscintigraphic diagnosis. From these data the tThis work was supported by the Ontario Cancer Treatment and Research Foundation Grant No. 105. Acknowledgements-1 wish to acknowledge the assistance of Mrs. J. Base of the Medical Records Department, and Dr. G. DeBoer and Mrs. J. Reid of the Biostatistics Division, and express my appreciation to Dr. R. S. Bush and Dr. J. W. Meakin for their constructive comments
Carcinoma
of the breast.
author concluded that where a preoperative diagnosis of involvement was made, the Iymphoscintigram was 90% accurate, and where a preoperative diagnosis of noninvolvement was made, the lymphoscintigram was 100% accurate. In view of the similarity of criteriaemployed in interpretation of the lymphoscintigram, our data were compared with those of Matsuo (Table I). The close correlation indicated validity of the procedure in patients with breast carcinoma and prompted the present study. METHODS
AND MATERIALS
Between April 1973 and December 197.5, 1072 patients referred to The Princess Margaret Hospital (PMH) with primary or recurrent breast carcinoma Table I. Percentage abnormal internal mammary lymphoscintigram by stage of disease-a comparison between studies of the Princess Margaret Hospital and Matsuo’ Princess Margaret Hospital No. % Stage Stage Stage Stage
I II III IV
213 505 146 28
16 25 57 65
Matsuo, S.3 No. % 52 22 25 7
17 27 44 100
regarding the manuscript. I am particularly grateful to Mrs. E. Capon for her patient dedication in compiling data and in preparing the manuscript. Finally, had it not been for the foresight and perseverance of many colleagues, whom limitations of space will not allow me to acknowledge individually, this work would never have materialized. $Philips-Duphar, Petten, Holland.
156
Radiation
Oncology 0 Biology 0 Physics
underwent parasternal lymphoscintigraphy as part of their initial investigation. All patients with primary tumors were staged according to the U.I.C.C. TNM classification’ except for a small group of patients with clinical Stage I disease but histologically positive axillary nodes who were considered Stage II in order to facilitate comparison of prognostic implications of the abnormal lymphoscintigram and axillary involvement. Based on these criteria, 213 patients were considered Stage I, 505 patients Stage II, 146 patients Stage III and 28 patients Stage IV. Sixty six per cent (336/505) of Stage II patients had histologically verified axillary involvement but no distinction has been made with respect to the degree of involvement. One per cent (6/505) of Stage II patients had clinical evidence of involvement and 19% (94/505) had histologically negative axillae. No data were available regarding the axilla in 69/505 or 14% of patients. Of Stage III patients, 72% (105/146) had histologically verified axillary involvement, 16% (24/146) histologically negative axillae, and in 12% (17/146) no data were available regarding the status of the axilla. The “unstaged” patients constitute a group with either obvious or suspected recurrence as well as patients with no obvious evidence of disease, treated previously and referred for follow-up purposes only. Of the 892 patients seen with primary disease, 424 presented with disease in the right breast, and 440 with disease in the left breast; 28 patients had had bilateral carcinoma at the time of their study. The majority of patients with primary disease were seen and examined post-operatively. Parasternal lymphoscintigrams were interpreted as normal (N), suspicious (S), abnormal (A), equivocal (E), or absent (0) (Fig. 1). The (N) and (A) studies are self-explanatory and could clearly be recognized. The (S) study presents evidence of impairment of lymphatic function with slightly decreased radiocolloid uptake and a measure of asymmetry which may be characteristic of early invasion, yet also attributable to changes secondary to recent surgery. These conclusions are based on the study of a few patients in whom we had the opportunity of recording disparity
July-August 1977,Volume 2, No. 7 and No. 8 between a preoperative and postoperative lymphoscintigram (Fig. 2). In studies interpreted as (E), the small number and unusual configuration of demonstrable nodes, combined with factors relating to the patient’s habitus, such as extreme obesity or previous upper abdominal surgery, suggested the likelihood of a technically unsatisfactory examination. The (0) study was recorded when no diaphragmatic or parasternal lymphatics could be demonstrated, despite repeated injections. As total absence of parasternal lymphatics is not a recognized normal variant, this appearance may represent fibrosis and lymphoreticular obliteration, possibly related to earlier chronic illness, and has been encountered in a few patients with a past history of tuberculosis. All patients were managed according to clinical dictates, and where radiotherapy was undertaken the parasternal portals were adjusted according to treated patient’s lymphoscintigram to ensure adequate treatment of relevant structures. RESULTS