Local recurrences and distant metastases after conservative breast cancer treatments: partly independent events.

BACKGROUND: Local disease recurrences are a concern in conservative breast cancer surgery, and many studies have attempted to identify risk factors for these events. It is important to distinguish local recurrences linked to increased risk of distant spread from those due to inadequate local treatment. PURPOSE: We evaluated the incidence of local and distant recurrences according to demographic, biological, and pathologic variables in a large series of women who were conservatively and uniformly treated for breast cancer, with the aim of identifying women in whom local failure is predictive for distant metastases and who are therefore candidates for aggressive systemic treatment. METHODS: Medical records of 2233 women who had been hospitalized at the Milan Cancer Institute from 1970 to 1987 were analyzed. All women received quadrantectomy and axillary lymph node dissection followed by radiotherapy for the breast. Quadrantectomy is breast-conserving removal of most of the affected quadrant by a radial incision that includes part of the skin. The end points considered were local failures (including local recurrences and new ipsilateral carcinomas) and distant metastases. Statistical analysis employed the competing risks and multiple failures approaches. RESULTS: There were 119 local recurrences, 32 new ipsilateral carcinomas, and 414 distant metastases as first events. The timing of local failures and distant metastases differed: The yearly probability for local failures was approximately 1% up to the 10th year and for distant metastases was 5% in the 2nd year and decreased progressively until the 8th year. Young age was an important risk factor, with peritumoral lymphatic invasion also predictive for local and distant recurrences. Tumor size and axillary lymph node involvement were not related to local recurrence but were important predictors of distant metastases. Extensive intraductal component was only a risk factor for local recurrence. Early (< 2 years) local failure predicted for distant metastases compared with later failure. In local failure patients, the 5-year survival rate was 69% from failure. CONCLUSIONS: Local recurrences and distant metastases are partially independent events that occur at different times; several predicting factors also differ. However, women with local recurrences have increased risk of distant metastases. In particular, women 35 years old or younger at first diagnosis who had initial peritumoral lymphatic invasion and local recurrence within 2 years are at high risk for distant spread. For recurrence in cases with an extensive intraductal component or where initial local surgery was possibly inadequate, women are at lower risk.

Prognosis of breast cancer in males: an analysis of 170 cases.

A statistical analysis was performed on a series of 170 consecutive cases of operable (M0) breast cancer in males. All the patients underwent surgery. The end-points considered were: (i) overall mortality, (ii) all neoplastic events and deaths without evidence of breast disease (first event). Five- and ten-year overall mortalities were 26.9 and 54.3%, respectively. A multiple regression analysis showed that tumour size and nodal status (pT and pN) were statistically significant as prognostic factors. With regard to first events, 12 local recurrences (thoracic wall), one nodal relapse in the axilla and one contralateral tumour were observed. Primary tumours, other than breast cancer, occurred in 11 patients. The observed probability of surviving at 10 years from the treatment was definitely lower than that of the general population. For the follow-up periods of 0-5 and 6-10 years, the excess death rate per 100 man-years was 9.98 and 13.43, respectively. It appears from the analysis that prognosis of breast cancer is worse in men than in women.

Breast conservation is the treatment of choice in small breast cancer: long-term results of a randomized trial.

From 1973 to 1980, 701 women with small breast cancer (less than 2 cm in diameter) were randomized into two different treatments. 349 patients received classic Halsted mastectomy and 352 patients received quadrantectomy, axillary dissection and radiotherapy on the ipsilateral breast. 24.6% of the patients in the mastectomy group and 27.0% of the patients in the conservation group had axillary metastases. Overall 10 year survival was 76% in the Halsted patients and 79% in the quadrantectomy patients; 13 year survival was 69% and 71%, respectively. No differences were observed after analysis by site and size of the primary tumour and age of the patients. Patients with positive axillary nodes had consistently better survival curves in the quadrantectomy group compared with the Halsted group (not significant). Among the quadrantectomy patients there were 11 local recurrences (with 4 deaths) while among the Halsted patients, 7 had local recurrences (5 deaths). There were 19 cases of contralateral breast carcinomas in the quadrantectomy group and 20 in the Halsted group. At 16 years from the beginning of the trial no evidence of oncogenic radiation risk was observed. In patients with small size carcinomas total mastectomy should have no role.

