Efferent vascular invasion in the axillary nodes in breast carcinoma: a potent prognostic factor.

Tumour cells in the efferent vessels of the axillary nodes in breast cancer (EV status) have been associated with poor prognosis since 1979. A prospective study (1980-1989) of all the nodes from 1037 consecutive female patients with unilateral breast cancer whose treatment included axillary node dissection yielded 471 node-positive cases. Tumour cells were found in the efferent nodal vessels of 210 patients, while 252 were negative. In the remaining 9 patients efferent nodal vessels could not be identified. At follow-up, 62% of the node-positive patients had died of breast carcinoma, in contrast to 32% of node-negative patients. The prognosis in cases with 1-3 versus 4+ tumour-bearing nodes was highly significant, 36% and 64%, respectively having died of breast carcinoma,. Prognosis was not dependent on the number of EV+ nodes in those cases showing efferent vascular invasion, one positive node was enough. Differentiation between these nodal growth forms thus provides a strong prognostic indicator, available to all with access to routine surgical pathology. We confirmed the significance of both variables using Cox's regression analysis and showed that the number of positive nodes adds significant prognostic information to that of EV status, which is the stronger of the two prognostic indicators. EV+ patients with more than three positive nodes have more than a three times higher risk of dying than EV- patients with three or fewer positive nodes.

'Missed' micrometastases--the extent of the problem.

The value of detecting micrometastases in patients with breast cancer has been debated for many years. The aim of this study was to determine whether and why such tumour deposits are missed at the time of reporting. The series comprised 272 patients treated surgically for breast carcinoma. For node-negative cases, the haematoxylin and eosin stained slides were re-examined. Those still remaining negative were stained with epithelial membrane antigen marker (EMA). Hilar sections were used in 76% of cases. Micrometastases were found in 35 cases reported as node-negative: 15 being identified on re-examination and 20 after staining with EMA, a gain of 44%, including 20 of embolic type. All were found in hilar sections of the nodes. The patients in whom micrometastases were found on further examination had significantly smaller tumour deposits than those reported as node-positive. In cases with infiltrating ductal carcinoma these presented as embolic growth, while those with infiltrating lobular carcinoma, for example, tended to colonize the nodal parenchyma, giving nodal growth. Differentiation between these growth patterns enables pathologists to distinguish between the dangerous embolic type and the less important nodal growth. In conclusion, many of these micrometastases can be detected if the slides reported as node-negative on first reading are re-examined. In those remaining negative, immunohistochemical staining is recommended.

Is a woman's date of birth related to her risk of developing breast cancer?

Some previous reports have shown seasonality in the date of birth in patients with breast cancer, others have not. In this study of 1,110 women with unilateral breast carcinoma significantly more cases had been born in the first than the second half of the year. This finding could, however, not be linked to the later development of breast cancer as their case-matched controls showed a similar trend. These results underline the importance of using relevant control material in such studies.

Annual Rhythm in the Growth of Human Breast Carcinomas as Reflected in the Histology of Their Growing Edge.

This histologic study of breast carcinoma, based on 100 consecutive cases, identifies a dynamic scenario at the tumor edge. Three main types of tumor edge were identified. An inactive edge, seen throughout the year, consisted of tumor cells lying in fibrous tissue that merged into the adjacent fatty tissue. An infiltrative edge was characterized by an acute microvascular response and the presence of fine lymph channels often containing embolic tumor cells. A capsular edge showed sharp tumor demarcation accompanied by proliferation and followed by lymphocyte infiltration. Infiltrative edges were found mainly in the first half of the year, and capsular edges in the second. Thus, the growth of individual breast carcinomas appears to be the result of a common series of growth phases at their advancing edge that follow an annual cycle. Int J Surg Pathol 8(1):39-47, 2000

Laser conization of cervical intraepithelial neoplasia grade 3: free resection margins indicative of lesion-free survival.

