Vol. 3, 817-819, May 1997 Clinical Cancer Research 817 Lymphoid Infiltration as a Prognostic Variable for Early-Onset Breast Carcinomas’ Sylvie M#{233}nard,2 Gorana Tomasic, Patrizia Casalini, Andrea Balsari, Silvana Pilotti, Natale Cascineffi, Bruno Salvadori, Maria Ines Colnaghi, and Franco Rilke Experimental Oncology [S. M., M. I. C.], Anatomical Pathology and Cytology [0. T., S. P.J, General Direction [P. C., F. R.j, and Surgical Oncology [N. C., B. S.], Istituto Nazionale per lo Studio e la Cura dci Tumoni, and Immunology [A. B.1, University of Milan, 20133 Milan, Italy ABSTRACT Infiltration by lymphoid cells is a common feature of many human tumors, including breast carcinomas, and the degree of infiltration has been suggested to be a measure of the host immune response. Our analyses in a series of 1919 cases of primary ductal and lobular infiltrating breast car- cinomas from women with a long-term follow-up revealed: (a) a 16-17% frequency ofinfiltrated tumors independent of the patient’s age at diagnosis; and (b) a strong positive correlation between survival rates and the presence of lym- phocytes at the tumor site in patients less than 40 years of age (P = 0.0002) but no association with prognosis in pa- tlents 40 years of age or older. Multivariate analysis indi- cated that lymphoid infiltration is independent of other conventional prognostic factors such as nodal status and tumor size in predicting survival. Thus, a possible immune response against the tumor seems to be relevant only in women with early-onset tumors. Because the immune system Is functionally maximum in younger years, declining with age, this finding might reflect a difference in the efficiency of the immune system. Alternatively, the biology of these tumors might differ, leading to a difference in immuno- genicity. INTRODUCTION Although notable improvements have occurred in the last two decades with mammography for early diagnosis and the introduction of adjuvant postsurgical therapy, breast cancer re- mains one of the major causes of death in women. Histological and immunohistochemical examinations have shown that breast Received 9/26/96; revised 1/23/97; accepted 1/28/97. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. I This work was partially supported by the Associazione Italiana per la Ricerca sul Cancro and the Fondazione Italiana per la Ricerca sal Cancro. 2 To whom requests for reprints should be addressed. Phone: 39-2-2390- 571; Fax: 39-2-2362-692. carcinomas, like many other human tumors, can be infiltrated by lymphoid cells. Breast tumors seem to be immunogenic based on evidence in experimental models, and in human tumors, the degree of infiltration has been suggested to be a measure of the host immune response (1, 2). However, perhaps because the evaluation criteria for tumor infiltrates are not sufficiently stan- dardized to yield reliable and reproducible results in different institutions, the prognostic significance oflymphoid infiltrate at the tumor site and the relative importance of these infiltrates as an indicator of host immune status remain controversial (3- 8). Because the immune system is functionally maximum in younger years, declining with age (9-11), lymphoid infiltration may have a different prognostic significance depending upon the age of the patient at diagnosis. We investigated this hypoth- esis in a series of 1919 cases of primary ductal and lobular infiltrating breast carcinomas from patients with a long-term follow-up. PATIENTS AND METhODS A series of 1919 patients operated on during a period from 1968 to 1979 in our institute for primary ductal, lobular, or mixed breast carcinoma were considered. About 40% of the node-positive patients received adjuvant chemotherapy after surgery, whereas all of the node-negative patients did not me- ceive any postsurgical treatment. All patients were treated with chemotherapy or hormonal therapy at the time of relapse. The diameter of the primary tumor and the axillaiy nodal status were obtained from histopathological reports. H&E- stained histological slides of each patient included in the metro- spective study were reviewed by pathologists for diagnostic reassessment of histotype and graded according to Bloom and Richardson. Lymphoid infiltration was evaluated morphologi- cally on H&E-stained slides selected by the pathologists as most representative of the case. Infiltrates were scored as positive when a dense or moderate cellular infiltration in the stroma surrounding the tumor nests inside the tumor mass was present and were scored as negative when only occasional inflammatory cells were found. Patients were grouped according to age at diagnosis (group 1, <40 years; group 2, 40-49 years; group 3, 50 years) and compared for overall survival from the date of surgery as a function of lymphoid infiltration. Only breast cancer deaths were considered as events. The median follow-up was 1 8 years, during which 886 cases of death from breast cancer were reg- istered. The log-rank method was used to statistically analyze the differences in survival. Multifactorial analysis was carried out using the Cox regression model. RESULTS Analysis of the frequency of lymphocyte-infiltrated tumors revealed no significant differences among the three age groups of patients (16, 17, and 16% in group 1, 2, and 3, respectively).