Staging in the Therapy of Cancer of the Breast

Transcription

1 Staging in the Therapy of Cancer of the Breast STEVEN G. SILVERBERG, M.D. Department of Pathology, University of Colorado School of Medicine, Denver, Colorado ABSTRACT Silverberg, Steven G.: Staging in the therapy of cancer of the breast. Am J Clin Pathol 64: , Clinical and pathologic staging of breast cancer are discussed. A new pathologic staging system is presented: numerical scores are assigned, in cases of infiltrating ductal carcinoma of no specific subtype, for tumor size, histologic grade, amount of stromal infiltration, vascular invasion, axillary lymph nodal metastases, and sinus histiocytosis in axillary lymph nodes. Staging by this system correlates well with survival in cases treated by radical mastectomy. The essential features to be studied in pathologic specimens of breast cancer are also indicated. (Key words: Breast cancer staging.) THE RELATIONSHIP between staging and therapy of breast cancer is dual in nature, because there are two very different forms of staging. The first of these is clinical staging, which by definition is done before therapy is instituted, and functions primarily as a means of aiding the clinician in choosing the optimal form of therapy in a particular case. The second, which may be of more interest to pathologists, is pathologic staging, which is best performed after initial therapy is accomplished and serves predominantly to provide prognostic data, although in many instances it may influence subsequent therapy as well. I propose to discuss both of these forms of staging, with emphasis on studies which my colleagues, Drs. Arun R. Chitale and Seymour H. Levitt, and I have performed to elucidate the relationship between pathologic factors and survival in breast cancer. The first feature of clinical staging that Received May 7, 1975; accepted for publication May 7, Supported in part by NCI grant #CA Reprints of this entire Research Symposium are available from the ASCP Meeting Services Department, 2100 West Harrison Street, Chicago, Illinois 60612, for $5.00 per copy. 756 must be emphasized is that it is, by definition, purely clinical, i.e., not influenced by subsequently obtained pathologic data. Thus, if the clinician's assessment of the axillary lymph nodes is negative, the subsequent finding of nodal metastases at the time of radical mastectomy does not change the patient's clinical stage. Obviously, the alteration of the clinical stage under such conditions would make it impossible to compare series of patients treated by different modalities, as for example when treatment does not include excision and examination of axillary lymph nodes. This principle applies equally to cancers other than mammary, and unfortunately it is frequently forgotten by clinicians and pathologists alike. In order to stage a cancer, of course, one must be certain that a cancer is present, so that pathologic confirmation of the diagnosis is necessary before clinical staging can take place. Clinical staging of breast cancer dates back approximately 70 years, since the first publication dealing with this topic was that of Steinthal 24 in He divided his cases into three stages, and advised against surgery in cases classified as Stage III

2 December 1975 STAGING IN THE THERAPY OF BREAST CANCER 757 Table 1. American Clinical Staging of Cancer of the Breast T Primary Tumor Tl T2 T3 Tumor of 2 cm. or less in greatest dimension Skin not involved; or involved locally with Paget's disease Tumor more than 2 cm. in size; or with skin attachment (dimpling of skin); or nipple retraction (in subareolar tumors). No pectoral muscle or chest-wall attachment Tumor of any size with any of the following; skin infiltration, ulceration, peau d'orange, skin edema, pectoral muscle or chest-wall attachment N Regional Lymph Nodes NO Nl N2 No clinically palpable axillary lymph node(s) (metastasis not suspected) Clinically palpable axillary lymph nodes that are not fixed (metastasis suspected) Clinically palpable homolateral axillary or infraclavicular lymph node(s) that are fixed to one another or to other structures (metastasis suspected) M Distant Metastasis MO Ml No distant metastasis Clinical and radiographic evidence of metastasis except those to homolateral axillary or infraclavicular lymph nodes Summary of Stages Stage I Stage II Stage III Stage IV T1.N0, MO T2, NO, MO T1,N1,M0 T2, Nl, MO T3, NO, MO T3, Nl, MO T3, N2, MO Tl, N2, MO T2, N2, MO All Ml (tumor involving most of the breast, the mammary skin, and/or the supraclavicular lymph nodes), since he found that none of his patients in this stage were cured by operation. Numerous other staging systems have evolved subsequently, but I should like to emphasize in this presentation the two that are most frequently used in this country. The first of these is the so-called "American Classification," representing a modification by an American Joint Committee in Cancer Staging of an earlier classification by the International Union Against Cancer. 