Japanese Journal of Clinical Oncology

Introduction

Metastasis to regional lymph nodes is an excellent determinant of the prognosis of breast cancer and is therefore an important factor in making decisions regarding postoperative adjuvant therapy.

The prognosis has been reported to vary according to the location of lymph node metastasis (location number) (1) as described in the General Rules for Clinical and Pathological Recording of Breast Cancer, produced by the Japanese Breast Cancer Society (2). It is also said that the greater the number of positive nodes, the poorer is the prognosis (3-7). On the other hand, some authors are of the opinion that dissection of the axillary nodes should not be carried out, even when treating infiltrating cancer, in order to avoid additional surgical stress (8-10). This has created great changes in the recognition of the importance of lymph node metastasis in breast cancer. However, lymph node dissection is currently a standard procedure in Japan, partly because surgery is aimed at radical clearance and partly so that information on the status of the regional lymph nodes (8,11,12) can be obtained, thus improving the accuracy with which prognoses can be predicted. With this in mind, to determine whether the number of positive lymph nodes or the location number would provide a more accurate basis for the prediction of prognoses, we compared the survival rates of 3922 patients with primary breast cancer in relation to the location of lymph node metastasis and the number of positive lymph nodes.

Patients and Methods

From all the patients with primary infiltrating breast cancer who underwent surgery combined with lymph node dissection up to level III including Rotter's nodes between 1946 and 1980, 3922 patients with n0 to n2 metastasis, excluding those with bilateral or multiple carcinomas, were selected for the present study. According to the General Rules for Clinical and Pathological Recording of Breast Cancer (2), the location number varies depending on the location of the primary focus in patients with positive parasternal lymph nodes. To avoid this complexity, patients with metastasis of the parasternal lymph nodes were excluded. Thus, in the present study, patients with three or fewer positive axillary lymph nodes were categorized as n1[alpha], those with four or more positive axillary lymph nodes as n1[beta] and those with one or more positive subclavicular lymph nodes as n2.

Table 1. Patients' characteristics: age, tumor size and histological type

Average age (years)	44.8 (range 24-89)
T:
T1	1426 cases
T2	1995
T3	253
T4	191
T0	57
Histological type:
a1; papillotubular	976 cases
a2; solid-tubular	762
a3; scirrhous	1835
b; special types	349

To examine the validity of the location number, survival rates calculated in relation to the location number and the number of positive lymph nodes were compared. Differences in survival were also analyzed in relation to the number of positive lymph nodes within the same location number. Survival rates were calculated by the Kaplan-Meier method and analyzed using the log rank test. Differences were regarded as statistically significant if the p value was <0.05.

Results

Tables 1 and 1 shows the background of the 3922 patients. Their mean age was 48.8 years (range 24-89 years). There were 2156 n0 patients, 1032 n1[alpha] patients, 285 n1[beta] patients and 449 n2 patients. The number of positive lymph nodes was 0 in 2156 patients, 1 in 597, 2 in 312, 3 in 186, 4 in 138, 5 in 77, 6 in 62, 7 in 46, 8 in 44, 9 in 51 and [ge]10 in 253. The clinical classification of the tumor size was T1 in 1426 patients, T2 in 1995, T3 in 253, T4 in 191 and T0 in 57. Histological analysis revealed 976 papillotubular carcinomas (a1), 764 solid-tubular carcinomas (a2), 1835 scirrhous carcinomas (a3),140 mucinous carcinomas (b1), 79 medullary carcinomas (b2), 117 invasive lobular carcinomas (b3), one adenoid cystic carcinoma (b4), seven squamous cell carcinomas (b5), three spindle cell carcinomas (b6) and two carcinomas with cartilaginous and/or osseous metaplasia (b8). Lymphatic permeation (ly) was rated as ly- in 3721 patients, ly+ in 160 and ly++ or more severe in 41. Fat infiltration (f) was f- in 3128 patients, f+ in 764 and f++ or more severe in 30.

As shown in Fig. 1, the 10-year survival rate based on the location number was 83.7% for n0 patients, 69.1% for n1[alpha] patients, 42.4% for n1[beta] patients and 28.8% for n2 patients, showing significant differences between the four grades (P < 0.0001). A comparison of survival rates in subgroups classified by the number of positive nodes revealed a significant difference between no and one(P < 0.0001), two and three (P = 0.0019) and nine and 10 (P = 0.0344) positive nodes. This means that the difference between two and three positive nodes had a greater impact on survival than that between three and four positive nodes, i.e. the current boundary between n1[alpha] and n1[beta].

Figure 1. Overall survivals of each subgroup categorized by location number (n0, n1[alpha], n1[beta] and n2). The 10-year survival rate based on the location number was showing significant differences between the four groups (P < 0.0001), 83.7% for n0, 69.1% for n1[alpha], 42.4% for n1[beta] and 28.8% for n2 patients).

