Cell proliferation of breast cancer evaluated by anti-BrdU and anti-Ki-67 antibodies: its prognostic value on short-term recurrences.

The prognostic value of breast cancer proliferative activity was evaluated in 385 women operated for primary, non-metastasised mammary carcinoma. Cell kinetics was measured using two immunohistochemical techniques. Cells in S-phase of cell cycle were labelled in vitro by incubation of fresh tissue fragments with 5-bromo 2-deoxyuridine (BrdU), a thymidine analogue. Nuclei of cells in active DNA synthesis were stained by an anti-BrdU monoclonal antibody (Mab). Cells in interphase and mitosis were detected with Ki-67, a Mab that is known to react with a nuclear antigen present in G1/S/G2/M phases of cell cycle, but not in resting cells. This reagent provides a means of evaluating the growth fraction of neoplastic cells. BrdU was incorporated in a proportion of tumour cells ranging from 0.1 to 65.5% (median 6.8%). In the panel of tumours presented in this report the median percentage of Ki-67 positive cells (Ki-67 score) was 9.0% (range 0.1-77%). The relationship between disease-free survival (DFS), BrdU labelling index, Ki-67 score and 13 different clinico-pathological variables was investigated by multivariate analysis, using the Cox proportional hazards model. Axillary node status (P = 0.009) and Ki-67 score (P = 0.038) emerged as independent prognostic factors. Nodal status and tumour growth fraction allowed division of patients into groups at different risk of relapse: tumours with a proliferative index below the median value showed a lower recurrence rate than tumours with a high proliferative activity (P < 0.001). In particular, no relapse occurred in pN0 patients bearing carcinomas with a Ki-67 labelling < 9.0% 4 years after surgery. These findings suggest that the evaluation of proliferative activity in breast cancer enhances the probability of correctly predicting outcome after surgery and could be of assistance in the planning of adjuvant therapies.

Prognostic value of CEA and ferritin assay in breast cancer: a multivariate analysis.

The prognostic significance of preoperative serum carcinoembryonic antigen (CEA) and ferritin levels was evaluated in 191 women operated for breast cancer. The influence of CEA, ferritin and another 11 clinical and pathological features on the disease-free survival was investigated in a multivariate analysis, using Cox's proportional hazard model. Axillary node status (P = 0.004), CEA level (P = 0.011), and the histological grade of the tumor (P = 0.029) emerged as independent prognostic factors. By contrast, no significant relationship was found between ferritin and disease-free survival. These three parameters were used to derive a prognostic index (I) for each patient. Multivariate analysis showed that its prognostic value was better than the value of any single factor (P less than 0.0001). The I score was used to divide patients into groups at different risk of recurrence: low, moderate and high (97.5%, 45% and 22.5% of recurrence-free patients at 3 years respectively). The data showed that the prognosis of patients with different combinations of node status and tumor grade was related to the level of CEA. Only women with very good (node-negative with well-differentiated tumors) or very bad prognosis (node-positive with four or more metastatic nodes and poorly differentiated tumors) had a disease-free survival independent of CEA values. These findings suggest that the preoperative measurement of CEA enhances the possibility of correctly predicting outcome and hence could be of assistance in the planning of adjuvant therapies.

Pelvic and para-aortic lymph nodal positivity in the ovarian carcinoma: its prognostic significance.

Our study is based on 29 patients with ovarian carcinoma in early stage (IA-IIB) having undergone total abdominal hysterectomy, with bilateral salpingo-oophorectomy, omentectomy, appendectomy and pelvic and paraaortic lymphadenectomy selective and bioptic. Out of the 29 patients 11 were classified I stage and 18 II stage. Within 3 years, out of 10 patients with node metastases, 1 is alive and free of disease, 6 deceased from the tumor and 3 are alive with residual tumor at various stages of invasion. Out of the 19 patients without nodes metastases 14 are alive and free of disease, 4 deceased from the tumor and 1 is alive with residual carcinoma. Survival related to histological type shows no statistically significant differences. Grading III has a survival of 27.6%, while the other two grades have a survival of 70% without significant differences. We can affirm that lymph nodes metastases represent the most reliable marker of high risk patients among the 3 risk factors (grading, histotype and nodes metastases) even if considered on a limited number of patients on the basis of preliminary data so obtained.