BACKGROUND: Various grades of cervical intraepithelial neoplasia may occur following laser conization for grade 3 lesions. The aim of this study was to assess lesion-free survival after laser conization in cases with/without free resection margins, and to test whether detection of human papillomavirus infection and/or p53 expression in the cone lesion were useful predictors of lesion-free survival. METHODS: In 598 women treated for cervical intraepithelial neoplasia grade 3 the state of the resection margins was recorded and related to the findings on follow-up, up to 15 years post-operatively. Lesion-free survival times were analyzed by the Kaplan-Meier method. The presence/absence of human papillomavirus infection and/or p53 expression in the primary lesion was investigated in every fifth case by in situ hybridization and immunohistochemistry respectively. RESULTS: Lesion-free survival was significantly more common after complete than incomplete excision of cervical intraepithelial neoplasia. In the latter, lesions tended to appear shortly after surgery, indicating the presence of residual disease. The few lesions appearing later were evenly divided between those with and those without complete excision. The results of the human papillomavirus and p53 investigations added no further information. CONCLUSIONS: The presence of cervical intraepithelial neoplasia in the cone margin gives strong indication of potential treatment failure. In its absence laser conization is highly effective in the treatment of cervical intraepithelial neoplasia, and has the advantage of providing a specimen suitable for the necessary histological investigation.

Prognostic implications of cervical intraepithelial neoplasia in a single cervical smear. an age-matched case-control study of women with negative smear histories.

Our aim was to investigate the prognostic implications of a single cervical smear showing cervical intraepithelial neoplasia (CIN) in a group of women with a previous series of negative smears, and to estimate their risk of developing histologically confirmed CIN 3. A retrospective case-control study was set up. It consisted of 171 cases and 513 age-matched controls, all with at least 3 negative and no positive smears between 1981 and 1988 inclusive. In all cases CIN had been diagnosed on cytology in 1989, while the controls had remained negative. The women were followed up to the end of 1995. The outcome was recorded in terms of regression, progression, persistence or surgical treatment. In women with a single smear showing CIN 1 or 2, the risk of developing histologically proven CIN 3 was 14 and 26 times that in women with negative smears. Negative control smears in the short term did not exclude subsequent progression. Thus women with a single cervical smear indicating CIN 1 had a greatly enhanced risk of producing a lesion that demanded intervention. Such cases should be observed closely with repeat smears over a period of at least 6 years.

Nodal tumour growth in breast cancer: the time-span of its biological progression.

This series of 1,154 women with unilateral breast carcinoma was treated by modified radical mastectomy with axillary dissection. Histological staging of nodal tumour growth in the axilla distinguished 4 populations in which the numbers of patients presenting for operation over the months of the year differed markedly. The findings are used to develop a hypothesis on nodal tumour growth in which the length of time needed to complete the growth sequence, from the entry of a micrometastasis to exit of tumour cells via the efferent nodal vessels, could be estimated. The results suggest that the time-span may be as much as 3 years, and probably more.

The size of a micrometastasis in the axilla in breast cancer: a study of nodal tumour-load related to prognosis.

Much has been written on micrometastases to the axilla in breast cancer but there is no consensus as to their size. In this study three levels of nodal tumour-load are defined following measurement of nodal tumour area on histology. The two cut-points described are both of clinical interest. The smallest deposits, up to 0.0001 cm2, include embolic growth on the afferent side of the node, which is, as reported previously, of poor prognosis. In such cases post-operative prognosis approaches that in the "node-positive", here defined as cases with an axillary tumour-load of 0.5 cm2 or more. Between these two groups is a collection of cases, 40% of the total series, with a prognosis similar to the node-negative. It is suggested that the deposits in this intermediate group should be termed micrometastases, the high risk cases with embolic growth reported as such and those with larger deposits as node-positive.

Staging nodal growth in breast cancer on a histological basis.