Among 1032 patients with n1[alpha] metastasis, there was a significant difference (P < 0.0001) in survival between those with one positive node (582 cases) and those with three positive nodes (157 cases), while no such difference was found between those with one positive node and those with two (293 cases). Thus, patients with one or two positive nodes were distinguishable from those with three within the n1[alpha] group (Fig. 2).

Figure 2. Overall survivals of n1[alpha] patients according to the number of positive nodes. Within n1[alpha], there was a significant difference (P < 0.0001) in survival between those with one positive node (582 cases) and those with three positive nodes (157 cases), while no such difference was found between those with one positive node and those with two positive nodes (293 cases).

Among patients at stage n1[beta], there was no significant difference (P = 0.4623) in survival between those with four positive nodes (105 patients) and those with [ge]7 positive nodes (86 patients), indicating that patients in those two groups follow similar survival curves (Fig. 3). There was a significant difference (P = 0.0091) in survival between patients with three positive nodes at stage n1[alpha] (157patients) and those with [ge]7 positive nodes at stage n1[beta] (86 patients) (Fig. 4). Therefore, the presence of three positive nodes has a different meaning from that of one or two positive nodes in survival terms, but is not equivalent to n1[beta].

Figure 3. Overall survivals according to the number of positive nodes in n1[beta] patients. Among n1[beta] patients, there was no significant difference (P = 0.4623) in survival between those with four positive nodes (105 patients) and those with seven or more positive nodes (86 patients).

Figure 4. Overall survivials in n1[alpha] patients with three positive nodes and n1[beta] with seven or more nodes. There was a significant difference (P = 0.0091) in survival between patients with three positive nodes at stage n1[alpha] (157 patients) and those with seven or more positive nodes at stage n1[beta] (86 patients).

What distinguishes n1[beta] from n2 is not the number of positive nodes but the location of the metastatic nodes, since n2 refers to subclavicular lymph node involvement. As mentioned previously, there was a significant difference in survival between n1[beta] patients and n2 patients as a whole. Even when limited to patients with [le]9 positive nodes, there was still a significant difference (P = 0.0141) in survival between n1[beta] patients (248 patients) and n2 patients (156 patients) (Fig. 5). A significant difference (P = 0.0286) also exists between n1[beta] patients (37 patients) and n2 patients (293 patients) who had [ge]10 positive nodes (Fig. 6). Within the n2 group, a comparison of survival rates between patients with [le]3 positive nodes (63 patients) and those with four or more (390 patients) showed better prognosis for the former group (P < 0.0001) (Fig. 7). A further comparison between n1[alpha] patients ([le]3 positive axillary nodes, 1032 patients) and n2 patients with [le]3 positive nodes ([le]3 positive axillary or subclavicular nodes, 63 patients) revealed better survival in n1[alpha] patients (P = 0.0100) (Fig. 8).

Table 2. Number of cases in subgroups categorized by location number and number of positive nodes

Parameter		No. of cases	%
Location number	n0	2156	55.0
	n1[alpha]	1032	26.3
	n1[beta]	285	7.3
	n2	449	11.4
Number of positive nodes	0	2156	55.0
	1	597	15.2
	2	312	8.0
	3	186	4.7
	4	138	3.5
	5	77	2.0
	6	62	1.6
	7	46	1.2
	8	44	1.1
	9	51	1.3
	>10	253	6.5

Discussion

Figure 5. Overall survivals in n1[beta] and n2 patients with 4-9 positive nodes. Even when limited to patients with [le]9 positive nodes, there was still a significant difference (P = 0.01451) in survival between n1[beta] patients (248 patients) and n2 patients (156 patients).

Lymph node metastasis of breast cancer is a prognostic factor of the greatest importance and data on its status have a great impact on decision making regarding postoperative adjuvant therapy (8). The General Rules for Clinical and Pathological Recording of Breast Cancer classify lymph node metastasis into n0, n1[alpha], n1[beta], n2, etc. (2). Excluding the complexity relating to parasternal lymph nodes within this classification, n0 corresponds to no lymph node metastasis, n1[alpha] to metastasis to [le]3 axillary nodes, n1[beta] to metastasis to [ge]4 axillary nodes, n2 to metastasis to subclavicular lymph nodes and n3 to metastasis to supraclavicular lymph nodes. More specifically, the distinction between n1[alpha] and n1[beta] is the number of positive nodes. Miura (5) and Hiratsuka et al.(6) reported that the greater the number of positive nodes, the poorer is the prognosis of breast cancer. Veronesi et al. (13) proposed the classification of lymph node metastasis by the level of invasion (levels I, II and III) and during the 1960s, Auchincloss (14) stated the importance of the metastatic site as well as the number of positive nodes. The location number in the General Rules (2) is a classification involving both the number of positive nodes and the metastatic level or location.

Figure 6. Overall survivals in n1[beta] and n2 patients with [ge]10 nodes. A significant difference (P = 0.0286) also exists between n1[beta] patients (37 patients) and n2 patients (293 patients) who had [ge]10 positive nodes.