Correlation of the lymphoscintigram with pathological stage of disease is illustrated in Table 2. The decrease in (N) lymphoscintigrams and increase in (A) lymphoscintigrams with advancing stage is clearly demonstrated. The incidence of (S) lymphoscintigrams in Stages I-III is fairly constant, suggesting an equal proportion of true (N) and (A) lymphoscintigrams which have been obscured by changes due to recent surgery. The (E) and (0) lymphoscintigrams constitute a very small proportion of all studies, and have been excluded from the analysis. It is interesting to note that lymphoscintigraphy in Stage IV breast carcinoma reveals only 65% abnormal studies. In the “unstaged” group, which includes a high proportion of patients with recurrence, this incidence is similarly 60%. The clinical counterpart of this observation is seen in autopsy series4 where patients dying from breast carcinoma had the highest incidence (69%) of internal mammary involvement of all patients with malignant disease, ne-
Table 2. Correlation of internal mammary lymphoscintigram with pathological staging in 1072 patients
Number
(N) Normal (S) Suspicious (A) Abnormal (E) Equivocal (0) Absent
with breast carcinoma
Stage I 213
Stage II 505
Stage III 146
Stage IV 28
% 65 16 16 1 2
% 54 17 25 2 2
% 21 19 57 1 2
% 28 7 65 0 0
Unstaged 180 % 29 9 60 2 0
Internal mammary lymphoscintigraphy
0 G. N. EGE
Fig. 1. Lymphoscintigrams: N. Discrete, symmetrical, bilateral parasternal nodes. S. Diminished radiocolloid uptake in R parasternal nodes. A. No radiocolloid uptake in upper R parasternal nodes with obvious asymmetry. E. Very faint, bilateral radiocolloid uptake. 0. No demonstrable nodes.
vertheless, some 30% of patients dying with disseminated disease had no involvement of internal mammary lymph nodes. Lymphoscintigraphic studies likewise reveal 28% and 29% normal studies in Stage IV and “unstaged” patients respectively. It would appear that after mastectomy and disruption of lymphatic pathways the parasternal lymphatics are not as readily at risk from local chest wall recurrence. Parasternal lymphoscintigram was correlated with the site of tumor in Stages I and II disease (Table 3). Tumors were designated as medial, lateral, upper (12
o’clock), subareolar and lower (6 o’clock). The percentage abnormal lymphoscintigrams is consistently higher for Stage II than Stage I but based on available figures, the difference is of borderline statistical significance (p = 0.053). Likewise, there is presently no significant correlation between site of primary tumor and abnormal lymphoscintigram. Stage III patients were not included in this analysis since these lesions were usually extensive, occupying more than one quadrant. Table 4 demonstrates data on 669 patients with
758
Radiation Oncology 0 Biology 0 Physics
July-August 1977, Volume 2, No. 7 and No. 8
Fig. 2. A. Lymphoscintigram carried out before Right mastectomy demonstrating a unilateral chain of normal nodes. B & C. 1 month after surgery-diminished radiocolloid uptake suspicious of tumor invasion. D & E. 5 months after surgery-return of normal reticuloendothelial function. Note. Reproducibility of image on three consecutive studies and unilateral parasternal nodes demonstrated by Right and Left subcostal injection of radiocolloid, a normal anatomic variant seen in 15% of studies.
Stages I-III disease and histologically involved and uninvolved axillae in whom parasternal lymphoscintigram was normal, abnormal or suspicious. It is evident that 35% of patients with axillary involvement have abnormal lymphoscintigrams but what is more significant is that 18% of patients with negative axillae may be at risk from unrecognized parasternal involvement. The poor prognosis associated with axillary involvement is well established. To identify the prog-
nostic value of the parasternal lymphoscintigram, we compared the relative risk of treatment failure in the presence of either axillary or parasternal involvement in conjunction with involvement of neither or both anatomic sites. Of 718 patients with Stages I and II disease, 439 had a clearly normal or abnormal lymphoscintigram with histological data available on the axillary nodes. Of these patients 85 (19%) had developed local recurrence or metastatic disease at the time of this review. Figures 3 and 4 illustrate respec-
Internal mammary lymphoscintigraphy
0 G. N. EGE
Table 3. Correlation of internal mammary lymphoscintigram with site of tumor in 718 patients with Stages I-II breast carcinoma Lateral
Sub-areolar and lower
Site
Medial
Stages
I
II
I
II
I
II
I
II
109
173
60
196
26
58
18
78
66 13 16 2 3
55 18 21 3 2
52 26 20 0 2
56 14 25 2 3
81 12 7 0 0
60 16 24 0 0
72 11 17 0 0
44 21 31 3 2
0
50
0
82
0
50
0
80
Total numbers (N) Normal (%) (S) Suspicious (%) (A) Abnormal (%) (E) Equivocal (%) (0) Absent (%) % Histologic axillary involvement
Table 4. Correlation of internal mammary phoscintigram with axillary histology in 669 patients Stages I-II breast carcinoma
lymwith
Upper
Stage
II
337patlents 77 recurrences
Axilla ?E m -2
Positive %
No.