Radical vulvectomy and inguinal lymphadenectomy versus inguino-pelvic lymphadenectomy combined with radical vulvectomy and the role of radiotherapy.

We studied 39 patients with stromal invasion exceeding 1 mm. Among them 3 underwent emivulvectomy and 8 simple vulvectomy; all had selective inguinal lymphadenectomy of one side the first and bilaterally the others. 17 women underwent radical vulvectomy and inguinal lymphadenectomy while 11 had radical vulvectomy and inguino-pelvic lymphadenectomy. Out of 21 patients with lymph nodal metastases, 11 had one side inguinal metastases, 2 had a single metastasis, 2 had double metastases, 1 had three metastases and 2 multiple ones. Survival rate decreased from 54.5% to 20.0% when patients had more than 3 monolateral inguinal metastases or bilateral ones, with increase of pelvic lymph nodal metastases; therefore, in those cases, pelvic lymphadenectomy can be associated to inguinal lymphadenectomy or, when the carcinoma is situated in the clitoridis, Bartolino's gland or vagina (the same could be done for melanoma of the vulva). The usefulness of radiotherapy is limited by the small response of vulvar tissue. In a series of 45 patients with clinical diagnosis of inguinal metastases, who could not undergo operation, only therapy, with electron beam therapy (9 meV) associated to inguinal fields (15 meV), had positive influence in 27% of the cases.

Hormonal and surgical treatment of endometrial adenocarcinoma.

From January 1st 1980 up to December 31st 1986, 93 endometrial adenocarcinomas were treated at the Chair B of the Institute of Gynecology and Obstetrics. Full anatomopathological and hormonal data are available for 81 cases on whom diagnostic and therapeutic protocols were applied. In this selected group, positive lymph nodes were shown in 10 cases. Lymph node positivity was compared with miometrial infiltration grade: there were only two cases of lymph nodal positivity among 49 adenocarcinomas in which the invasion was more than 10 mm from the serosa, 8 lymph nodes metastases out of 32 adenocarcinomas with a distance between 10 and 5 mm and with distance less than 5 mm.

Complications of axillary, inguinal, pelvic and para-aortic lymphadenectomy.

Post-axillary lymphadenectomy complications have been checked in 1097 patients. Lymphedema occurred in 4.6% of cases, brachial injuries in 2% and necrosis with wound dehiscence in 0.44%. Pelvic lymphadenectomy complications have been studied in 139 patients who underwent Wertheim's operation and in 4 cases treated with Schauta-Mitra's operation for cervix or endometrium cancer. Para-aortic and pelvic lymphadenectomy complications have been considered in 92 patients who underwent Wertheim's operation, in 10 patients treated with anterior pelvic exenteration and in 1 patient who underwent posterior pelvic exenteration. The complications of para-aortic and pelvic selective lymphadenectomy have been checked in 101 patients. We had 3 peri-operatory deaths, 5 severe gastrointestinal complications (3 deceased for fistulae) and 2 intra-operatory iliac vessel injuries. Uretero-vaginal fistulae occurred in 6.2% of the cases also treated with radium-therapy and in 2.2% of the others. Intra/post-operatory bleeding was respectively 1500 +/- 450 ml and 450 +/- 300 ml. The complications of inguino-femoral and inguino-pelvic lymphadenectomy for vulvar cancer have been checked in 35 patients who had necrosis and wound dehiscence in all cases and lower limb thrombophlebitis in 2 cases.

Hormonal and surgical treatment of endometrial adenocarcinoma: actuarial survival.

We studied the survival period in two groups of patients with endometrial adenocarcinoma treated at the Chair B Institute of Gynecology and Obstetrics. The first series includes 30 of the 52 patients treated from 1976 to 1979. The second series includes 81 patients treated from 1980 to 1986. Lymph nodal positivity was present in 5 cases out of 30 patients belonging to Group I: all the interested lymph nodes were in the pelvic areas. Lymph nodal metastases were, instead, present in 10 cases as regard patients of Group II. Pelvic lymph nodes were involved in all the cases; in 5 of them also the paraaortic nodes were involved.

The correlation between the spread of metastases by level in the axillary nodes and disease-free survival in breast cancer. A multifactorial analysis.