This study describes the axillary tumour-load in 484 women with breast carcinoma with spread to one or more nodes. The aim was to relate tumour-load to nodal histology. The tumour area and that of residual lymphoid tissue was measured from standardised nodal sections. The presence/absence of tumor cells in the efferent vessels (EV) defined their nodal status as EV+ or EV-. The former has a poor prognosis. While the number of EV+ cases increased with the total tumour-load, the number of EV- cases decreased. In the EV+ there was high positive correlation between tumour-load and number of deaths from breast cancer, with a corresponding negative correlation in the EV-. Twice as many patients with EV+ nodes died of breast cancer compared to the EV- group. Investigation of 164 consecutive tumour-bearing nodes showed a similar pattern. Irrespective of EV status the area of residual lymphoid tissue remained constant. Although the lymphoid area was similar the tumour-load was twice as high in the EV+ cases. These findings stress basic biological differences in the growth of breast carcinoma in the nodes. Patients with the smallest micrometastases that are found in the afferent lymphatics of the node and the EV+ patients in which tumour cells are present in the efferent nodal vessels have a poor short-term prognosis. The patients with larger micrometastases in the nodal lymphoid tissue and also EV- patients with the next highest tumour-load are both of low prognostic risk, with the exception of the few EV- with an exceptionally high tumour-load.

Breast cancer: poor short-term prognosis in cases with moderate lymphocyte infiltration at the tumour edge: a preliminary report.

Lymphocyte infiltration in breast carcinoma has long been associated with favourable prognosis, however it has also been related to poor prognosis. In this study of 128 consecutive cases lymphocyte infiltration, its absence, or presence and degree was recorded at the tumour edge adjacent to fatty tissue in 100 cases, to other tissues in the remaining 28 in which no such edge was found. In the former there was a highly significant prognostic difference between those with moderate infiltration, which was of poor short-term prognosis, and those with other degrees of infiltration (none, slight and marked). Thus, lymphocyte infiltration in breast cancer can give information on both good and poor prognosis in over 80% of cases if its site and degree are taken into consideration. The remaining cases are histologically distinct. Their survival was similar to that in the total material. The mechanisms involved are as yet open to speculation. In view of increasing surgical reluctance to remove the axillary nodes it is of interest that the present investigation can be carried out on the routine diagnostic specimen from the primary and that the relation between survival and axillary nodal status, significant in the total material, no longer held in these groups.

Expression of E-cadherin and catenins in invasive mammary carcinomas.

E-Cadherin has been shown to be an invasion tumor suppressor gene, but few epidemiological studies have revealed relationships between loss of E-cadherin expression and invasive tumor growth and/or metastasis. The adhesive function of E-cadherin is dependent on the integrity of the catenin components which link E-cadherin to the actin filaments. In order to achieve a better correlation between the loss of cell adhesion and metastasis in cancer, we decided to investigate both E-cadherin and the catenins. 157 archival primary mammary carcinomas were immunohistochemically studied using antibodies against E-cadherin, alpha-, beta- and gamma-catenin. The following results were obtained: (a) Independent of the presence of E-cadherin, loss of expression of one or multiple catenins was noted; (b) loss of E-cadherin and alpha-catenin expression was more pronounced in lobular-type than ductal-type carcinomas; c) axillary lymph node metastases were completely lacking only in the group where expression of E-cadherin, alpha- and beta- catenin was preserved: d) no correlation between expression of c-erbB-2 and E-cadherin or one of the catenins was found. The results demonstrate for the first time that consideration of both the expression of E-cadherin and of the three catenins is useful in evaluation of the metastatic potential of mammary carcinomas.

Breast cancer.

Seasonal variation has been demonstrated in connection with several aspects of primary breast carcinoma. This report describes a seasonal variation in the growth of breast carcinoma in the axillary nodes that has not been reported previously and has prognostic implications. The nodes from a series of 301 node-positive breast cancer patients were investigated prospectively for the presence/absence of tumour cells in their efferent lymphatic vessels, the former being of poor prognosis. Their presence, i.e. positive EV-status, is common in nodes with established tumour growth. Many more patients coming to operation in the first 6 months of the year showed such findings, while more of negative EV-status were found in the second half (chi(2)=13, P<0.0005). Positive EV-status was, as expected, associated with poor prognosis relative to EV-negative (chi(2)=14). Its prognostic impact did not alter with season. It may be of note that seasonal variation in the arrival of micrometastases at the nodes has also been reported recently. These two phenomena may have a common pathogenesis.