Quadrantectomy versus lumpectomy for small size breast cancer.

Between 1985 and 1987 quadrantectomy plus external radiotherapy and lumpectomy plus external and interstitial radiotherapy were compared in a randomized trial of patients with small carcinomas of the breast. Quadrantectomy involves excision of 2-3 cm of normal tissue around the tumour plus the removal of a sufficiently large portion of overlying skin and underlying fascia whilst lumpectomy removes only the tumour mass with a narrow margin of normal tissue. Patients in both groups also received total axillary dissection. 705 cases were evaluable, 360 quadrantectomies and 345 lumpectomies. No differences in distant metastases and survival were observed in the two groups. However, lumpectomy patients had a much higher frequency of local recurrences (7.0 vs. 2.2%). Since a local recurrence needs a second operation and creates severe psychological distress to the patient, conservative surgical procedures should include generous excision of normal tissue around the primary carcinoma plus intensive postoperative radiotherapy.

Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients.

Breast conservation has become well-established in the treatment of early mammary carcinoma. However, a standardised treatment modality has not emerged. We have analysed the data from 1,973 patients treated in three consecutive randomised trials by four different radiosurgical procedures: Halsted mastectomy, quadrantectomy plus radiotherapy, lumpectomy plus radiotherapy, and quadrantectomy without radiotherapy, to compare the outcomes of these procedures in terms of local recurrence rate and overall survival. Eligibility criteria were similar in the three trials, and comparability between the four subgroups was excellent. Median follow-up for all patients was 82 months. The annual rates of local recurrence varied markedly according to the treatment. Patients treated with Halsted mastectomy and quadrantectomy plus radiotherapy had low annual rates of local recurrence (0.20 and 0.46, respectively) while both lumpectomy plus radiotherapy and quadrantectomy without radiotherapy had significantly higher rates (2.45 and 3.28, respectively). Patients under 45 years of age had a much higher incidence of local recurrences, while in women over 55 years local recurrences were much less frequent. Overall survival curves were identical in the four groups of patients, so that the three breast conserving radiosurgical procedures had the same survival rates as Halsted mastectomy. However, local recurrence rates were markedly influenced by the treatment method, patient age and specific histological features.

Argyrophilic carcinoma of the male breast. A neuroendocrine tumor containing predominantly chromogranin B (secretogranin I).

Argyrophilic tumors were diagnosed in 28 of 134 (20.8%) consecutive male patients who had a carcinoma of the breast removed between 1961 and 1990. Histologically, most argyrophilic tumors showed uniform cellularity and prevalent expansive growth. Ultrastructural observation disclosed the presence of electron-dense cored granules in the cytoplasm of the tumor cells. By immunocytochemistry, 17 of 28 argyrophilic tumors (60.7%) contained chromogranin B (secretogranin I)-immunoreactive cells, whereas chromogranin A was present in four of these 17 tumors only (14.2%). Immunoblotting studies showed chromogranin B immunoreactivity similar to that found in normal neuroendocrine cells. Despite these findings, which would argue for a distinct morphologic and immunochemical entity, no statistically significant differences between argyrophilic and common male breast carcinomas were found when a number of clinicopathologic features and relapse-free survival were considered.

Stereotactic excisional breast biopsy performed by interventional radiologists using the advanced breast biopsy instrumentation system.

