Johan A. Andersen

Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies.

In 110 consecutive, medicolegal autopsies of young and middle-aged women (range 20-54 years) the breasts were examined by an extensive histopathologic method and by correlative specimen radiography. Malignancy was found in 22 women (20%) of which only one was known to have had clinical invasive breast cancer (IBC). At autopsy 2 women had IBC (2%), the remaining in situ carcinoma (in situ BC) of microfocal type (18%), i.e. 15 (14%) intraductal carcinomas (DCIS), 4 (3%) lobular carcinoma in situ (LCIS) and one (1%) both DCIS and LCIS. Forty-five per cent of the women with malignancy had multicentric and 41% had bilateral lesions. Forty-five per cent of all histologically confirmed malignant lesions were identified by specimen radiography. Adenosis, benign epithelial hyperplasia, papilloma and duct ectasia were positively associated with malignancy. In addition malignancy was significantly more frequent among women aged more than 40 years, with late age at first full-term pregnancy, with alcohol abuse and with steatosis or cirrhosis of the liver. The results suggest that clinically occult in situ BC are frequent in young and middle-aged women.

Lobular Carcinoma In Situ of the Female Breast: Short-Term Results of a Prospective Nationwide Study

In a Danish nationwide prospective study of in situ carcinoma of the breast, 112 women with ductal carcinoma in situ, treated with excision only, were registered from 1982 to 1987. Within a median follow-up of 53 months, a crude recurrence rate of 22% (25 cases) was found, of which five cases recurred as invasive carcinomas and 20 cases as in situ carcinomas. The histopathologic review included a single-parameter analysis of histological growth pattern, size of lesion, nuclear size, presence of comedonecrosis, and subhistologic type. A strong inter-relationship was found for histological growth pattern, nuclear size, and comedonecrosis. These parameters were also significantly related to recurrence. Cases that had clinical symptoms had a high recurrence rate as compared with cases that were discovered by mammography only or incidentally.In a Danish nationwide prospective study of in situ carcinomas and atypical lesions of the breast, 88 women, comprising 69 patients with lobular carcinoma in situ (LCIS) and 19 patients with combined lobular and ductal carcinoma in situ (LCIS + DCIS), were accrued from 1982 through 1987. All cases were treated with excision only. Within a median follow-up time of 61 months, a recurrence rate of 17% (15 cases) was found, excluding nine cases of refinding of LCIS. No contralateral recurrences occurred. The recurrences were in eight cases invasive carcinomas (IC), in six cases LCIS + DCIS, and in one case DCIS alone. The recurrence rates among cases of LCIS and of LCIS + DCIS were not significantly different. The histopathological review included an estimate of the number of lobules with LCIS and nuclear size, both of which were significantly related to recurrence. The risk of developing IC was calculated to be increased by a factor 11 as compared with the reference population.

Lobular carcinoma in situ. A long-term follow-up in 52 cases.

During a retrospective histological study based on examination of 3299 female breast tissue specimens with otherwise benign diseases, 52 cases of lobular carcinoma in situ were found. Five cases presented previous invasive breast carcinoma, and one of these developed subsequently invasive carcinoma during the first year after the biopsy. Out of 47 cases without previous invasive breast carcinoma, 10 developed subsequently 12 invasive carcinomas. Eight were ipsilateral and were revealed within the 1st, 2nd, 3rd, 5th, 7th, 14th, 18th, and 22nd year, respectively. Four were contralateral and were found within the 7th, 8th, 12th, and 24th year after the primary biopsy. The average follow-up period was 15 years. Strict follow-up of patients with lobular carcinoma in situ, carried out by a permanent team, is considered a realistic alternative to mastectomy.