Heparin coating of human breast carcinoma cells in vivo.

Mast cells, the only source of heparin in the body, are common in breast carcinoma. Due to metachromatic staining of heparin-proteoglycans released from the mast cells toluidine blue may stain connective tissue a reddish-purple. This study shows that tumour cells in the vicinity may also be coated with metachromatic substance. Such bl vivo coating does not appear to have been reported previously. In experimental studies in vitro coating has been described following suspension of mouse tumour cells in a heparin solution and preincubation of ascitic tumour cells in heparin has given reduction in survival time after transplantation. In human breast carcinoma stromal metachromasia may under certain circumstances be indicative of poor prognosis. The biological implications of in vivo tumour cell coating with heparin are under investigation.

Human papillomavirus infection in progressive and non-progressive cervical intraepithelial neoplasia.

Human papillomavirus (HPV) infection is common in cervical intraepithelial neoplasia (CIN) and is widely held to be responsible for its progression to grade 3. This thesis is examined here. Comparison of the level of HPV changes in 133 lesions that had not progressed to that in those from 197 women with histologically proven CIN 3 failed to reveal significant differences in their level of HPV infection on cytology, histology or in situ hybridization. However, in both these groups, some of the cases that did not show HPV positivity on in situ hybridization with probes reacting with the common HPV types did show evidence of HPV DNA using a general primer-mediated polymerase chain reaction. This may indicate low-copy number infections or non-productive infections. Such reactions were more frequent in the women with progressive lesions, and it is probable that they may also have been at greater risk of cervical infection in general. The present findings suggest that a further factor, a cocarcinogen, may be involved in progression to CIN 3, HPV being a common forerunner, providing a proliferative environment and thus favoring such an event.

Prognostic role of oestrogen and progesterone receptors in patients with breast cancer: relation to age and lymph node status.

AIMS: To consider the prognostic role of oestrogen receptor and progesterone receptor status in relation to the age at surgery, length of follow up and lymph node status. METHODS: The study population comprised 977 patients with histologically confirmed breast carcinoma, with a median follow up of nine years. The actuarial life table method was used to test for survival differences. The Cox proportional hazard model was used to test for interaction effects between each hormone receptor and age, lymph node status and length of follow up. As the analysis involved multiple subgroups, significance was set at the 1% level (p < 0.01). RESULTS: When the patients were subdivided into groups according to lymph node status and age, progesterone and oestrogen receptor status predicted prognosis in middle aged (46-60 years) patients with lymph node positive breast cancer. Their prognostic effect in this subgroup, however, was restricted to the first five years after surgery. Progesterone receptor status was the strongest predictor of outcome. CONCLUSION: The prognostic power of oestrogen and progesterone receptor status varies depending on age, lymph node status and length of follow up after surgery.

Breast cancer: two micrometastatic variants in the axilla that differ in prognosis.

Measurement of the area of the tumour deposits present in routine sections from the axillary nodes from a series of 1069 breast cancer patients showed that 138 cases had a single micrometastasis (0.2 cm2 or less), while in 29 a similar load was spread over two or more nodes. These 167 cases represent 15% of the patients in the series. Twentyfive of them had died of breast cancer within a mean follow-up of 6 years. They had smaller micrometastases than those surviving (P < 0.0025). Histological examination in the 138 with single micrometastases showed that two variants were present. In one, tumour growth was confined to the capsular lymphatics and/or the subcapsular sinus. In the other, tumour growth was present in the nodal lymphoid tissue, and, on occasion, at the other sites as well. Those with growth in the lymphoid tissue had a better prognosis than those without (P < 0.0035). Prognosis in the former was comparable to that in the node-negative cases, while in those lacking such growth it was similar to that in the node-positive. The presence of these two variants could explain divergent reports in the literature on prognosis in cases with micrometastases. While the mechanisms behind this apparent paradox remain speculative, the observation can be of diagnostic interest in routine surgical pathology.

