Japanese Journal of Clinical Oncology

Pathology Material

In the first study, we prepared HE-stained sections of n0 invasive ductal carcinomas (IDC) which were resected from 100 patients who underwent radical mastectomies at the Cancer Institute Hospital, Tokyo, and who were followed up for more than 10 years. Ductal carcinoma in situ (DCIS) and carcinomas of special histological types were excluded from the study. Fourteen patients suffered recurrences and 12 of these recurrences occurred within 10 years after initial mastectomy.

For the second study, another series of 145 n0 breast carcinomas was prepared. This series comprised HE-stained slides of main tumors from 145 women who consecutively underwent modified radical mastectomy at the National Cancer Center Hospital, Tokyo, in 1988. We excluded two with metachronous bilateral carcinomas, one with synchronously bilateral carcinoma, and 12 for whom primary tumor sections were not available. Among the effective 130 patients with n0 breast carcinomas, 13 had recurrence of the carcinoma and eight of them died from the recurrence. The average follow-up period for living patients was 89.6 months, varying from 14 to 121 months.

Pathological Diagnostic Criteria

Four candidate parameters (nuclear atypia, mitotic counts, the diameter of fat infiltration, and the diameter of stromal invasion in n0 breast carcinoma) were examined in the first study based on previous reports of their prognostic significance in n0 breast cancer (9-12). By combining the nuclear atypia and mitotic counts, nuclear grades were defined as the sum of scores for the nuclear atypia (1 for low-degree atypia; 2 for intermediate-degree atypia; 3 for high-degree atypia) with the scores for the mitotic counts per 10 high-power fields (×40 objective lens) (1 for 0-4 mitoses; 2 for 5-9 mitoses; 3 for [ge]10 mitoses). The nuclear grade was 1, 2 and 3 when the sum of scores for the nuclear atypia and those for mitotic counts were 2-3, 4 and 5-6, respectively.

The diameter of fat invasion or stromal invasion implied their maximum length across the invasive part. If there are multiple foci of invasion, the maximum length of fat or stromal invasion was determined by the sum of the maximum diameters of each invasive focus. The maximum size of tumor stromal invasion ([le]10 mm vs [ge]11 mm) and the degree of fat invasion by the tumor (<3 mm vs [ge]3 mm) that had been routinely reported were confirmed by M.K.

Study of Interobserver Variation

In the first study, interobserver variation was examined among pathologists. Three panel pathologists (H.T., F.A., M.K.) independently judged the nuclear atypia and mitotic counts of the series of 100 n0 IDCs. It was defined as partial agreement if two pathologists gave an identical point and the other gave a point that differed by only one. If all three gave an identical point, it was defined as complete agreement.

Study of Prognostic Value

The prognostic significance of the nuclear grade, stromal invasion and fat invasion was also examined in the first study. Correlation with prognosis of the 100 patients was studied for each diagnosis of the nuclear grade given by each pathologist and the median value of the nuclear grade scores.

In the second study, the prognostic significance of the nuclear grade, which was judged as the most effective prognostic indicator in the first study, was examined again. For internal standardization of the criteria among the three panel pathologists, consensus histological typing and nuclear grade were determined using a discussion microscope with HE-stained slides of another 130 tumors.

Effect of Resection-fixation Interval on Mitotic Counts

When mitotic cells die, it is after they have completed the final mitotic divisions (14). Therefore, the interval between the removal of tissue and formalin fixation may affect the scoring of mitotic figures between different hospitals, as specimen processing differs between hospitals. In order to determine the effect of the removal-fixation interval on the number of mitoses, the mitotic counts were compared between 12 paired carcinoma specimens: one which was formalin fixed soon after resection and the other which was fixed after storage in a refrigerator overnight.