; .$ ; .s 22 &P
A N
150 197
ZE 53
S
78
45 152 47
35 46 18
439
4/14
I
n 0
patlenis
I 65 6128
-1M
tAx
tAX
-1M
-IM
+ IM
+IM
-AX
tAX
-AX
+Ax
rl
I IO
-IM
53
Fig. 4. Relative risk of treatment failure associated with axillary (histologic) and parasternal (lymphoscintigraphic) findings in 337 patients with Stage II breast carcinoma.
29/90
371175
rl
7/58
19
II
85recurrences
I 427
26
37/175
18 62
244
425
StageI and
29/9c
Negative No. %
both parasternal lymphatics and the axilla as opposed to involvement of neither site is considerable and the difference significant (p values
INTERNAL MAMMARY LYMPHOSCINTIGRAPHY IN BREAST CARCINOMA: A STUDY OF 1072 PATIENTS? GCJNES Head,
Department and Assistant
N.
EGE, M.D.,
of Nuclear Professor,
F.R.C.S.,
D.M.R.T.,
F.F.R.,
F.R.C.P.(C)
Medicine,
The Princess Margaret Hospital, 500 Sherbourne Street, Toronto, Ontario, M4X 1K9, Canada Department of Radiology, University of Toronto, Ontario, Canada
Data comparable to the results of surgical excision and histological examination of internal mammary nodes can be obtained from parasternal lymphoscintigraphy. Unlike surgical extirpation, the technique is simple, can be repeated, and provides a significant, non-invasive means of individual patient assessment. Preliminary data on the prognostic implications of the abnormal lymphoscintigram indicate relevance of the technique in clinical staging of breast carcinoma and the more rational management of this disease. Parasternal
lymphoscintigraphy,
Radionuclide
lymphoscintigraphy,
INTRODUCTION Prognosis in breast carcinoma remains unaltered, despite aggressive therapeutic approaches; although related directly to the stage of disease, only axillary nodes have been readily accessible for clinical and pathological examination. Since the earlier recognition of the extent of disease will inevitably promote a more rational approach towards management, we have been evaluating radiocolloid lymphoscintigraphy as a means of examining the parasternal lymphatics. The technique, specific radiocolloid requirements, reproducibility and reliability of the method, criteria for interpretation of the lymphoscintigram and normal variability of parasternal lymphatics have been published.’ The technique consists of the bilateral subcostal injection into the posterior rectus sheath of a small volume (0.1-0.2 ml) of radiocolloid of suitable W’“Tc antimony co1loidS with a physical properties. particle size of 4-12 rnp has provided diagnostic quality scintigraphic images within 3 hr after injection. No complications have been encountered in over 3000 studies to date. Matsuo3 utilized the same technique in preoperative evaluation of 106 patients with breast carcinoma. At the time of mastectomy the ipsilateral parasternal lymphatics were removed, examined histologically, and results compared with the preoperative lymphoscintigraphic diagnosis. From these data the tThis work was supported by the Ontario Cancer Treatment and Research Foundation Grant No. 105. Acknowledgements-1 wish to acknowledge the assistance of Mrs. J. Base of the Medical Records Department, and Dr. G. DeBoer and Mrs. J. Reid of the Biostatistics Division, and express my appreciation to Dr. R. S. Bush and Dr. J. W. Meakin for their constructive comments
Carcinoma
of the breast.
author concluded that where a preoperative diagnosis of involvement was made, the Iymphoscintigram was 90% accurate, and where a preoperative diagnosis of noninvolvement was made, the lymphoscintigram was 100% accurate. In view of the similarity of criteriaemployed in interpretation of the lymphoscintigram, our data were compared with those of Matsuo (Table I). The close correlation indicated validity of the procedure in patients with breast carcinoma and prompted the present study. METHODS
AND MATERIALS
Between April 1973 and December 197.5, 1072 patients referred to The Princess Margaret Hospital (PMH) with primary or recurrent breast carcinoma Table I. Percentage abnormal internal mammary lymphoscintigram by stage of disease-a comparison between studies of the Princess Margaret Hospital and Matsuo’ Princess Margaret Hospital No. % Stage Stage Stage Stage
I II III IV
213 505 146 28
16 25 57 65
Matsuo, S.3 No. % 52 22 25 7
17 27 44 100
regarding the manuscript. I am particularly grateful to Mrs. E. Capon for her patient dedication in compiling data and in preparing the manuscript. Finally, had it not been for the foresight and perseverance of many colleagues, whom limitations of space will not allow me to acknowledge individually, this work would never have materialized. $Philips-Duphar, Petten, Holland.
