1976, British Journal of Radiology, 49, 12-26

The detection and significance of calcifications in the breast: a radiological and pathological study By Rosemary R. Millis, M.R.C.Path. Breast Unit, Royal Marsden Hospital, Fulham Road, London, S.W.3. R. Davis, A.I.ST., and A. J. Stacey, M.Phil., M.lnst.P.* Division of Physics, Institute of Cancer Research and Royal Marsden Hospital, Fulham Road, London, S.W.3. (Received February, 1975, and in revisedform June, 1975) ABSTRACT

The radiological detection of calcification is compared using xeroradiography, non-screen film and a film-screen combination. The "threshold" values of the smallest detectable size of calcification, under simulated clinical conditions, are found to be approximately 100 /urn for xeroradiography and 400 /J.m for both the film techniques in this study. The incidence of calcification seen on the preoperative mammograms of patients with carcinoma of the breast is 48*5 per cent. Further calcification revealed by histological examination raises the overall incidence of calcification in mammary carcinomas to 63 per cent. The incidence on preoperative mammograms in benign breast disease is 20 per cent. The radiological features of calcification occurring in malignant and benign breast lesions are recorded, and no definitive distinguishing features are established. The histological appearance of calcification in malignant and benign breast disease is discussed.

The significance of calcification within the breast has been recognized for over a quarter of a century (Leborgne, 1949), and it may occur in both malignant and benign disease. The radiological appearance of calcification associated with malignant disease has been described as clusters of numerous fine, irregular particles. In benign lesions the particles are reported to be larger (sometimes very large and irregular when present in fibroadenomas), more uniform in shape and size, fewer in number, and more diffusely distributed throughout the breast (Leborgne, 1953; Gershon-Cohen, Yui and Berger, 1962; Patton, *Present Address: Department of Medical Physics, Charing Cross Hospital (Fulham), Fulham Palace Road, London W6 8RF.

Poznanski and Zylack, 1966; Egan, 1972; Wolfe, 1972). Calcification is most commonly found in intraduct carcinoma, but is also reported in other types of mammary carcinoma. In benign lesions it occurs in areas of mammary dysplasia, duct ectasia, duct papillomas and fat necrosis. There are few detailed reports of its histological features in the human breast (Koehl et al., 1970; Hassler, 1969; Levitan, Witten and Harrison, 1964; Patton et al., 1966). Calcification is the most frequent indication of early breast cancer (Rogers and Powell, 1972) and may be seen before a mass is palpable or radiologically detectable. The pattern may be diagnostic of a carcinoma even when the radiological features of an associated mass are equivocal. The detection of calcification may therefore be the only indication for biopsy and hence it is essential to establish: (1) the optimum conditions required to demonstrate its presence; (2) the significance of the pattern of the particles within the breast. The material, methods and results in this paper are thus presented in two parts. In Part I, various radiological regimes are described, and their relative merits in the detection and measurement of calcifications are examined. Part II considers the incidence and significance of the quantity, size and spatial distribution of these calcifications in malignant and benign breast disease in the light of evidence provided by related pathological studies.

Part I: The radiological detection and measurement of calcification In some of the experiments, paraffin blocks containing sections of breast tissue of known histology were used to provide a wide range of sizes of naturally-occurring calcifications. The blocks, measuring approximately 3 x 2 cm and varying in thickness between 2 and 10 mm, were radiographed on each of the three detecting systems throughout the range of applied tube voltage with the two

MATERIALS AND METHODS

Experiments were conducted with an X-ray tube fitted with a rotating molybdenum anode (Table I, gives the relevant technical data) and three detecting systems employing non-screen film, a film-intensifying screen combination and the xeroradiographic "System 125" respectively (further details are shown in Table II). 12

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1976

The detection and significance of calcifications in the breast: a radiological and pathological study TABLE I TECHNICAL DETAILS OF THE X-RAY TUBES

Filtration (mm.Al) Type

Inherent

Added

Focus-detector distance (cm)

Focal spot size (mm)

Applied tube voltages (kVp)

1. Siemen's "Mammomat" (Rotating Molybdenum Anode)

Be. window

30 ^m Mo

45 and 183 cm

0-6x0-6

28, 30,45 and 50 (constant potential generator)

2. Siemen's (Rotating Tungsten Anode)

Glass window

0-SmmAl

83 cm

0-6x0-6

35 and 50 (constant potential generator)

TABLE II

X-ray focus

X-ray focus

A

DETAILS OF THE THREE DETECTING SYSTEMS

Type 1. Non-screen film Kodak PE 4006

Processor Kodak automatic

Processing time, minutes 1-5

2. Medichrome film; vacuum packed with one intensifying screen

Automatic with special chemicals

2-5

3. Selenium platexeroradiography vide:—GillbeP., 1973

Xerox "125" system

1-5

t

\ Paraffin 1 block

A

Paraffin block

5 cm B

.. i c (b)