Statistical Analysis

Interobserver agreement on the nuclear atypia, mitotic counts and nuclear grade was tested using the pairwise kappa ([kappa]) for two raters and the generalized [kappa] for more than two raters (15-17). According to Landis and Koch (18), the [kappa] statistics were divided into several scales for strength of agreement. The strength of agreement was estimated by referring the quantity of ratio of [kappa] to the standard error (SE) of the [kappa] value [SE([kappa])], i.e. [kappa]/SE([kappa]), to the values of the standard normal curve (17).

Overall survival curves were drawn by the method of Kaplan and Meier (19). The difference in curves was tested by the log-rank test (20).

Variations in Criteria of the Nuclear Grade Among Pathologists

In the first study, complete agreement was obtained in 21% of the tumors for nuclear atypia, 44% for mitotic counts and 45% for nuclear grades among the three pathologists. Partial agreement was obtained in 91% of scores of nuclear atypia, 89% of mitotic counts and 78% of nuclear gradings (Table 1).

The strength of agreement among the three pathologists was slight for nuclear atypia, and fair for mitotic counts and nuclear grade (Table 1). The overall agreement estimated by [kappa]/SE([kappa]) was 9.890 for the nuclear atypia, 6.858 for mitotic counts and 7.854 for the nuclear grade. All these values indicated that the agreement between the three pathologists was significantly beyond chance.

The strength of agreement by the [kappa] value between two of the three pathologists for nuclear atypia was judged to be fair (0.21-0.40) or slight (0.00-0.20), and that for mitotic counts and the nuclear grade was moderate (0.41-0.60) or fair. The pairwise agreement estimated by [kappa]/SE([kappa]) for mitotic counts and the nuclear grade was significantly beyond chance, whereas such agreement for the nuclear atypia was significant only between pathologists A and C (Table 2).

In the secondary observation using a discussion microscope, the three pathologists always reached agreement upon the cases which were not agreed at first. Therefore, we concluded that consensus among panel pathologists could be obtained in almost all cases by discussion.

Prognostic Value of the Nuclear Grade (1)

All of the nuclear grades given by each individual pathologist showed a correlation with the prognosis in the first study. The nuclear grade 1 carcinoma was a low-risk group with a 10-year recurrence rate of 3-9%. In the two observers' grading, the recurrence rate of the nuclear grade 2 carcinoma group was equivalent or worse than that of the nuclear grade 3 carcinoma group. Using nuclear grade median values from the three pathologists, nuclear grade 2 and 3 cases, which constitute nearly half of all n0 IDC cases, were shown to be at a 2.8-fold higher risk of recurrence within 10 years after surgical therapy in comparison with the nuclear grade 1 IDC group (Table 3).

The degree of fat infiltration and the size of stromal invasion by a primary tumor were not associated with the higher recurrence rate. The recurrence rates were 12% (five of 42) in the patients with tumors with [le]10 mm stromal invasion and 14% (nine of 65) in the patients with tumors with <3 mm fat infiltration. On the other hand, the recurrence rates were 16% (nine of 58) in patients with tumors with >10 mm stromal invasion and 14% (five of 35) in those with tumors with [ge]3 mm fat infiltration.

Table 3. Correlation of the median value of nuclear grades scored independently by each panel pathologist for 100 invasive ductal carcinomas with their recurrence

Median nuclear grade	Number of patients (%)
	Recurrence/total		Recurrence (within 10 yr)/total
Grade 1	4/47 (9)		3/47 (6)
Grade 2	4/20 (20)	} 10/53 (19)	3/20 (15)	} 9/53 (17)
Grade 3	6/33 (18)		6/33 (18)

Table 4. Identification of a high-risk group for recurrence from 145 consecutive patients with n0 breast carcinoma by the consensus nuclear grade among three panel pathologists