The Advanced Breast Biopsy Instrumentation (ABBI) system, which uses surgical cannulas up to 20 mm in diameter, is an alternative to conventional surgical biopsy for the diagnosis of non-palpable breast lesions. Since the need for radiological skill outweighs the surgical content of the technique, we evaluated the feasibility of complete management of the procedure by interventional radiologists. 35 of the 111 patients originally scheduled for the procedure were excluded, three because the lesion could not be visualized and 32 because of insufficient thickness of the compressed breast. The procedure had to be abandoned in one case due to a technical failure. 77 stereotactic excisional breast biopsy procedures were performed using the ABBI system in 75 patients with suspicious non-palpable mammographic lesions. The procedure was carried out under local anaesthesia in the radiology department, using a dedicated Lorad (R) radiographic system. 31 (40%) masses without calcifications, 11 (14%) masses with calcifications and 35 (46%) clusters of microcalcifications without tumour mass were sampled. 43 (56%) benign lesions and 34 (44%) malignant lesions were diagnosed. The overall mean diameter of the lesions was 8.7 mm (range 3-22 mm). All 34 patients with malignancies and lobular carcinoma in situ subsequently underwent surgery, the results of which are reported. Three (4%) haematomas were detected and aspirated percutaneously. Two technical problems occurred: an ABBI cannula malfunction, and a computer failure of the digital imaging system during the procedure. The average procedure time was 80 min and the cost of each procedure was 2,800,000 Italian lire (1555 US$). It is concluded that tissue sampling with the ABBI system can be performed entirely by radiologists without significant problems. The procedure was well tolerated by all patients. The quality of the biopsy specimen was identical to that of a surgical specimen but with the advantages of stereotactic precision for localization of the lesion.

Analysis of 100 cases of Paget's disease of the breast.

Of 100 cases of Paget's disease of the breast admitted to the National Career Institute of Milan from 1940 to 1974, 91 were statistically evaluated. They were divided in two groups according to presence or absence of a palpable nodule. The results of surgical treatment in terms of 5 and 10 year survival rates were 59 and 44%, respectively, with a median survival of 9 years. For the two separate subgroups, those with a palpable nodule were 38 and 22% for 5 and 10 years, respectively, while those without a palpable nodule were 92 and 82% for 5 and 10 years, respectively. For the two groups the median survival was 3.6 and 16.4 years, respectively. The extent of surgery should be dependent on the presence of absence of palpable nodules under the nipple. For the two groups (with and without) extended radical mastectomy and the Patey-Dawson mastectomy are recommended.

Clinical data and estradiol receptor evaluation in breast cancer biopsies.

To determine the correlation between the response to the estradiol receptor test and some fundamental properties of the tumor and the host, a study was conducted on 337 patients. Primary carcinomas, including lobular carcinomas, and recurrences or metastases are characterized by similar frequencies of response to the estradiol receptor test (68% positive, 26% negative and 6% borderline), while normal breast tissue is characterized by a higher frequency of negative results (3% positive, 71% negative and 26% borderline). Postmenopausal patients show a shift of estradiol receptor levels towards higher values with respect to premenopausal patients. Contemporaneously, an increase in estradiol receptor concentrations with patient age is observed. The clinical stage appears in influence estradiol receptor content only in postmenopausal patients, for whom an increase in the tumor size is accompanied by a decrease in the estradiol receptor levels. The apparent association constant of the receptors assumes values ranging from 1.5 to about 300 X 10(9) M-1 and does not appear to be related to either the type of tumor tissue or to the clinical stage of the tumor, age, or menopausal status of the patients.

PIP: This study reports a statistical analysis of a series of 337 (of 1200 tested) cases of mammary gland tumors for whom complete clinical information was available; estrogen receptor (ER) content was analyzed at various stages of breast cancer with regard to pathologic characteristics, such as the size of the tumor and involvement of axillary nodes, with respect to menopausal status and age of patient. This correlation study showed that primary carcinomas, including lobular carcinomas, and recurrences or metastases were characterized by similar frequencies of response to the ER test (68% positive, 26% negative, and 6% borderline), whereas normal breast tissue was characterized by a higher frequency of negative results (with only 3% positive, 71% negative, and 26% borderline). A shift to higher ER-level values was seem among postmenopausal patients vs. premenopausal ones. At the same time, an increase in ER concentrations with patient age was observed. In postmenopausal, but not in premenopausal, patients clinical stage of the tumor seemed to influence ER content; for these patients, an increase in tumor size was accompanied by a decrease in ER levels. The apparent association constant of the receptors does not appear to be related to either the type of tumor tissue or the clinical stage of the tumor, age, or menopausal status of the patient.