156
Radiation
Oncology 0 Biology 0 Physics
underwent parasternal lymphoscintigraphy as part of their initial investigation. All patients with primary tumors were staged according to the U.I.C.C. TNM classification’ except for a small group of patients with clinical Stage I disease but histologically positive axillary nodes who were considered Stage II in order to facilitate comparison of prognostic implications of the abnormal lymphoscintigram and axillary involvement. Based on these criteria, 213 patients were considered Stage I, 505 patients Stage II, 146 patients Stage III and 28 patients Stage IV. Sixty six per cent (336/505) of Stage II patients had histologically verified axillary involvement but no distinction has been made with respect to the degree of involvement. One per cent (6/505) of Stage II patients had clinical evidence of involvement and 19% (94/505) had histologically negative axillae. No data were available regarding the axilla in 69/505 or 14% of patients. Of Stage III patients, 72% (105/146) had histologically verified axillary involvement, 16% (24/146) histologically negative axillae, and in 12% (17/146) no data were available regarding the status of the axilla. The “unstaged” patients constitute a group with either obvious or suspected recurrence as well as patients with no obvious evidence of disease, treated previously and referred for follow-up purposes only. Of the 892 patients seen with primary disease, 424 presented with disease in the right breast, and 440 with disease in the left breast; 28 patients had had bilateral carcinoma at the time of their study. The majority of patients with primary disease were seen and examined post-operatively. Parasternal lymphoscintigrams were interpreted as normal (N), suspicious (S), abnormal (A), equivocal (E), or absent (0) (Fig. 1). The (N) and (A) studies are self-explanatory and could clearly be recognized. The (S) study presents evidence of impairment of lymphatic function with slightly decreased radiocolloid uptake and a measure of asymmetry which may be characteristic of early invasion, yet also attributable to changes secondary to recent surgery. These conclusions are based on the study of a few patients in whom we had the opportunity of recording disparity
July-August 1977,Volume 2, No. 7 and No. 8 between a preoperative and postoperative lymphoscintigram (Fig. 2). In studies interpreted as (E), the small number and unusual configuration of demonstrable nodes, combined with factors relating to the patient’s habitus, such as extreme obesity or previous upper abdominal surgery, suggested the likelihood of a technically unsatisfactory examination. The (0) study was recorded when no diaphragmatic or parasternal lymphatics could be demonstrated, despite repeated injections. As total absence of parasternal lymphatics is not a recognized normal variant, this appearance may represent fibrosis and lymphoreticular obliteration, possibly related to earlier chronic illness, and has been encountered in a few patients with a past history of tuberculosis. All patients were managed according to clinical dictates, and where radiotherapy was undertaken the parasternal portals were adjusted according to treated patient’s lymphoscintigram to ensure adequate treatment of relevant structures. RESULTS Correlation of the lymphoscintigram with pathological stage of disease is illustrated in Table 2. The decrease in (N) lymphoscintigrams and increase in (A) lymphoscintigrams with advancing stage is clearly demonstrated. The incidence of (S) lymphoscintigrams in Stages I-III is fairly constant, suggesting an equal proportion of true (N) and (A) lymphoscintigrams which have been obscured by changes due to recent surgery. The (E) and (0) lymphoscintigrams constitute a very small proportion of all studies, and have been excluded from the analysis. It is interesting to note that lymphoscintigraphy in Stage IV breast carcinoma reveals only 65% abnormal studies. In the “unstaged” group, which includes a high proportion of patients with recurrence, this incidence is similarly 60%. The clinical counterpart of this observation is seen in autopsy series4 where patients dying from breast carcinoma had the highest incidence (69%) of internal mammary involvement of all patients with malignant disease, ne-
Table 2. Correlation of internal mammary lymphoscintigram with pathological staging in 1072 patients
Number
(N) Normal (S) Suspicious (A) Abnormal (E) Equivocal (0) Absent
with breast carcinoma
Stage I 213
Stage II 505
Stage III 146
Stage IV 28
% 65 16 16 1 2
% 54 17 25 2 2
% 21 19 57 1 2
% 28 7 65 0 0
Unstaged 180 % 29 9 60 2 0
Internal mammary lymphoscintigraphy
0 G. N. EGE
Fig. 1. Lymphoscintigrams: N. Discrete, symmetrical, bilateral parasternal nodes. S. Diminished radiocolloid uptake in R parasternal nodes. A. No radiocolloid uptake in upper R parasternal nodes with obvious asymmetry. E. Very faint, bilateral radiocolloid uptake. 0. No demonstrable nodes.