Figure 7. Overall survivals in n2 patients. Within the n2 group, a comparison of survival rates between patients with [le]3 positive nodes (63 patients) and those with [ge]4 (390 patients) showed better prognosis for the former group (P < 0.0001).

Figure 8. Overall survivals in n1[alpha] and n2 patients with [le]3 positive nodes. A further comparison between n1[alpha] patients ([le]3 positive axillary or subclavicular nodes, 63 patients) revealed better survival in n1 [alpha] patients (P = 0.0100).

The present study revealed a significant difference in survival between different location number, i.e. n0, n1[alpha], n1[beta] and n2, confirming the validity of the location number as a prognostic factor. With regard to the number of positive nodes, comparisons of x and x + 1 positive nodes showed no significant difference in survival between patients with one and two positive nodes, while there was a significant difference between those with two and three positive nodes. Although patients with three and four positive nodes showed a slight difference (P = 0.056) in survival, it was not as great as that observed between those with two and three positive nodes. No significant difference in survival was found between patients with four and five positive nodes, but the difference between those with nine and 10 positive nodes was significant.

When the results were analyzed from the viewpoint of the location number, the absence and presence of a significant difference in survival between one and two and two and three positive nodes, respectively, suggested that it is unreasonable to combine patients with one to three positive nodes in a single group and that patients with one or two positive nodes should be distinguished from those with three. Within the n1[beta] group, there was no significant difference in survival between patients with four positive nodes (the minimum number of positive nodes possible in this group) and those with seven or more. This confirms the appropriateness of the existing category n1[beta]. The necessity for differentiating between n1[alpha] patients with three positive nodes and those with one or two raises the question of whether patients with three positive nodes should be included in category n1[beta]. Since there was a significant difference in survival between n1[alpha] patients with three positive nodes and n1[beta] patients with seven or more, n1[alpha] patients with three positive nodes should also be distinguished from n1[beta] patients. Fisher et al. (4) observed that the 5-year recurrence rate in patients with one to three positive nodes was lower than that in patients with four or more (47 vs 77%) and concluded that patients with three positive nodes should be discriminated from those with four. Our present results suggest that the conventional boundary between one to three positive nodes and four positive nodes requires reconsideration.

Metastasis to subclavicular lymph nodes is the criterion on which classification to stage n2 is based. Since the survival rate varied according to the number of positive nodes within the n2 group, predictions of the prognosis should take into account the number of positive nodes. Comparisons of n1[beta] and n2 patients after subgrouping by the number of positive nodes (4-9 and [ge]10) also revealed a significantly poorer prognosis for n2 than for n1[beta]patients although, among the patients with 4-9 positive nodes, the mean number of positive nodes in the n1[beta] group (5.4) was less than that in the n2 group (6.7). In addition, a comparison between n1[alpha] patients and n2 patients with three positive nodes showed a significantly poorer prognosis in the n2 patients. This result supports the view of Veronesi et al. (13) that lymph node metastasis of breast cancer should be implicated in prognosis in relation to the level in the axilla and is consistent with the finding reported by Adair et al. (3) that level III metastasis contributes to a decreased survival rate. According to Fisher's new biology, lymph node metastasis does not extend in parallel with the progress of breast cancer; however, these results suggest that breast cancer may have some of the features of Halstedian biology.

Although the attitude towards lymph node dissection for patients with breast cancer is now changing, it is still crucial to determine the metastatic status or to be able to stage accurately by means of lymph node dissection, as proposed by Elizabeth et al. (12) When the prognosis of breast cancer is considered from the viewpoint of lymph node metastasis, the location number as described in the General Rules is an excellent classification for predicting survival. However, one should be aware of possible differences in the prognosis depending on the number of positive nodes, as this is masked by the location number.

Acknowledgments

This study was presented, and received an award for excellence, at the 27th meeting of the Japanese Society for Cancer and Lymph Node Research. The authors thank Dr I. Kimijima for his valuable assistance in the preparation of this paper.

References

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2. General Rules for Clinical and Pathological Recording of Breast Cancer, 12th ed. Tokyo: Japanese Breast Cancer Society 1996.

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11. Senofsky GM, Moffat FL, Davis K, Marsi MM, Clark KC, Robinson DS, et al. Total axillary lymphadenectomy in the management of breast cancer. Arch Surg 1991;126:1336-42. MEDLINE Abstract

12. Elizabeth CD, Lawrence NS, Wiley WS, Smith BL. Does information from axillary dissection change treatment in clinically node-negative patients with breast cancer. Ann Surg 1997;226:279-87. MEDLINE Abstract

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14. Auchincloss H. Significance of location and number of axillary metastases in carcinoma of the breast. Ann Surg 1963;158:37-46.

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Received July 24, 1998; accepted November 9, 1998
For reprints and all correspondence: Yoshihito Utada, Department of Breast Surgery, Cancer Institute Hospital, 1-37-1, Kami-ikebukuro, Toshima-ku,Tokyo 170-8455, Japan

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