Nipple discharge as a sign of preneoplastic lesions and occult carcinoma of the breast: clinical and galactographic study in 103 consecutive patients.

A clinical and galactographic investigation was carried out on 103 patients with hematic, serous-hematic, and serous nipple discharge. The age of the patients ranged from 18 to 72 years. A single papilloma was found in 20 cases, diffuse papillomatosis in 2 cases, atypical ductal hyperplasia in 8 cases, and ductal carcinoma in 4 cases (3 of these were infiltrating and 1 was noninfiltrating associated with a diffuse papillomatosis). Mammography gave no indications of carcinoma in any of the 4 cases. In the remaining 49 patients, pictures of ductal hyperplasia, periductal mastitis or sclerosis, sclerosing adenosis, or ductal ectasia were observed. The various types of lesions were often associated. Lacunae, stenosis, or occlusion of the ducts, evidenced by galactography, correlated well with the histologic findings of proliferative lesions of the ductal epithelium. Nevertheless, in practice, it should be the type of discharge that indicates surgery rather than galactographic or cytologic data, which appeared to have little diagnostic value. The frequency with which preneoplastic (or limit) lesions, and also nonsuspect carcinomas were found in patients with a significant nipple discharge confirm the importance of this symptom for a secondary prevention of early diagnosis of mammary neoplastic lesions originating from galactophorous ducts. Finally, complete resection of the galactophorous ducts must be considered as the best treatment in all patients with a suspicious nipple discharge that requires surgery.

Hormones in male breast cancer.

Urinary levels of testosterone, 5 alpha-androstanediol, 17-hydroxycorticosteroids, pregnanediol, and circulating levels of testosterone, 17 beta-estradiol, dehydroepiandrosterone-sulfate, prolactin, luteinizing hormone, follicle-stimulating hormone and sex hormone-binding globulin, were measured in 10 male patients with breast cancer and in a suitable group of healthy controls. No difference, either in blood or in urine, was observed between the two groups in the hormonal levels. The lack of abnormalities in peripherally detectable hormones suggests that the well recognized hormone dependency of male breast cancer may be due to some endocrine imbalance in the central (diencephalic) regulation of the sex steroids pathway. Alternatively, abnormal response of breast tissue to normal hormonal stimuli might be hypothesized in these patients.

[Conservative treatment of breast cancer. A therapeutic trial in progress at the Cancer Institute of Milan]. / Traitement conservatif du cancer du sein. Essai thérapeutique en cours à l'Institut du Cancer de Milan.

The report describes a clinical trial on conservative surgery in progress at the National Cancer Institute of Milan, Italy. The randomized clinical trial compares radical mastectomy with a more conservative procedure consisting of mammary resection plus axillary dissection plus radiotherapy. The resection comprises an entire quadrant of the breast together with the overlying skin. After surgery the patients receive 6 000 rads to the residual breast tissue over five to six weeks, starting 15 days after operation. The cosmetic results are satisfactory in the majority of cases. The trial is limited to cases with tumors less than 2 cm (T1N0M0). Patients with histologically positive lymph nodes (N+) are submitted to adjuvant chemotherapy with CMF for one year. From September 1973 to October 1976, 331 cases entered the trial. One hundred sixty seven were treated with radical mastectomy and 164 with conservative procedure. Axillary metastases were found in 23 per cent of the radical and in 29 per cent of the conservative surgery group. Four local-regional recurrences have occurred till now, two in each group. Five cases in the radical mastectomy group and one in the conservative group had distant metastases. The clinical trial will collect some 500 cases by the end of 1977 and significant preliminary results are expected to be available from the beginning of 1979.

Inflammatory cancer of the breast: analysis of 114 cases.