Lobular carcinoma in Situ of the breast: An approach to rational treatment

A review of 3299 benign breast lesions was carried out. Lobular carcinoma in situ (LCIs) was discovered in 52 cases; and of these, 44 had been treated by biopsy alone. During the follow‐up period averaging 15.9 years, 11 patients developed invasive breast cancer (IBC): 9 ipsilateral lesions, and 4 contralateral. This was about 12 times the frequency expected. The development of IBC had no relation to the patients age, nor could any correlation be drawn between the time periods which elapsed from the time of the diagnosis of the in situ cancer to the development of IBC. The ipsilateral occurrence of IBC was not significantly different from the contralateral. Careful lifelong follow‐up seems to be the rational treatment for women whose breast biopsy shows LCIs.

Precancerous and cancerous breast lesions during lifetime and at autopsy. A study of 83 women

Among 83 consecutive, unselected female autopsy cases, 6 had been treated for invasive breast carcinoma (IBC) during lifetime. At autopsy, of these six women, two had IBC in the contralateral breast, and another two had in situ carcinoma. Among the 77 women without previous clinical breast cancer, one case of IBC and 14 cases of in situ carcinoma were found at autopsy. Thus, the total occurrence of primary malignant breast lesion was as high as 25.4%. Assuming that all IBCs evolve from in situ forms and that in situ carcinomas do not undergo total regression, our results seem to indicate that about one third of all in situ carcinomas develop into IBC.

Immunohistochemical localization of urokinase‐type plasminogen activator, type‐1 plasminogen‐activator inhibitor, urokinase receptor and α2‐macroglobulin receptor in human breast carcinomas

We have investigated the localization of urokinase‐type plasminogen activator (u‐PA), type‐1 plasminogen‐activator inhibitor (PAI‐1), u‐PA receptor (u‐PAR) and α2‐macroglobulin‐receptor/low‐density‐lipoprotein‐receptor‐related protein (α2MR/LRP) in human breast tumors by immunohistochemical methods. Frozen sections of 133 primary breast carcinomas, 6 ductal carcinomas in situ and 33 lymph‐node metastases were stained with monoclonal antibodies. Formalin‐fixed sections of 15 primary tumors and 2 lymph‐node metastases were stained with polyclonal antibodies. In primary tumors, u‐PA and PAI‐1 immunoreactivities were intense in macrophages and mast cells, and moderate in benign and malignant epithelial cells as well as in myofibroblasts and endothelial cells. A sub‐group of poorly differentiated tumors showed particularly strong staining of stromal fibroblasts. u‐PA immunoreactivity was also present in lymphocytes. α2MR/LRP and u‐PAR immunoreactivities were intense in macrophages, but apart from these cells, α2MR/LRP was found only in fibroblasts, and u‐PAR only in tumor cells located peripherally in tumor‐cell clusters and glands and some myofibroblasts in the adjacent stroma. Lymph‐node metastases showed staining for u‐PA and PAI‐1 both of cancer cells and of stromal fibroblasts, also staining for u‐PA of lymphocytes. Similarly to some of the poorly differentiated primary tumors, approximately half of the metastases showed very strong staining of stromal fibroblasts, and extracts of these metastases had higher u‐PA and PAI‐1 levels, as determined by ELISA, than extracts of metastases without this staining pattern. α2MR/LRP was present only in fibroblasts and u‐PAR only in some tumor cells. The presence of u‐PA, PAI‐1, α2MR/LRP and u‐PAR was controlled biochemically by immunoblotting analyses, ligand‐blotting analyses, and direct and reverse zymography. The spatial distribution and the variation in concentration of the various components of the plasminogen‐activation system point to a complex, multifunctional role for the 4 proteins in and/or during the development and spread of breast cancer.

Prognostic significance of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in primary breast cancer

The uPA-mediated pathway of plasminogen activation is central to cancer metastasis. Whether uPA and PAI-1 are related to local recurrence, metastatic spread or both is not clear. We present a retrospective study of 429 primary breast cancer patients with a median follow-up of 5.1 years, in which the levels of uPA and PAI-1 in tumour extracts were analysed by means of an enzyme-linked immunosorbent assay. The median values of uPA and PAI-1, which were used as cut-off points, were 4.5 and 11.1 ng mg(-1) protein respectively. The levels of uPA and PAI-1 were correlated with tumour size, degree of anaplasia, steroid receptor status and number of positive nodes. Patients with high content of either uPA or PAI-1 had increased risk of relapse and death. We demonstrated an independent ability of PAI-1 to predict distant metastasis (relative risk 1.7, confidence limits 1.22 and 2.46) and that neither uPA nor PAI-1 provided any information regarding local recurrence.

