Clinical and Investigative Medicine

 

Biologic characteristics of breast cancer detected by mammography and by palpation in a screening program: a pilot study

Edward Tweedie,* MD
Katia Tonkin,† MB
Nancy Kerkvliet,* RT
Gordon S. Doig,‡ DVM, MSc
R. Keith Sparrow,§ MD
Frances P. O'Malley,*† MB

Clin Invest Med 1997;20(5):300-307.

[résumé]

From *the Department of Pathology, London Health Sciences Centre, †the Department of Oncology, London Regional Cancer Centre, ‡the Department of Biostatistics, London Health Sciences Centre, and §the Department of Radiology, London Health Sciences Centre, London, Ont.

Presented in part at the 84th annual meeting of the United States and Canadian Academy of Pathologists, Toronto, March 11­17, 1995.

Original manuscript submitted Jan. 30, 1997; received in revised form July 9, 1997; accepted July 15, 1997)

Reprint requests to: Dr. Frances P. O'Malley, Department of Pathology, London Health Sciences Centre, London ON N6A 4G5; fax 519 667-6749; frances@lhsc.on.ca

Contents

Abstract

 Objective: To compare the histopathologic features and expression of p53 and c-erb B2 in the tumours detected by mammography only (clinically occult tumours) and the tumours detected by a nurse examiner (clinically palpable tumours).

Setting: London branch of the Ontario Breast Screening Program, which uses both clinical breast examination and mammography as screening methods.

Interventions: Pathologic review and immunohistochemical staining of all tumours detected between 1990 and 1993.

Outcome measures: Categorization of tumours by detection method and analysis of tumour size, grade, type, lymph node status and c-erb B2 and p53 expression in each group.

Results: From 1990 to 1993, 131 tumours were detected in patients ranging in age from 50 to 85 years (median 63 years). Sixty-seven occult tumours and 64 palpable lesions were detected. The occult tumours were significantly smaller (1.34 cm v. 2.29 cm, p < 0.0001) than the palpable ones and included a higher proportion of special-type lesions and ductal carcinoma in situ (43.3% v. 10.9%, p < 0.0001). Occult invasive carcinomas were of lower grade than palpable carcinomas (68.4% grade 1, 21.1% grade 2, 10.5% grade 3 v. 32.8% grade 1, 36.1% grade 2, 31.1% grade 3, p < 0.0001). Fewer occult lesions showed axillary nodal metastases (19.6% v. 40.6%, p = 0.02). No statistically significant differences were found for p53 or c-erb B2 positivity between the 2 groups.

Conclusion: Tumours detected by different screening methods in a screening program have different pathologic characteristics.

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Résumé

Objectif : Comparer les caractéristiques histopathologiques et l'expression du p53 et du c-erb B2 dans les tumeurs dépistées par mammographie seulement (tumeurs occultes sur le plan clinique) et les tumeurs détectées par examen infirmier (tumeurs palpables sur le plan clinique).

Contexte : Section de London du Programme de dépistage du cancer du sein de l'Ontario qui utilise à la fois l'examen clinique des seins et la mammographie comme méthodes de dépistage.

Interventions : Examen pathologique et coloration immunohistochimique de toutes les tumeurs détectées entre 1990 et 1993.

Mesures des résultats : Catégorisation des tumeurs selon la méthode de détection et analyse de la taille, du degré et du type de la tumeur, de l'état des ganglions lymphatiques et de l'expression du c-erb B2 et du p53 dans chaque groupe.

Résultats : De 1990 à 1993, on a détecté 131 tumeurs chez des patientes dont l'âge variait de 50 à 85 ans (médiane : 63 ans). On a détecté 67 tumeurs occultes et 64 lésions palpables. Les tumeurs occultes étaient beaucoup plus petites (1,34 cm c. 2,29 cm, p < 0,0001) que les tumeurs palpables et comportaient une proportion plus élevée de lésions de type spécial et de carcinomes canalaires in situ (43,3 % c. 10,9 %, p < 0,0001). Le degré des carcinomes occultes de type envahissant était moins élevé que celui des carcinomes palpables (68,4 % degré 1, 21,1 % degré 2, 10,5 % degré 3 c. 32,8 % degré 1, 36,1 % degré 2, 31,1 % degré 3, p < 0,0001). Les lésions occultes avec métastases aux ganglions axillaires (19,6 % c. 40,6 %, p = 0,02) étaient moins nombreuses. On a trouvé aucune différence importante dans le statut positif du p53 ou du c-erb B2 entre les 2 groupes.

Conclusion : Les tumeurs détectées par des méthodes différentes de dépistage dans le cadre d'un programme de dépistage présentent des caractéristiques pathologiques différentes.