11 This classification was presented in 1962, and has remained fairly constant since. It involves the TNM classification concept, which has also been utilized in cancers of many other organs. A summary of the three classes of involvement for T (primary tumor), the three for N (regional lymph nodes), and the two for M (distant metastases), together with the four clinical stages derived from combinations of these, is presented in Table 1. Despite the undoubted expertise of the people who formulated this classification, and its somewhat more American flavor than that of the international classification from which it was derived, I have not found it to be as widely used in this country as the second classification that I will present, testifying perhaps to the fact that medicine is not practiced by committees. The complexity of the TNM classification, in relation to both breast and other cancers, appears to be the factor that militates against its wide acceptance. The clinical classification more frequently utilized today is the Columbia

3 758 SILVERBERG A.J.C.P. Vol. 64 Table 2. The Columbia Clinical Classification Stage A. Stage B. Stage C. Stage D. No skin edema, ulceration, or solid fixation of tumor to chest wall. Axillary nodes not clinically involved No skin edema, ulceration, or solid fixation of tumor to chest wall. Clinically involved nodes, but less than 2.5 cm. in transverse diameter and not fixed to overlying skin or deeper structures of axilla Any one of five grave signs of advanced breast carcinoma: 1. Edema of skin of limited extent (involving less than one-third of the skin over the breast) 2. Skin ulceration 3. Solid fixation of tumor to chest wall 4. Massive involvement of axillary lymph nodes (measuring 2.5 cm. or more in transverse diameter) 5. Fixation of the axillary nodes to overlying skin or deeper structures of axilla All other patients with more advanced breast carcinoma, including: 1. A combination of any two or more of the five grave signs listed under Stage C 2. Extensive edema of skin (involving more than one-third of the skin over the breast) 3. Satellite skin nodules 4. The inflammatory type of carcinoma 5. Clinically involved supraclavicular lymph nodes 6. Internal mammary metastases as evidenced by a parasternal tumor 7. Edema of the arm 8. Distant metastases Clinical Classification (Table 2), which was proposed more than 20 years ago by Haagensen and colleagues. 11 The usefulness of this classification in predicting the therapeutic results in patients treated by classic radical mastectomy has been confirmed by several investigators, and is demonstrated again in our own series (Table 3), in which the clinical staging was done retrospectively from data obtained from patient charts. Obviously, the best studies of this sort are those that are undertaken prospectively, since the value of any staging system is largely dependent upon the skill and zeal of those who do the staging. The usefulness of the Columbia or any other clinical classification in influencing the mode of therapy will obviously vary from one institution to the next, depending upon the clinical philosophy in vogue. To those who do not believe in performing surgery without a good chance of cure, patients in advanced stages will be considered inoperable. For others, an advanced clinical stage merely means that the operation undertaken must be either more radical or combined with adjuvant radiotherapy or chemotherapy. An "early" clinical stage or other evidence of apparently limited cancer may, in some institutions, lead to very limited forms of therapy as well. I shall leave it to those who are discussing specific therapeutic modalities to comment on their solutions to these problems. It is generally agreed that one of the most important if not the single most important prognostic indicators in mammary carcinoma is the presence or absence of axillary lymph nodal metastases. It has also recently become apparent that the number of axillary nodes involved by metastases is equally important. 