The differences in the cytological histories of women with high- and low-grade cervical intraepithelial neoplasia.

This study concerns 330 women from each of whom we had received a cervical smear showing cervical intraepithelial neoplasia in 1989. They were divided into two groups. One consisted of 197 cases that had progressed to histologically confirmed cervical intraepithelial neoplasia grade 3 between 1989-90, the other of those that had not done so. Their laboratory records (1981-92) were analysed. These showed clear differences in their cervical histories. Those that had progressed rapidly to grade 3 (on histology) were characterized by a short history of abnormal smears. Those that had not progressed over the years tended to have had a series of fluctuating low-grade lesions. On this basis it is suggested that a woman with a negative cervical-smear history, presenting with intraepithelial neoplasia irrespective of grade, should be carefully monitored over the following year to define the nature of the lesion present.

Micrometastases to the axilla in breast cancer: their size and season of presentation.

In a series of 1,069 breast cancer patients there were no significant differences in the numbers of node-negative or node-positive cases undergoing operation in the two halves of the year. This held also for cases with nodal micrometastases (0.2 cm2 or less). There were two histological types. Their distribution according to season was similar. Using the mean tumour area those presenting in the first half of the year were smaller than the others (p < 0.001), and more cases were under 0.000 cm2 (p < 0.005). In these cases the tumour cells tended to be in the capsular lymphatics and subcapsular sinus. In keeping with their histology, deaths were also more frequent than with those presenting in the second half of the year, in which the micrometastases were larger and had usually infiltrated the nodal lymphoid tissue. Thus the metastatic process in the primary appears to be active in the first part of the year when the smallest of the micrometastases are found entering the nodes. This may be a reflection of the growth form of the primary.

Node-positive breast cancer: axillary micrometastases, their incidence and some implications.

In node-positive breast carcinoma, the presence of tumour cells in the efferent vessels (EV) of the axillary nodes (positive EV status) was shown to be of poor prognosis in 1979. Later the presence of nodal micrometastases was also related to survival. This report describes a new subgroup in this system that is of potential therapeutic interest. It consisted of the 40% of the EV-positive cases with micrometastases (< 0.2 cm2) in their nodes, in addition to nodes with macrometastases. In them the difference in prognosis associated with EV status no longer held. Their prognosis did not differ markedly from that in the EV-negative patients. In the absence of such 'additional' micrometastases, the prognostic difference was still highly significant. There was also some indication that the presence of micrometastases consisting of embolic tumour growth alone may be associated with early death in EV-negative cases, in keeping with the prognosis in cases with lone micrometastases.

The cervical smear record: its relevance to the subsequent development of cervical neoplasia.

BACKGROUND: Our aim was to investigate the previous smear history in women with cervical intraepithelial neoplasia grade 1-3 or squamous carcinoma and define its relevance to the lesion present in 1989. METHODS: All 850 women with a laboratory record of cervical intraepithelial neoplasia or cervical squamous carcinoma in 1989 were studied. We retrieved their cytological and histological cervical diagnoses for the period 1981 to 1992 from the laboratory files. On this basis we assessed their previous smear history and short term clinical outcome. RESULTS: Half the women had a negative record prior to 1989, irrespective of the grade of their lesion in that year. Cervical intraepithelial neoplasia grade 1 had previously been found in 16%, grade 2 in 10%, and grade 3 in 7%. These levels were not related to the grade present in '89, but as in those with a negative record, were proportional to the number of women examined, and thus reflect the frequency of such lesions in the screened population in general. In all, 310 were treated operatively for cervical intraepithelial neoplasia grade 3 following abnormal findings in 1989. In such cases abnormal findings were also common in '88, although 45% of them still had a negative smear history. The group with no previous record, i.e. unscreened, contained significantly more invasive cases. CONCLUSIONS: In women with cervical intraepithelial neoplasia in 1989, their previous smear history did not indicate the grade of lesion present. The relevance of their previous abnormal slides to that lesion is thus questionable. The findings, however, suggest that progressive lesions may be acute in origin, superimposed in some cases on a history of similar morphological abnormalities.