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Introduction

 Breast cancer is a leading cause of death, and its incidence is increasing.1 Randomized controlled studies of breast screening have shown that screening improves survival in screened women over 50 years of age.2,3 To help show or explain a screening benefit, many studies have compared the pathologic characteristics of tumours detected through screening with tumours found clinically.4­7 Mammography is the most studied and best used screening method. Clinical breast examination (CBE) is also a component of some programs, either alone or in combination with mammography; however, direct comparison of these 2 screening methods is lacking. Since the Ontario Breast Screening Program (OBSP) uses both CBE and mammography, the 2 methods may be directly compared.

The OBSP is a service of the Ontario Cancer Treatment and Research Foundation and is funded through the Ontario Ministry of Health.8,9 It is open to women 50 years of age and older who have no history of breast cancer, breast implants or implant removals (explants). Women may participate on their own or be referred by their physician. A nurse examiner performs a CBE and teaches breast self-examination. Routine 2-view mammography is then performed and interpreted by experienced radiologists. Physical and mammographic findings are recorded on a worksheet. Patients who do not have breast cancer are invited for rescreening every 2 years.

The London branch of the OBSP screened 13 000 women from its inception in July 1990 to December 1993. Of these, 11 000 (84.6%) constituted a prevalence cohort.

The aim of this study was to compare the biologic features of the tumours detected by mammography only with those detected by physical examination in the screening program. The pathologic characteristics of the tumours included the established prognostic markers; namely, tumour size, lymph node status, histologic grade and histologic type. We also studied p53 and c-erb B2 immunopositivity within these tumours, since mutations in the tumour suppressor gene p53 and overexpression/amplification of the oncogene c-erb B2 have been shown to be useful as prognostic indicators in primary breast cancer.10­16

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Methods

Study group

All breast tumours initially detected at the London branch of the Ontario Breast Screening Program from July 1990 until December 1993 were included in the study. After reviewing the worksheets, we divided these tumours into 2 groups: palpable and occult. Lesions were classified as palpable if a nurse examiner had detected a palpable abnormality before a screening mammogram was taken. Occult tumours were lesions detected by abnormal mammogram when clinical breast examination failed to reveal a significant abnormality.

Pathologic examination

Pathology reports were reviewed to determine tumour size and axillary lymph node status. For palpable tumours, the maximum dimension, as measured grossly, was recorded. For nonpalpable tumours, the largest diameter, as measured on the glass slide, was recorded. Size was determined only for invasive carcinoma, since most ductal carcinoma in situ (DCIS) was nonpalpable and difficult to assess accurately in terms of size. Although a few patients with purely in situ lesions underwent a lymph node dissection, node dissection results were considered only for cases of invasive carcinoma. Any case with at least 1 involved node was categorized as node-positive. These patients were not further stratified on the basis of the total number of nodes that were positive.

All hematoxylin- and eosin-stained histologic tumour sections of each case were assessed by 2 reviewers (E.T. and F.P.O'M.). Both reviewers were blinded as to whether the tumour was clinically occult or palpable. The lesions were divided into 3 broad categories: DCIS, special-type (ST) carcinoma and carcinoma of no special type (NST) (i.e., invasive ductal carcinoma, not otherwise specified). ST carcinoma included pure tubular, cribriform, mucinous, lobular and metaplastic carcinomas as well as DCIS lesions with foci of microinvasion (invasion of less than 0.1 cm). The remaining carcinomas classified as NST included cases with focal special-type features but having mainly features of no special type. All invasive carcinoma was graded according to Elston's modification of the Bloom and Richardson method.17,18 Any discrepancies between the 2 reviewers were resolved by consensus while viewing the tumour through a multiheaded microscope.

One representative tissue block of each case was selected for immunohistochemical studies. Four-micron sections were taken from this representative block and stained for p53 protein (D07, DAKO, dilution 1:25) and c-erb B2 protein (CB11, Novocastra, dilution 1:25)19 using microwave antigen retrieval20 and the avidin-biotin-complex method.21 Protein expression was considered positive if an estimated minimum 5% of tumour cells demonstrated any intensity of immunoreactivity.

Statistical analysis

The Chi2 test or Fisher's exact test were used for noncontinuous variables when appropriate. Wilcoxon rank-sum test was used for continuous variables. A p value of less than 0.05 was considered statistically significant.

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Results

In total, 131 breast tumours from 130 women were examined; 1 woman had bilateral tumours that were synchronous primary tumours. Sixty-seven of these tumours were occult and 64 were palpable. The median age of the women was 63 years, with a range of 50 to 85 years. Although 42 of these women had reported having a previous mammogram, only 19 (14.5%) of all the woman had had a mammogram performed in the preceding 2 years and were thus considered to have incident screened tumours.