One hundred and fourteen cases of inflammatory breast cancer were reviewed. Actuarial survival curves, independent of the stage and type of treatment, showed a median survival of less than 15 months. As regards the three different subgroups of 80, 14, and 20 women, N0-1-2M0, N3M1 respectively, the acutuarial survival curves showed figures of median survival that decreased from 14 to 4 months, according to the extent of the disease. Survival rates for the subgroups of patients treated by radical mastectomy, radical mastectomy followed by radiotherapy, and radiotherapy alone were not significantly different. Neither the more sophisticated therapeutic approaches intended to modify the hormonal medium of the patients, nor the combined chemotherapy plus radiotherapy, proved to be successful. Inflmmatory breast cancer should be considered a systemic disease; consequently, in spite of discouraging results, only a systemic therapeutic approach, consisting of aggressive combination chemotherapy and perhaps immunostimulation, seems worthwhile.

Conservative surgery for infiltrating lobular breast carcinoma.

BACKGROUND: Some reports state that infiltrating lobular breast carcinoma (ILC) should not be treated by conservative methods because of a high risk of local recurrence. The aim of this study was to determine whether patients with conservatively treated ILC have a higher risk of intrabreast relapse than those with infiltrating ductal carcinoma (IDC). METHODS: Some 286 consecutive patients with ILC of the breast were compared with 1903 women with IDC treated at the Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, over the same interval (1973-1989). Patients in both series received the same treatment: quadrantectomy, complete axillary dissection and radiotherapy to the breast. Adjuvant treatment was administered according to nodal and menopausal status (chemotherapy or tamoxifen). Follow-up lasted until December 1994, with a median of 137 months for patients with ILC and 133 for those with IDC. Histology slides were reviewed to assess the presence of multifocality (ILC 4.5 per cent versus IDC 3.6 per cent and extensive intraduct component (ILC 0.3) per cent versus IDC 6.4 per cent). RESULTS: No difference in cumulative local recurrence rate was found between the two groups at 10 years (approximately 7 per cent). CONCLUSION: Conservative surgery is equally safe for patients with infiltrating lobular or ductal carcinoma of the breast.

[Percutaneous transhepatic biliary drainage in obstructive jaundice. Report of 19 cases (author's transl)]. / Il drenaggio biliare transepatico percutaneo nell'ittero ostruttivo. Considerazioni su 19 casi.

The development of percutaneous transhepatic techniques of access to biliary tree with the fine needle made possible the wide diffusion of percutaneous biliary drainage. Results of 19 attempts of biliary drainage are presented; success rate in positioning external or external-internal drainage was 79% (92.3% in the last year). The technique employed is described and discussed comparing it with the methods proposed by other authors. Early therapeutic effects and long-term benefits on bilirubin levels and survival were good. Only 2 major complications were observed (hepatic abscess and biliary subcapsular cyst) but they did not require surgery. Cholangiocarcinomas and ilar hepatic metastases appeared to be elective indications to definitive palliative drainage, but pre-surgical or palliative drainage is also recommended in all cases of obstructive jaundice. Careful follow-up and check of patients with the biliary drainage improves the drainage function and reduces the complications.

Conservative treatment for breast cancer of limited extent. Results of a randomized trial.

From 1973 to 1980, a controlled clinical trial was carried out at the National Cancer Institute of Milan to compare the Halsted mastectomy with breast quadrantectomy and axillary dissection followed by radiotherapy in patients with breast cancer of less than 2 cm in size. Cases of breast cancer classified as T1N0 were randomized into the two treatment procedures: 349 cases were treated with the Halsted mastectomy and 352 with the quadrantectomy technique. The two series were comparable with regard to age distribution, size, site of primary tumor, menopausal status and frequency of axillary metastases. Three local recurrences occurred in the Halsted group and one in the quadrantectomy group. Actuarial curves showed no difference in the two series with regard to disease-free and overall survival. In view of these results, mastectomy appears to be an unnecessary mutilation for patients with breast carcinomas less than 2 cm in size and no palpable axillary nodes.

Results of a breast-cancer-surgery trial compared with observational data from routine practice.