Tumor histology	Number of patients (%)*
	Subtotal	Recurrence	Death
A. Higher-risk group
Invasive ductal (grade 2)	19	5 (26)	2 (11)
Invasive ductal (grade 3)	42	4 (10)	3 (7)
Invasive lobular	2	1 (50)	1 (50)
Metaplastic	3	1 (33)	1 (33)
Subtotal	66	11 (14)	7 (11)
B. Lower-risk group
DCIS, predominantly DCIS	28	0	0
Invasive ductal (grade 1)	23	1 (5)	1 (5)
Mucinous	7	1 (14)	0
Typical medullary	4	0	0
Apocrine	1	0	0
Intracystic papillary	1	0	0
Subtotal	64	2 (3.1)	1 (1.6)
C. Excluded cases
No residual primary tumors	12	2	0
Metachronous bilateral	1	0	0
Synchronous bilateral	2	1	1

*% recurrence (or % death) is given simply by dividing the number of patients who suffered recurrence (or death) by the subtotal number of patients. These values differ from those estimated from survival curves.

Prognostic Value of the Nuclear Grade (2)

We tried to confirm the impact of the nuclear grade on the prognosis of n0 breast carcinoma by another study. The second study differed from the initial one in that consecutive n0 cases including all histological types were examined, and that the grade and type of each tumor were given after consensus among the three pathologists had been reached using a discussion microscope.

Of the 130 tumors, 46 cases were of special histological types other than IDC. Another 84 IDCs were classified into 23 tumors of nuclear grade 1, 19 of nuclear grade 2 and 42 of nuclear grade 3. Recurrence occurred in one, five and four patients with IDCs of nuclear grade 1, 2 and 3, respectively. Recurrences also occurred in three special types: one patient each with mucinous carcinoma, carcinoma with cartilaginous metaplasia and invasive lobular carcinoma (ILC). The latter two, who died from recurrence of breast cancer, were histologically of a high nuclear atypia and had high mitotic counts.

In the putative high-risk group that comprised 66 patients (19 with nuclear grade 2 IDC, 42 with grade 3 IDC, two ILC and three metaplastic carcinomas), recurrence and cancer death occurred in 11 and seven, respectively (Table 4). In contrast, in the putative low-risk patient group composed of 64 patients (23 with grade 1 IDC, 28 with DCIS or predominantly DCIS, seven with mucinous carcinoma, four with medullary carcinoma, and one each with apocrine carcinoma and intracystic papillary carcinoma), recurrence and cancer death occurred in two and one, respectively. From the Kaplan-Meier survival curves, the rates of recurrence and cancer death in the higher-risk and lower-risk groups at 120 months after surgery were estimated to be 22.0 and 3.6%, and 13 and 1.7%, respectively. These two curves differed significantly, and the combination of histological type and nuclear grade effectively identified a higher risk of n0 breast carcinoma (Fig. 1).

Figure 1. Survival curves of two patient groups with n0 breast carcinoma: a. the higher-risk group (n = 66); b. the lower-risk group (n = 64), according to the criteria presented in Table 5. (A) Disease-free survival curves. (B) Overall survival curves. The two curves differ significantly in (A) (P < 0.02) and (B) (P < 0.05).

Among the eight patients who died of recurrent breast cancer, five had nuclear grade 3 carcinomas, comprising three IDCs, one metaplastic carcinoma and one ILC, two had IDC of nuclear grade 2 and one had IDC of grade 1, whereas in four surviving patients with recurrent carcinoma, three had nuclear grade 2 IDC and one had nuclear grade 3 IDC.