vertheless, some 30% of patients dying with disseminated disease had no involvement of internal mammary lymph nodes. Lymphoscintigraphic studies likewise reveal 28% and 29% normal studies in Stage IV and “unstaged” patients respectively. It would appear that after mastectomy and disruption of lymphatic pathways the parasternal lymphatics are not as readily at risk from local chest wall recurrence. Parasternal lymphoscintigram was correlated with the site of tumor in Stages I and II disease (Table 3). Tumors were designated as medial, lateral, upper (12
o’clock), subareolar and lower (6 o’clock). The percentage abnormal lymphoscintigrams is consistently higher for Stage II than Stage I but based on available figures, the difference is of borderline statistical significance (p = 0.053). Likewise, there is presently no significant correlation between site of primary tumor and abnormal lymphoscintigram. Stage III patients were not included in this analysis since these lesions were usually extensive, occupying more than one quadrant. Table 4 demonstrates data on 669 patients with
758
Radiation Oncology 0 Biology 0 Physics
July-August 1977, Volume 2, No. 7 and No. 8
Fig. 2. A. Lymphoscintigram carried out before Right mastectomy demonstrating a unilateral chain of normal nodes. B & C. 1 month after surgery-diminished radiocolloid uptake suspicious of tumor invasion. D & E. 5 months after surgery-return of normal reticuloendothelial function. Note. Reproducibility of image on three consecutive studies and unilateral parasternal nodes demonstrated by Right and Left subcostal injection of radiocolloid, a normal anatomic variant seen in 15% of studies.
Stages I-III disease and histologically involved and uninvolved axillae in whom parasternal lymphoscintigram was normal, abnormal or suspicious. It is evident that 35% of patients with axillary involvement have abnormal lymphoscintigrams but what is more significant is that 18% of patients with negative axillae may be at risk from unrecognized parasternal involvement. The poor prognosis associated with axillary involvement is well established. To identify the prog-
nostic value of the parasternal lymphoscintigram, we compared the relative risk of treatment failure in the presence of either axillary or parasternal involvement in conjunction with involvement of neither or both anatomic sites. Of 718 patients with Stages I and II disease, 439 had a clearly normal or abnormal lymphoscintigram with histological data available on the axillary nodes. Of these patients 85 (19%) had developed local recurrence or metastatic disease at the time of this review. Figures 3 and 4 illustrate respec-
Internal mammary lymphoscintigraphy
0 G. N. EGE
Table 3. Correlation of internal mammary lymphoscintigram with site of tumor in 718 patients with Stages I-II breast carcinoma Lateral
Sub-areolar and lower
Site
Medial
Stages
I
II
I
II
I
II
I
II
109
173
60
196
26
58
18
78
66 13 16 2 3
55 18 21 3 2
52 26 20 0 2
56 14 25 2 3
81 12 7 0 0
60 16 24 0 0
72 11 17 0 0
44 21 31 3 2
0
50
0
82
0
50
0
80
Total numbers (N) Normal (%) (S) Suspicious (%) (A) Abnormal (%) (E) Equivocal (%) (0) Absent (%) % Histologic axillary involvement
Table 4. Correlation of internal mammary phoscintigram with axillary histology in 669 patients Stages I-II breast carcinoma
lymwith
Upper
Stage
II
337patlents 77 recurrences
Axilla ?E m -2
Positive %
No.
; .$ ; .s 22 &P
A N
150 197
ZE 53
S
78
45 152 47
35 46 18
439
4/14
I
n 0
patlenis
I 65 6128
-1M
tAx
tAX
-1M
-IM
+ IM
+IM
-AX
tAX
-AX
+Ax
rl
I IO
-IM
53
Fig. 4. Relative risk of treatment failure associated with axillary (histologic) and parasternal (lymphoscintigraphic) findings in 337 patients with Stage II breast carcinoma.
29/90
371175
rl
7/58
19
II
85recurrences
I 427
26
37/175
18 62
244
425
StageI and
29/9c
Negative No. %
both parasternal lymphatics and the axilla as opposed to involvement of neither site is considerable and the difference significant (p values