BACKGROUND: The strength of randomised controlled trials (RCTs) is that they allow investigators to draw reliable inferences about treatment differences; physicians can then make a choice between different options. Their weakness is that they are conducted on a set of patients who cannot be regarded as a random sample from the population that will be treated outside the trial. Observational data collected in a prospective clinical database may provide more realistic estimates. METHODS: At the Istituto Nazionale de Tumori of Milan an RCT was started in 1973 (MI1) in which Halsted mastectomy was compared with quadrantectomy plus axillary dissection and radiotherapy (QUART), a breast conserving treatment, for "early-stage" primary breast cancer. In addition, a prospective clinical database was established to collect, in standard format, information on all women undergoing breast conservation thereafter and followed up at the Institute. 1760 women were treated with QUART, 350 of them being accrued in the years 1973-80 in the context of the MI1 trial. The remaining 1408 received QUART after the MI1 trial, up to December, 1984. RESULTS: In the years after the trial, the criteria for use of QUART became more liberal. However, after adjustment for baseline characteristics, out-trial patients fared no worse than trial patients in terms of survival or distant metastasis. Out-trial patients did have a slightly higher rate of local recurrence, probably because of subtle and multiple changes in the surgical procedures since the time of the trial. INTERPRETATION: The results of QUART in out-trial patients resembled those reported from research settings. In this instance, the results of clinical trials did not exaggerate the benefits obtainable in routine practice.

Surgical treatment of phyllodes tumors of the breast.

Eighty-one female patients with phyllodes tumors of the breast, surgically treated from 1974 to 1983, were studied. Their age ranged from 9 to 88 years. According to histology, the series was divided into three groups, of 28 (34.5%) benign tumors, 32 (39.5%) border-line tumors, and 21 (25.9%) malignant tumors. Because ten patients were lost to follow-up, only 71 women could be evaluated. All the patients had received surgical treatment: 51 women had been treated conservatively (11 enucleations, 40 wide resections), and 20 had undergone radical operations (13 underwent total and five underwent subcutaneous mastectomies, whereas one underwent modified and one underwent radical mastectomy). The mean follow-up, for the three groups, was 106 months for benign, 84 months for borderline, and 82 months for malignant tumors; in no case was radical surgery followed by local recurrence: of 51 women conservatively treated, 14 experienced local relapse, i.e., one of 24 women with benign, ten of 22 with borderline, and three of 8 with malignant lesions. Only two of 47 patients (4.2%) with borderline or malignant tumors developed distant metastasis and died from disease. No relationship between tumor size and risk of local recurrence could be demonstrated, and no difference could be identified between borderline and malignant lesions, in terms both of local and distant relapse. Local recurrences do not appear to affect survival: as a consequence, wide resection should be the primary treatment. Enucleation is to be proscribed. Total mastectomy has been indicated for very large tumors and for local recurrences of borderline and malignant lesions. Axillary dissection is not worthwhile.

Conservative treatment of early breast cancer. Long-term results of 1232 cases treated with quadrantectomy, axillary dissection, and radiotherapy.

One thousand two hundred and thirty-two women with invasive breast cancer lesions measuring less than 2 cm in diameter, clinically assessed as T1N0-1M0, were treated from 1970 to 1983 at the National Cancer Institute of Milan with quadrantectomy, axillary dissection, and radiotherapy (QUART). Pathologic evidence of lymph-nodes metastases was found in 32% of the patients. Overall survival at 5 and 10 years from surgery was 91% and 78%, respectively. The cumulative probability of survival tends to decrease with increasing tumor size: the 7-year survival rate was 84% in cases in which lesions measured from 1.6 to 2.0 cm, and 94% in cases in which the lesions were less than 0.5 cm. Tumor site in the treated breast did not affect distant outcome. No difference was found between the patients without node metastases and patients with one node involved, whereas the patients with more than one node showed a lower probability of survival. The survival curves of 352 cases treated inside a randomized trial and that of 880 cases routinely treated appear to be superimposable. Local recurrences and new primary ipsilateral tumors were, respectively, 35 (2.8%) and 19 (1.6%); 56 women with local recurrences or second tumors underwent second surgery (total mastectomy, 43; wide resection, 11). Five of them died from distant spread of breast cancer, while 49 are alive and well. In the contralateral breasts 45 carcinomas were recorded during the follow-up time. The results of the present analysis of a large number of T1 cases reconfirm the safety of integrated radiosurgical conservative treatments.