6>15,21 Table 4 shows the relationship between nodal metastases and 5-year survival in all cases of patients with mammary carcinoma having radical mastectomy in our series, while the same relationship is limited to cases of infiltrating ductal carcinoma (a more uniform group, representing about two thirds of all of our cases) in Table 5. In both of these tables, it can be seen that the survival rate with one or two positive axillary lymph nodes closely approximates that in cases without nodal metastases. Since the lymph-node findings are of such prognostic importance, the accuracy of their clinical assessment must be considered. Our own findings (Table 6) are similar to those in the literature, and indi-

4 December 1975 STAGING IN THE THERAPY OF BREAST CANCER 759 cate that the false-negative rate of clinical assessment of axillary nodes can be stated as either 20 or 40%, depending upon whether the finding of one or two positive nodes pathologically is considered a false negative. Similarly, the false-positive rate is 28% at best and 46% at worst. This inaccuracy of clinical staging has led to the concept of pathologic staging, in which the case is staged on the basis of pathologic findings after the primary surgical treatment. In the simplest variant of the system, cases with negative axillary lymph nodes are Pathologic Stage A, while those with nodal metastases are Pathologic Stage B. It should be emphasized that axillary metastases merely serve as an indicator of an unfavorable relationship between the tumor and the host. Metastases in axillary lymph nodes, in and of themselves, are not lethal, but merely suggest that other tumor spread has probably taken place. Thus, the "cure" of axillary nodal metastases will not necessarily cure the patient, nor is the converse true, a fact that must be kept in Table 3. Columbia Classification of Lesions in 304 Patients Treated by Radical Mastectomy Retrospective Stage A B C D Number of Cases Number 5-Year Survivors % 5-Year Survival mind when listening to the passionate advocates of various forms of therapy. Since the positivity or negativity of the axillary lymph nodes does not provide us with an infallible prognostic indicator, other factors should be considered in attempting to derive a system of pathologic staging. Both the anatomic level of the nodes involved 1 and the size and invasiveness of the nodal metastases 12 have been proposed as important criteria, but these factors are both correlated with the number of nodes involved, and thus can be subju- Table 4. Five-year Survival in Relation to Local Lymph Nodal Involvement (All Cases) Total No. Cases No. \ ith Follow -up No. Patients Alive at 5 Years Survival No lymph nodal metastasis 1-2 positive lymph nodes 3-4 positive lymph nodes 5-8 positive lymph nodes 9-12 positive lymph nodes >13 positive lymph nodes Lymph nodal metastases (all cases) Table 5. Five-year Survival in Relation to Local Lymph-node Involvement (Infiltrating Ductal Carcinoma Only) Total No. of Cases No. with Follow-up N. o. Alive at 5 Years % Survival No lymph nodal metastases 1-2 positive lymph nodes 3-4 positive lymph nodes 5-8 positive lymph nodes 9-12 positive lymph nodes >13 positive lymph nodes Lymph nodal metastases (all cases)

5 760 SILVERBERG AJ.C.P. Vol. 64 Table 6. Accuracy of Clinical Assessment of Axillary Nodal Metastases Pathologic Findings Clinical Assessment Total Cases No Metastases 1 oi-2 Positive Nodes >3 Positive Nodes No metastases Metastases (59.5%) 38 (27.9%) 41 (20.3%) 24 (18.0%) 41 (20.3%) 71 (54.1%) gated to the latter determination. A very important prognostic factor is the histologic type of cancer, and Dr. Hartmann has already covered that subject. Since the various histologic types of breast cancer differ so greatly in natural history and prognosis, I shall confine my pathologic staging system to infiltrating ductal carcinomas of no specific subtype, which comprise the great majority of all breast cancers encountered in practice. The factors I will consider are tumor size, tumor grade, amount of stromal infiltration, vascular invasion, axillary lymph nodal metastases, and sinus histiocytosis in axillary lymph nodes. Several studies have shown that the size of a primary breast cancer is inversely related to patient survival. 