Axillary lymph nodes were separated from 492 radical or modified radical mastectomies for primary breast cancer and examined according to their anatomical level corresponding to their position along the theoretical pathway of lymph drainage from the breast. The patterns of metastasis and the relationship between metastatized levels and disease-free survival were investigated to see whether complete axillary dissection is necessary for the staging and the planning of adjuvant therapy in breast cancer. Progressive involvement from level I (proximal) to level III (distal) was found in 206 specimens (80.8% of tumors with axillary metastases), while discontinuous or "skip" metastases were present in 49 (19.2%), including 38 (14.9%) with positive nodes at level II or III but not at level I. "Skip" metastasis was more frequent when fewer than four nodes were positive, and not related to either the size of the primary tumor or its location. The effect of age, menopausal status, tumor size, node status, number of positive nodes, anatomic level of axillary node involvement, estrogen and progesterone receptors, and adjuvant therapies on disease-free survival was evaluated using a multivariate proportional hazard model and life table analysis. This showed that disease-free survival was strongly related to the number of positive nodes (P less than 0.001), tumor size (P = 0.001) and level of node involvement (P = 0.01) as independent prognostic factors. Moreover, the subset of patients with four or more positive nodes and involvements of level III had a higher risk of recurrence (25% recurrence-free patients 5 years after mastectomy). The high frequency of "skip" metastases and the prognostic value of both the level of involvement and the number of metastatic nodes suggest that a complete axillary dissection is needed in the surgical management of breast cancer to obtain all the data useful in the planning of adjuvant therapy.

Surgical strategy management following lymph nodal positivity at the three levels (a retrospective and perspective study).

The purpose of this study is to evaluate the type of distribution, regular or irregular, of metastases in lymph nodes of I, II and III level. We inted also to establish if the levels of lymph nodal areas represent an evaluation index of prognostic risk more effective than other ones. The results evidenced that in 19.2% of all the classes N+ metastases were not increasing regularly from the level I to the level III. The influence of seven factors on disease free survival has been evaluated: pT, pN, number of metastatic nodes, ER+ or ER-, PgR+ or PgR-, grading, metastatic level at axillary lymph nodes. The present report points out that only the extent of tumor and lymph nodal level have a statistically significant influence on disease free survival. Comparison among disease free survival curves stage N0 with N+ at I level and with N+ at II level revealed that there is no significant difference of survival among these classes, while the comparison between the first 3 classes and N+ at III level is statistically significant.

Two cases of clinical Ib stage cervix carcinoma with exclusive metastases to presacral lymph-nodes.

There is regular progression of metastases through different stations of pelvic lymph nodes as far as para-aortic lymph-nodes in 81.1% of the cases examined of cervix carcinoma. In this paper we report two cases of squamous carcinoma of the cervix with metastases limited to one presacral lymph node, while other pelvic and para-aortic lymph nodes were free. These cases are two examples of irregularity of invasion of metastases from cervix carcinoma. It is extremely rare that presacral station is single and first invaded without extension of lower lymph nodal level. Our technique of pre-sacral lamina excision in connection with the inferior bridge of para-aortic and para-caval connective tissue during para-aortic lymphadenectomy is confirmed. The fatal outcome of the first patient's case is related to such risk factors lymph nodes metastases, deep infiltration of the cervix and involvement of lower section of the uterus. The second patient was free of disease within four months from surgery.

Lymph nodal metastases and the clinical stage of cervix carcinoma.

It has been proved that surgery is essential both for therapy and for diagnostic staging of gynaecological cancer. We have studied 131 patients who underwent pelvic and paraaortic lymphadenectomy. Out of the cases of the 1st clinical stage, the staging error was 16.4%. 10 cases were understage: 3 belonged to the 2nd surgical stage, 6 to the 3rd one and 1 to the 4th one. Out of 61 patients at the 2nd clinical stage, 44.2% were overstaged and 36.1% were understaged; in fact 16 belonged to the 3rd and 6 to the 4th surgical stage. 1 woman of the 6 belonging to the 3rd stage was at the 4th surgical stage. All 3 patients of the 4th stage had both clinical and surgical correct staging. The results show the determinant meaning of node metastases and their spreading for a correct surgical staging. According to the regular distribution of metastases, it has been shown that in 81.1% there is a regular rule while in 18.9% there is not a metastatic regular distribution. This study confirms the reliability of our surgical statement based on lymph nodal radical excision.