(a)

1. The geometry employed to radiograph the paraffin blocks. The "Mammomat" (See Table I) was used with the three detecting systems described in Table II. (A) In air at 183 cm. (B) In phantom at 45 cm. The block is shown in the middle of the phantom at level " B " : radiography was repeated with the block positioned at levels "A" and "C". FIG.

with appropriate experience) who recorded the position of each particle that they could see. By relating these observations to the corresponding key radiograph, the minimum size detected by each person was determined, and by taking the mean of those measured for all observers the "threshold size" established. Each person also indicated whether one radiograph was of "better" or "worse" quality than another. Although such terms are virtually impossible to define, they are of value in practice, since the judgement is compounded of several impressions such as resolution, contrast pattern, etc. and is relevant to the decisions that have to be made in radiology. In the discussions below it is referred to as image quality. To determine the influence of breast architecture on the detection of calcifications, experiments were repeated using six suitable mastectomy specimens in place of the simple phantom shown in Fig. 1B. One of the specimens containing a very wide range

arrangements shown in Fig. 1. The set up, illustrated in Fig. 1A, was chosen to minimize the effects of focal spot dimensions and magnification, and thereby to provide radiological images of optimum quality. Each radiograph was viewed through an optical microscope fitted with a graduated eye-piece micrometer, and the "sizes" of the radiological images of the calcifications were measured. ("Size" is defined as the greatest linear dimension of each particle, corrected for magnification due to projection.) The best radiographs were selected for each block to enable the measurements of size to be made as a key for the comparison of subsequent radiographs. The blocks were placed within a phantom consisting of polythene sheets (15x15x0-5 cm) to simulate fatty breast tissue, and radiographed with the geometry shown in Fig. 1B which more closely resembles clinical conditions in which the calcification may be separated from the detector by the scattering medium. The processed radiographs were inspected by a number of observers (never less than five people 13

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49, No. 577 Rosemary R. Millis, R. Davis and A. J. Stacey

of calcification sizes was further radiographed with the tungsten anode X-ray tube to assess the effect of the harder radiation on image quality. Details of this equipment are given in Table I. For reasons which are stressed below, studies with these specimens were limited to the use of non-screen film and xeroradiography. Throughout this work, great care was taken to use optimum exposure conditions, and to eliminate errors due to under- and over-exposure, by obtaining a series of radiographs on each detecting system for every change in radiological or geometrical parameter. RESULTS

The radiographs taken with the geometry shown in Fig. 1A gave values of "threshold" of approximately 100 ju,m for each of the detecting systems at all available tube voltages. The image quality obtained with Medichrome and PE 4006 deteriorated with an increased tube voltage, while the effect was hardly noticeable in xeroradiography. With the arrangement indicated in Fig. 1B, several important facts were established concerning the "threshold" size (defined above). (1) The variations in the positions of the paraffin blocks, illustrated as A, B and C in Fig. 1B did not affect any of the "threshold" values measured on the three radiographic systems. (2) At 28 and 30 kVp the "threshold" for xeroradiography was approximately 100 ju,m, while the values for both Medichrome and PE 4006 film were raised to 400 fxvcv. (3) When film techniques were used, increasing the voltage above 30 kVp led to a rapid loss in film quality due to the scatter arising from the configuration shown in Fig. 1B. For xeroradiography, however, the threshold values remained at 100

[xm. although the image quality showed some deterioration. (4) No measurable differences were found between the PE 4006 and Medichrome films throughout these experiments and therefore the examinations of the six mastectomy specimens were confined to the uses of PE 4006 film and xeroradiography. Comparative studies of the conventional radiographs and xeroradiographs of the breast specimens confirmed "threshold" values of approximately 400 jtim and 100 pm respectively, and clearly demonstrated the value of the "edge" effect of xeroradiography. The comparatively large exposure latitude of the xeroradiographic plate and the edge effect combine to give better detection of calcifications both when it is sparse and when it is found in areas such as the subareolar region where increased attenuation causes pronounced opacity in film techniques. Results obtained with the mastectomy specimens did not differ significantly from those obtained with the paraffin blocks embedded in the phantom. The xeroradiographs of the mastectomy specimen, taken with the tungsten target X-ray tube, using the same projection as that employed with the molybdenum tube showed:— (1) xeroradiographs taken with the tungsten anode did not alter the "threshold" values although they were of reduced contrast; (2) increases in applied tube voltage had small effect on xeroradiography, but resulted in severe deterioration of the image quality of the film; (3) all conventional radiographs taken with the tungsten tube (used in our technique) were considered to be of "unacceptable quality" for clinical work.