4,18 One of the most recent of these is the study derived from the National Breast Project, 4 in which tumor size was found to be directly correlated with positivity of axillary lymph nodes, number of axillary lymph nodes involved by tumor, tumor recurrence, and mortality rates. On the other hand, this study concluded that tumor size was considerably less important as a prognostic factor than are other factors that may be present from the inception of a breast cancer. In our own study, tumor size did not seem to affect the 5-year survival rates until the maximal diameter was recorded as more than 5.5 cm. Below this level, the 5-year survival rate approximated 60%, but decreased to 35% with tumor sizes greater than 5.5 cm. The tumor grade represents the histologic estimation of anaplasia, and is best quantitated by the criteria of the World Health Organization. 19 In this schema, numerical values are assigned for: (1) degree of structural differentiation as shown by tubular formations; (2) variation in size, shape and staining of nuclei; (3) frequency of hyperchromatic nuclei and mitotic figures. The total score places a tumor into grade I, II, or III, the last being the most anaplastic. In our material, considering only infiltrating ductal carcinomas of no specific type, there was a definite correlation between tumor grade and 5-year survival, the survival rate being 79% for grade 1,43% for grade II, and 33% for grade III. In carcinomas of intraductal and infiltrating ductal types, some correlation can be made between the extent of infiltrative growth and eventual survival. 20 Pure intraductal carcinomas constitute only a very small percentage of the total number of cases seen (approximately 5% in our own series), and do not appear to be associated with either axillary nodal metastases or mortality. Intraductal carcinomas with less than 10% infiltrative growth also comprise about 5% of cases, and are associated with occasional involvement of axillary nodes, an excellent 5-year survival rate, and a small but significant incidence of mortality after 5 years. The other 90% of tumors studied show anywhere between 10 and 100% infiltrative growth. The survival rates at 5 years in our series approximated 60-70% with up to 90% infiltrative growth, and subsequently decreased to 40-45% when this extent of infiltration was exceeded.

6 December 1975 STAGING IN THE THERAPY OF BREAST CANCER 761 Vascular invasion in the primary tumor has been shown in several studies to carry a very grave prognostic significance. 8,13 In the present series, vascular invasion was detected with routine (hematoxylin and eosin) stains in only 10% of cases, but the 5-year survival rate in those cases was 19%, compared with 56% in cases in which this finding was absent. We believe that vascular invasion can be demonstrated more frequently with the use of elastic and other special stains, but that its prognostic significance would be diluted by the addition of those cases in which the invasion is not immediately obvious. The detection of metastases in axillary lymph nodes is also important to establishing the prognosis in breast cancer. In several recent studies, it has been concluded that patients with metastases in one to three nodes do almost as well as those with entirely negative nodes. 6 In our own material, for infiltrating ductal carcinomas, the survival rates were identical for patients with negative axillae and patients with one or two positive lymph nodes. The gross 5-year survival rate decreased, however, from 66% in these cases to 31% in patients with three or four positive lymph nodes, remained at about the same level in patients with five to eight positive nodes, and then decreased to approximately 12% when nine or more nodes were involved. Thus, we would place the cut-off points for significant differences in survival at the levels of three and nine positive nodes. Finally, some measure (histologic or other) of host resistance to tumor should be included in any prognostic schema. We have had more success with sinus histiocytosis 2,21 than with other histologic markers, although other authors have demonstrated correlations between other lymph-node reactive patterns and ultimate survival in breast cancer, 25 and certainly more sophisticated measurements of hosttumor interrelationships should do even better. 