Table 5. Histological criteria for high-risk node-negative primary breast carcinoma for NSAS-BC

A. High-risk group* Invasive ductal carcinoma, nuclear grade 2 and 3 with invasive focus of >5 mm in diameter Invasive lobular carcinoma (all) Carcinoma with squamous metaplasia, osseous and cartilaginous metaplasia, or spindle-cell metaplasia (all) B. Low-risk group Invasive ductal carcinoma, nuclear grade 1 Ductal carcinoma in situ Invasive ductal carcinoma with predominantly intraductal component (with invasive foci < 5 mm in diameter) Lobular carcinoma in situ Mucinous carcinoma[dagger] Typical medullary carcinoma Special types other than A2-A3 and B2-B6 Evaluation of nuclear grade[Dagger] Nuclear atypia Score 1 Uniform nuclei in size and shape with unremarkable hyperchromatism Score 2 Between scores 1 and 3 Score 3 Pleomorphic nuclei and hyperchromatism with fine-granular or reticular pattern often associated with large nucleoli Mitotic counts After choosing the fields that appear to contain the largest number of mitotic figures Score 1 <5 per 10 HPF (×400) Score 2 5-10 per HPF Score 3 >11 per 10 HPF Sum of scores in nuclear atypia and mitotic counts 2, 3 Nuclear grade 1 4 Nuclear grade 2 5, 6 Nuclear grade 3

HPF, high-power fields.
*When the classification between IDC and special type is difficult, the case would be better classified as IDC.
[dagger]In invasive carcinoma, if the component of mucinous carcinoma occupied >2/3 of the tumor, it was classified as mucinous carcinoma. Otherwise, the tumor was IDC.
[Dagger]In the case of heterogeneity in the grade, the higher grade is taken if the higher-grade part occupies a significant (>10-20%) area of the tumor. Otherwise, the lower grade is taken.
In the case of unilateral multifocal carcinoma, the judgment was made for the highest-grade tumor.

Effect of Resection-fixation Interval on Mitotic Counts

The three pathologists gave a consensus mitotic count for each tumor specimen using a discussion microscope. Ten of 12 tumors showed consistent points. In one tumor, an increase in mitotic count was observed in the specimen that was fixed on the following day rather than in the specimen that was fixed immediately after resection. There was no significant difference in the mitotic counts between specimens of the two groups.

Establishment of Histological Criteria

Based on these results, the histological criteria for high-risk n0 breast carcinomas for NSAS-BC were established (Table 5). Patients with nuclear grade 2 and 3 IDC, all ILC, and all carcinomas with squamous, spindle-cell and osseous or cartilaginous metaplasia were classified as the higher-risk group. DCIS and carcinomas with an invasive component of [le]5 mm in diameter were excluded, because predominantly intraductal carcinoma with [le]5 mm invasion as well as DCIS are shown to have an excellent prognosis (21).

The criteria for mitotic counts are to be adjusted according to the properties of the eyepiece lens of the examining microscope (22).

Because the nuclear grading of ILC is difficult and is often disagreed upon by pathologists, all ILC cases were included in the higher-risk group. Medullary carcinoma with lymphoid stroma, or typical medullary carcinoma, was excluded from the high-risk group despite its high nuclear grade because of its excellent prognosis (23). Three types of carcinoma with metaplasia (squamous metaplasia, spindle-cell metaplasia and osseous or cartilaginous metaplasia) usually have a high nuclear grade, and all these cases were included in the high-risk group because their prognosis did not differ from that of IDC (23). Other special types of carcinoma are not included in the higher-risk group in these criteria.

DISCUSSION

The reliability and reproducibility of histopathological criteria as prognostic indicators have often been questioned in clinical trials. However, recent studies suggest that interobserver reproducibility of histological grading of breast cancers can be achieved when a grading scheme with specified guidelines is used (24,25). The pairwise agreement between two pathologists and the overall agreement among the three pathologists for mitotic counts and nuclear grade were always estimated to be fair or moderate in the first study. Similar agreement on nuclear atypia was also significant, although its strength was weaker. The lower concordance in the score for nuclear atypia in comparison with other parameters was compatible with the work by Frierson et al. (25). The discrepancies among pathologists in nuclear grade may occur not only from differences in the pathologists' internal criteria, but also from the intermediate nature of tumors. Since the three pathologists were able to give a consensus nuclear grade for each of the carcinoma cases in the second study, it was suggested that standardization of the central criteria among a large number of collaborating pathologists can be acquired with satisfactory reproducibility.