A single case (a DCIS lesion) was associated with a normal mammogram, while all other lesions from both palpable and occult groups were associated with mammographic abnormalities. This DCIS case was palpated by a nurse examiner, who felt a hard, irregular lump superolateral to the left nipple. The mammogram revealed dense breast tissue in the area of the palpable mass; however, no definite mass was identified. Pathologic examination demonstrated a 1.5-cm nodule composed of noncomedo low-grade DCIS showing micropapillary and cribriform growth patterns. Small laminated calcifications were associated with the lesion.

Lesion type

Fig. 1 shows the distribution of lesion types in each group. The occult group comprised 9 (13.4%) DCIS, 20 (29.9%) ST carcinomas and 38 (56.7%) NST carcinomas. In contrast, there were 4 (6.2%) DCIS cases, 3 (4.7%) ST carcinomas and 57 (89.1%) NST carcinomas in the palpable group. Overall, there was a higher proportion of ST and DCIS lesions in the occult group (43.3% v. 10.9%, p < 0.0001). Twenty of 23 (87%) ST tumours were occult; these included 8 lobular (7 classic and 1 pleomorphic), 8 tubular, 1 cribriform and 1 mucinous carcinomas, as well as 1 encysted papillary carcinoma with microinvasion and 1 noncomedo DCIS with microinvasion. The ST tumours in the palpable group included 2 metaplastic carcinomas and 1 classic lobular carcinoma.

Histologic grade

A high proportion of the invasive carcinomas in the occult group (68.4%, 39/57) were grade 1, while only 21.1% (12/57) were grade 2 and 10.5% (6/57) were grade 3. The palpable invasive carcinomas, on the other hand, showed an almost equal distribution across all 3 grades: 20/61 (32.8 %) were grade 1, 22/61 (36.1%) were grade 2 and 19/61 (31.1%) were grade 3 (Fig. 2). One of the occult lesions was not included because its invasive component was too small to be assigned a valid grade. Of the 9 occult DCIS lesions, 6 were high-grade (comedo) and 3 were low- or intermediate-grade (noncomedo). The 4 palpable DCIS were equally distributed between the high-grade (comedo) category (2/4) and the noncomedo category (2/4).

Axillary lymph node metastases

Fifty-one occult (88%) and 59 palpable (98%) invasive carcinomas had associated axillary lymph node dissections. Ten of the 51 occult tumours (19.6%) were associated with at least 1 positive node. This was significantly (p = 0.02) lower than the positive nodal rate in the palpable group, which was 40.6% (24/59).

Size

The 58 measured occult tumours had a median size of 1.34 cm (range 0.2 to 9.0 cm), which was significantly lower (p < 0.0001) than the median size of the 61 palpable tumours (2.29 cm, range 0.9 to 8.5 cm). Fig. 3 shows the size distribution and the large degree of overlap between the groups. Although the occult tumours were generally smaller, 6 cases were greater than 2.0 cm. One unusual tumour with minimal desmoplasia was 9.0 cm in diameter and escaped detection by palpation. Conversely, many lesions detected by palpation were small; 18 (26%) had a diameter of 1.5 cm or less.

p53 status

Nine of 64 occult tumours (14.1%) were p53-positive, including 2 high-grade DCIS lesions, 1 ST (classic infiltrating lobular) tumour and 6 NST tumours. Three occult cases could not be assessed because of a loss of tumour from deeper sections taken from the tissue block. Thirteen (20.3%) of the 64 palpable tumours (2 high-grade DCIS and 11 NST) were p53-positive. This difference was not statistically significant.

c-erb B2

Fourteen (21.9%) of the 64 occult cases (5 DCIS, 2 ST and 7 NST tumours) were c-erb B2 positive. This percentage was not statistically significantly different from the palpable lesions, of which 12 (19.0%) of 63 (1 DCIS and 11 NST) were immunoreactive for c-erb B2. Three occult cases could not be assessed because the lesion was lost on deeper sectioning of the block. Staining of 1 palpable case could not be interpreted owing to the absence of tumour in the stained sections.

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Discussion

Many studies have compared screen-detected breast tumours to those detected clinically. These studies have generally concluded that screening detects tumours with comparably favourable pathologic features.4­7 Most studies analyse all screen-detected lesions as a group, even though they constitute a heterogeneous population. This study shows that, when tumours are grouped on the basis of whether they are palpable, significant pathologic differences are revealed. This information may assist in determining the relative contributions of mammography and CBE to screening. Although some of the major randomized breast-screening studies have used both tests, very little attention has been paid to this issue, and further study has been recommended.2,3 The combination of methods is required to identify which of the mammographically detected tumours are truly "clinically occult," i.e., cannot be detected with CBE.

The nurse examiners successfully detected 64 of the 131 tumours. It appears that lesions need to be at least 1 cm in diameter to be palpable.22 Several tumours were quite small, but others likely could not be palpated because of breast size or texture or because of firmness or depth of the tumour.