3,5,9,17 In our own series, the presence of sinus histiocytosis in any of the axillary lymph nodes was associated with an improved prognosis, particularly with tumors of moderate or poor histologic differentiation and tumors involving moderate numbers (one to eight) of regional lymph nodes. 21 Patients with well-differentiated tumors and those showing no nodal metastases had excellent survival rates regardless of the presence or absence of sinus histiocytosis, while those with more than nine cancer-bearing axillary nodes had uniformly poor survival. Other pathologic factors that appeared to have very little relationship to survival in our series included the location of the tumor 7 and the pattern of the borders between tumor and surrounding mammary tissue. 22 Fibrocystic dysplasia coexisting with breast cancer improved the survival slightly, but its significance was much less than that of the factors summarized above. 23 Thus, we have attempted to use the more important findings to arrive at a pathologic staging system that includes more than axillary nodal metastases. Numerical scores have been assigned as illustrated in Table 7, and the relationship of the scores to survival has been determined empirically (Table 8). Patients with scores of 6-8 (Stage A) had a 5-year survival rate of 81%, compared with survival rates of 49% with scores of 9-10 (Stage B), 17% with scores of (Stage C), and 9% with scores of 13 or higher (Stage D). All patients with the score of 6 survival, while all those with scores of 14 or 15 succumbed to thendisease, but absolute numbers were small, thus making it impossible to predict the results of treatment with 100% accuracy in any given case. Of fundamental importance to the pathologist is the question of what constitutes adequate study of a mastectomy specimen in a case of breast cancer. This question has recently been considered by the Pathology Working Group of the

7 762 SILVERBERG A.J.C.P. Vol. 64 Table 7. Scores for Pathologic Features of Prognostic Significance Infiltrating Ductal Carcinomas Treated by Radical Mastectomy Maximal tumor diameter Less than 5.5 cm. 5.5 cm. or more Tumor grade I II III % stromal infiltration Less than 90% 90% or more Vascular invasion Absent Present Axillary lymph nodal metastases 0, 1 or 2 positive nodes 3-8 positive nodes 9 or more positive nodes Sinus histiocytosis in axillary lymph nodes Absent Present Breast Cancer Task Force, 16 as well as in our laboratory, 10 and certain criteria have been established. These are believed to be applicable to the standard laboratory of the practicing pathologist, and are obviously less strict than those which would be applied in a laboratory involved in a protocol for the study of breast cancer. The gross description of the specimen should include the identification, measurements, and list of structures included: appearance of the nipple and mammary skin; the size, location, and general description and extent of circumscription of the primary tumor; presence or absence of dermal or muscle invasion; description of the remainder of the mammary tissue, including presence or absence of multiple tumor nodules; number of lymph nodes present (if any) in each axillary division, with the size of the largest node, and gross evaluation of nodal metastases. Sections submitted for histologic evaluation should include at least four from the primary tumor, including several through its margins; a section through the nipple and one through skin overlying tumor; and at least one section from each mammary quadrant. Specimen mammography should be utilized when indicated. In cases of noninfiltrating cancer, at least eight sections of tumor should be examined. Axillary lymph nodes, if present, should be divided into those at Levels I (below the inferior margin of the pectoralis minor muscle), II (between the pectoralis muscles), and III (above the superior margin of the pectoralis minor, in the apex of the axilla). All nodes identified grossly should be examined histologically. Since recent studies 6 have shown that the absolute number rather than the percentage of positive nodes is important prognostically, we believe that tedious clearing and serial sectioning technics add little information of any value. The report of the microscopic examination of the specimen should include a summary of all histologic types of cancer present in the specimen, with final classification determined by the type with the worst prognosis; a complete description of Table 8. Relation of Pathologic Scores to Survival Infiltrating Ductal Carcinomas Treated by Radical Mastectomy Pathologic Stage Score Number of Cases Number with Follow-up Number of 5-year Survivors 5-year Survival A B C D % 48.7% 17.2% 8.7%