Interobserver variations in mitotic counts may also occur from variation in the quality of specimens, as well as from the properties of the light microscope and the intermediate nature of the tumor itself. In practical terms, it would be impossible to standardize the interval between tumor resection and formalin fixation between collaborating hospitals. Based on the present data, we decided that we do not control such variation between the institutes for the NSAS-BC protocol study. The criteria for mitotic counts should be adjusted according to the type of eyepiece lenses and relay lens of the light microscope (22).

This study aimed to establish histological criteria that would identify a high-risk patient group with a recurrence rate of [sim]20-30%. Tumor size is not always associated with the prognosis of patients with n0 breast carcinoma (2,9), and the occurrence of pectoral muscle invasion and skin invasion is low, even if they are strongly correlated with tumor relapse (3,11). The four histological factors we examined in the first study were generally considered to be correlated with prognosis of n0 breast carcinoma, and the combination of these factors was expected to provide effective criteria in the NSAS-BC protocol study.

Of the four histological factors examined, the sizes of stromal invasion and fat infiltration were not correlated with recurrence rate in the study of 100 IDCs. The nuclear grade, composed of nuclear atypia and mitotic counts, was reproducibly shown to be correlated with recurrence in both the first and second studies. It is assumed that the criteria used in these studies could identify n0 breast carcinoma with a recurrence rate of [sim]22%. From the survival curves, the relative risk for 10-year recurrence of the higher-risk group was estimated to be six times as high as that of the lower-risk group. Thus, we judged that nuclear grading in combination with histological type is the best choice to identify high-risk n0 breast cancer in Japan.

In the NSAS-BC protocol study, determination of the nuclear grade is to be performed by the pathologists who are in charge of routine pathological diagnosis in each hospital. The next important step was the standardization of central criteria among the pathologists to maintain the reliability of this protocol study. For that purpose, frequent slide conferences using a slide projector, TV monitor, or the Internet, and the distribution of a color atlas of typical and problematic cases would be effective. In addition, review of randomly sampled entry cases by the panel pathologists would be necessary for continuous monitoring of the quality of pathological judgments.

In Japan, the diagnosis of ILC is usually only given for a `classical' type ILC, and other types including solid, alveolar and atypical, or pleomorphic have usually been classified as IDC. Classical ILC tended to show a better prognosis than variant ones (26), and under the Japanese criteria, ILC has a better prognosis than `scirrhous' type IDC (27). Nonetheless, we judged that the classical ILC still falls within the higher-risk group. There are no solid histological criteria to differentiate ILC from IDC of strand pattern, and typical medullary carcinoma from IDC of solid pattern. The establishment of guidelines for differentiation of these histological types by studying interobserver variation and the correlation with prognosis would be essential.

Acknowledgments

This work was supported by a grant-in-aid for studies of post market anticancer drugs from the Human Science Foundation entrusted from the Ministry of Health and Welfare, Japan. We thank Dr S. Hirohashi (National Cancer Center Research Institute, Tokyo) for helpful suggestions on the design of this study and Dr M. Takada (Nippon Roche K.K., Tokyo) for helpful suggestion for the statistical analyses. We also thank Ms M. Kitahara and Ms T. Takarabe for their excellent assistance, and the staff of the Department of Surgery, Cancer Institute Hospital, and the staff of the Department of Surgery, National Cancer Center Hospital, for providing patient follow-up data.

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Received March 27, 1998; accepted May 20, 1998
For reprints and all correspondence: Hitoshi Tsuda, Pathology Division, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104, Japan
Abbreviations: NSAS-BC, National Surgical Adjuvant Study of Breast Cancer; CMF, cyclophosphamide, methotrexate and 5-fluorouracil; HE, hematoxylin-eosin; DCIS, ductal carcinoma in situ; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; SE, standard error

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