Although mammography identified virtually all of the neoplasms in this group (130/131), the accepted sensitivity for mammography is variously stated to be between 75% and 90%.23­25 Mammographic detection is reduced by large amounts of fibrous and glandular tissue. As the women screened were largely postmenopausal, the sensitivity of mammography was better than expected for a general population. In addition, the clinical examination results were known to the radiologist. This may have artificially inflated the sensitivity of the radiographic detection.

The difference in the distribution of the histologic lesion types between the occult and palpable groups is statistically significant (p < 0.0001). ST tumours, particularly infiltrating mucinous, cribriform and tubular carcinomas, are usually associated with less aggressive biologic behaviour.26­28 Such lesions were found almost exclusively in the occult group, mainly because of their small size. Diffuse growth pattern and lack of tissue desmoplasia -- factors common in infiltrating lobular carcinomas -- may also limit palpability. Similarly, the higher rate of DCIS in the occult group (13.6% v. 6.2%) was expected because these tumours do not usually form discrete palpable masses.

Histologic grade, frequency of lymph node metastasis and tumour size are established as prognostic indicators in breast cancer.26,29­31 Small size, lymph-node-negative status and low grade are the characteristics that largely account for the reported favourable prognosis in breast tumours detected through screening.32 These favourable prognostic indicators were significantly more common in the occult group than in the palpable group in this study. Size is the major factor that determines palpability; it therefore follows that the occult lesions were smaller. Size and lymph node status have been shown to act as independent but additive prognostic indicators.29 Palpability also appears to be associated with lymph node status. A recent study has shown that the rate of nodal positivity in nonpalpable tumours is much lower than that in palpable tumours,33 a finding that is confirmed in our study. The relation between grade and size is more difficult to define. The Swedish 2-country study concluded that grade increases as tumours grow.32 However, McKinney and associates34 showed no significant change in grade with size when comparing palpable with nonpalpable tumours. DNA ploidy studies in screen-detected tumours have shown a near-diploid DNA profile.35 We know from the murine system that gross aneuploidy signifies infinite growth transformation.36 Thus, clinically occult tumours may not have acquired all the molecular events needed for sustained progressive growth and metastasis, although these tumours must be assumed to have an increased risk of such molecular abnormalities.36 The high rate of grade 1 tumours in the occult group was partly attributable to the large number of special-type tumours in this group, most of which were grade 1.

Additional prognostic indicators in early breast cancer are being sought to help better stratify these patients into therapeutic subsets.37 We looked at c-erb B2 and p53.

c-erb B2 is a proto-oncogene encoding for a membrane protein with protein-kinase activity. Its amplification and overexpression in breast cancer has been extensively studied, and its usefulness in prognosis in lymph-node-negative disease is controversial,38­41 although it is more uniformly accepted as an adverse prognostic marker in lymph-node-positive tumours.42 Overexpression appears to confer resistance to nonanthracycline-based chemotherapy.41 It is well recognized that there is a high rate of overexpression in high-grade DCIS,43 and this was also demonstrated in this study.

p53 is a well-known tumour suppressor gene identified more than a decade ago.44 A number of studies evaluating mutations of p53 in breast cancer have shown an association with poor clinical outcome.11­14,31 In this study, there was no difference between the 2 study groups with respect to the immunohistochemical expression of either oncoprotein; therefore, these markers failed to reveal additional inherent biologic differences related to palpability. The sample size is small; thus, these negative findings may be a result of insufficient statistical power. To be conclusive, these findings need to be confirmed in a larger series of cases.

The association of smaller size, more favourable histology and lower rate of lymph node metastasis in mammographically detected versus clinically detected tumours has been demonstrated by many studies.5­7 However, there is little information on the biologic characteristics of clinically occult and palpable tumours detected in the same screening program. The use of CBE as well as mammography has allowed the detection of these 2 groups of tumours. Most breast screening programs use mammography only; thus, tumours that may have been detected by clinical examination cannot be separated from the purely clinically occult cancers within these programs. The Canadian National Breast Screening Study partially addressed this issue.2,23 The authors reported that 85 (67%) of the 127 invasive carcinomas detected by mammography only were node negative, whereas 88 (62%) of the 141 tumours detected by physical examination alone or in combination with mammography were node negative.

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Conclusion

We have demonstrated 2 subsets of breast tumours detected through screening -- palpable and nonpalpable -- which have significantly different pathologic prognostic features. Most of these tumours represent prevalence-screened tumours detected during the first 3 years of operation of the London branch of the OBSP. This is a pilot study and represents early findings in 1 centre of the OBSP. A larger multicentre study is needed, ideally with long-term follow-up, to determine the clinical significance of these findings.

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Acknowledgements

We wish to thank the staff at the London branch of the OBSP for their cooperation with, and support of, this study.

The study was supported by a grant from the Breast Cancer Society of Canada.

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