Carcinoma in situ of the female breast. 10 year follow-up results of a prospective nationwide study

In a Danish nationwide prospective study of in situ carcinoma of the breast, a total of 275 women, treated with excision alone, were registered from 1982 to 1989. The series included 142 cases of ductal carcinoma in situ (DCIS), 100 cases of lobular carcinoma situ (LCIS), 26 cases of DCIS+LCIS, and seven cases of atypical hyperplasia (AH). Within a median follow-up of 120 months, a crude recurrence rate of 28% (76 cases) was found, of which 53% (40 cases) recurred as invasive carcinomas (IC) and 47% (36 cases) as CIS. CIS recurrences appeared after median 18 months, compared to median 42 months for IC recurrences. No statistical difference was found with respect to development of IC between the three groups of DCIS, DCIS+LCIS, and LCIS. The majority of recurrences were ipsilateral, also for LCIS. Forty four of 49 recurrences following DCIS, and seven of nine recurrences following DCIS+LCIS occurred as local recurrences. Histopathologically, in DCIS a strong association was found between large nuclear size and comedonecrosis. Univariate analysis showed a significant association to recurrence for nuclear size, comedonecrosis, and size of the original lesion. Multivariate analysis showed that only comedonecrosis and size of lesion were independent predictors of recurrence, however, specimen margins were not included in the analysis, as this parameter could not be adequately evaluated in the present series. Nuclear size of original DCIS lesion was related to histologic grade of the IC recurrence. The recurrence rate for DCIS of small nuclear size increased from 6% at five years of follow-up to 16% at 10 years, possibly due to a slower growth rate and a continued but delayed risk. Similarities were found between LCIS and DCIS of small nuclear size, both showing a continued risk and comparable rate of recurrence. Further, progression of IC to similar, highly differentiated type was seen, indicating a linkage between biological behavior of the two histological types.

A DANISH RANDOMIZED TRIAL COMPARING BREAST-PRESERVING THERAPY WITH MASTECTOMY IN MAMMARY CARCINOMA Preliminary results

The present study comprises 847 women operated upon for invasive breast carcinoma at 19 surgical departments and enrolled in protocol DBCG-82TM from January 1983 to November 1987. Among them 662 (78%) were allocated for breast-preserving therapy or mastectomy by randomization, while 185 patients (22%) did not accept randomization. Within the randomized group 6% could not be entered into adjuvant protocols, i.e. subsequent programmes of postoperative therapy and follow-up. This left 619 evaluable patients. In the non-randomized series 26% did not fulfil the demands for entrance into the adjuvant protocols, leaving 136 evaluable patients, 60 of whom had chosen a breast-preserving operation and 76 mastectomy. In the randomized series the patients in the two treatment arms were comparable in age, menopausal status, site of tumour, pathoanatomical diameter of the tumour, number of removed axillary lymph nodes, number of metastatic axillary lymph nodes, and distribution on adjuvant regimens. Ninety per cent of the patients in the randomized group accepted the method offered, whereas 10% declined and wanted the alternate form of operation. The median follow-up period was approximately 1.75 years. The cumulative recurrence rate in the randomized group was 13% and in the non-randomized group 7%. These results are preliminary. Life-table analyses have not so far demonstrated differences in recurrence-free survival either in the randomized or the non-randomized series.

Radial scar in the female breast. A long-term follow-up study of 32 cases

In a retrospective histologic study of 1862 benign breast tissue specimens, 32 cases were found to have radial scar. The radial scar was multicentric in 44%, and found in breasts with fibrocystic disease and/or duct ectasia. During a follow‐up period of 19.5 years (range, 15–24 years), one patient developed breast cancer compared with an expected rate of 0.94. Therefore, local excision of radial scar without further follow‐up is sufficient.