8 December 1975 STAGING IN THE THERAPY OF BREAST CANCER 763 multiple foci of tumor, if present; the histologic grade, extent of circumscription, extent of lymphocytic or other inflammatory infiltrate, and presence or absence of vascular invasion in each tumor; the associated presence of non-infiltrating (in situ lobular or intraductal) carcinoma; the extent of involvement, if any, of structures adjacent to mammary tissue by the tumor; characterization of associated benign mammary tissue, with emphasis on the presence or absence of fibrocystic dysplasia; the number of lymph nodes in each axillary division containing metastases; and the appearance of uninvolved axillary nodes, with emphasis on the presence or absence of sinus histiocytosis. A report of this sort should prove of value not only in the immediate evaluation of the individual patient, but in subsequent chart-review studies of populations with breast cancer as well. References 1. Berg JW: Significance of axillary node levels in study of breast carcinoma. Cancer 8: , Black MM, Kerpe S, Speer FD: Lymph node structure in patients with cancer of the breast. AmJ Pathol 19: , Deodhar SD, Crile G Jr, Esselstyn CB Jr: Study of the tumor cell-lymphocyte interaction in patients with breast cancer. Cancer 29: , Fisher B: Cancer of the breast: Size of neoplasm and prognosis. Cancer 24: , Fisher B, Saffer EA, Fisher ER: Studies concerning the regional lymph nodes in cancer VII. Thymidine uptake by cells from nodes of breast cancer patients relative to axillary location and histopathologic discriminants. Cancer 33: , Fisher B, Slack NH: Number of lymph nodes examined and the prognosis of breast carcinoma. Surg Gynecol Obstet 131:79-88, Fisher B, Slack NH, Ausman RK, et al: Location of breast carcinoma and prognosis. Surg Gynecol Obstet 129: , Friedell GH, Betts A, Sommers SC: The prognostic value of blood vessel invasion and lymphocytic infiltrates in breast carcinoma. Cancer 18: , Gewant WC, Chasin L, Tilson MD, et al: Lymph node-breast carcinoma interrelations in tissue culture. Surg Gynecol Obstet 133: , Compel C, Silverberg SG: Pathology in Gynecology and Obstetrics. Second edition. Philadelphia-Toronto, J. B. Lippincott, in press 11. Haagensen CD: Diseases of the Breast. Second edition. Philadelphia-London-Toronto, W.B.Saunders, Huvos AG, Hutter RVP, Berg JW: Significance of axillary macrometastases and micrometastases in mammary cancer. Ann Surg 173:44-46, Kister SJ, Sheldon CS, Haagensen CD, et al: Reevaluation of blood-vessel invasion as prognostic factor in carcinoma of the breast. Cancer 19: , Maehle BO, Hartveit F: Prognostic typing in breast cancer. J Clin Pathol 26: , McLaughlin CW Jr, Coe JD: Cancer of the breast a continuing challenge: Report of 375 consecutive patients with long-term follow-up. Ann Surg 169: , Pathology Working Group, Breast Cancer Task Force: Standardized management of breast specimens. Am J Clin Pathol 60: , Richters A, Kaspersky CL: Surface immunoglobulin positive lymphocytes in human breast cancer tissue and homolateral axillary lymph nodes. Cancer 35: , Say CC, Donegan WL: Invasive carcinoma of the breast: Prognostic significance of tumor size and involved axillary lymph nodes. Cancer 34: , Scarff RW, Torloni H: Histological Typing of Breast Tumours. Geneva, World Health Organization, Silverberg SG, Chitale AR: Assessment of significance of proportions of intraductal and infiltrating tumor growth in ductal carcinoma of the breast. Cancer 32: , Silverberg SG, Chitale AR, Hind AD et al.: Sinus histiocytosis and mammary carcinoma. Study of 366 radical mastectomies and an historical review. Cancer 26: , Silverberg SG, Chitale AR, Levitt SH: Prognostic significance of tumor margins in mammary carcinoma. Arch Surg 102: , Silverberg SG, Chitale AR, Levitt SH: Prognostic implications of fibrocystic dysplasia in breasts removed for mammary carcinoma. Cancer 29: , Steinthal CF: Zur Dauerheilung des Brustkrebses. Beitr Z Klin Chir 47:226, Tsakraklides V, Olson P, Kersey JH, et al.: Prognostic significance of the regional lymph node histology in cancer of the breast. Cancer 34: , 1974