Part II: The correlation between radiological and pathological findings and their significance in malignant and benign disease and ring-like calcifications occurring in duct ectasia, were not included. Xeroradiographs were taken of a high proportion of the malignant surgical specimens and of all benign biopsy specimens. Stereoscopic views were taken of selected specimens (Boag, Stacey and Davis, 1971; 1972). Histology was available for all cases. Where calcification was the only basis for biopsy, the surgical specimen was xeroradiographed prior to pathological examination, and a frozen section only performed on an obvious tumour. When no obvious

MATERIALS AND METHODS

During the six-month period of this study, 68 patients with carcinoma of the breast and 135 patients with benign breast disease who were treated by surgery had pre-operative mammograms. The 68 cases of carcinoma, together with 27 patients with benign breast disease in whom calcification was considered a significant radiological abnormality, were studied in detail. Cases with extremely sparse and widespread calcification, the distinctive large calcifications of a fibroadenoma or the typical round 14

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1976

The detection and significance of calcifications in the breast: a radiological and pathological study

Results have been tabulated wherever possible. dominant abnormal area was seen or felt, multiple tissue blocks were taken for permanent paraffin sections. All specimens were fixed and processed RESULTS routinely. Three blocks were taken from each Incidence of calcification in carcinomas and benign grossly obvious carcinoma, and multiple blocks from breast disease the other specimens. Special stains were performed Calcification was found in the region of the when considered appropriate, a Von Kossa stain for tumour in 33 of 68 pre-operative mammograms of calcium salts being performed on one section from patients with carcinoma of the breast, an incidence each carcinoma. of 48-5 per cent. In ten additional cases in which If the amount of calcification seen on the histology calcification was not seen on the pre-operative slides was significantly less than demonstrated on the mammogram, it was found in histological sections, xeroradiograph, further tissue was examined. In bringing the overall incidence of calcification in this order to locate the calcification, blocks and reserve series to 63 per cent. tissue were subjected to further radiological examinXeroradiographs of the operation specimen which ation. contained the carcinoma were available for 20 of the The following features of the calcification seen on 33 cases in which calcification was seen on the preoperative mammogram. Although the calcification the pre-operative mammograms were noted: was more easily demonstrated, no significant (1) the presence or absence of a mass; additional amount was seen (Fig. 2A). (2) the appearance of the mass; The presence of calcification was confirmed on (3) the location of the calcification in relationship to histology in all but two cases: in each of these two the mass; (4) the size, number and spatial distribution of the exceptions only two or three small particles had been visible on the pre-operative mammogram. calcifications within the breast. The size of the calcification particles was measured Calcification was not seen in the pre-operative using a graduated micrometer eye-piece and a mammograms of 35 cases of carcinoma. Xeroradiodissecting microscope. For those of irregular shape graphs of 22 of these operation specimens containing the greatest linear dimension was recorded. The the carcinoma were available for study, but calcifiapproximate range of size of the particles seen on cation could not be demonstrated even in the ten both projections was recorded for each patient. cases in which calcification was found on histology Particles over 1,000 /Am were considered coarse, sections. those between 500 /urn and 1,000 ^u,m intermediate, Calcification was seen as a significant abnormality and those less than 500 jum fine. The distribution of on the pre-operative mammograms of 27 of the 135 the calcification was often difficult to determine. An patients who had benign breast disease on biopsy attempt was made to note, using both views, whether (20 per cent). Specimen radiography in this benign they were closely packed within a small or large group did not reveal additional evidence of calcifiarea or widespread within a quadrant, or scattered cation. over the entire breast. The following histological features of all the Clinical and radiological features of carcinomas and carcinomas (both with and without calcification) and benign breasts containing calcification the benign lesions containing calcification were A summary of the clinical features and the appearnoted where relevant: ances of the pre-operative mammograms from the (1) the histological diagnosis of the associated lesion patients with both malignant and benign breast including the type and grade of carcinoma lesions in which calcification was seen, are shown in Tables III-VII. (Bloom and Richardson, 1957); (2) the pathological size of the tumour and the number of involved axillary lymph-nodes; 1. Relationship of calcification to other radiological (3) the histological site and the size of the particles. features The latter was measured using an eye-piece micromTable III shows that in 14 cases of carcinoma, eter, and the greatest linear dimension recorded. calcification was the only radiological abnormality, Size was difficult to assess since in some cases many although a definite clinical mass was palpable in four small particles were clustered closely together; and of these patients. However, in 19 other patients with the aggregate was then measured; in addition, carcinoma with a clinically palpable lump, amass was larger deposits were often shattered during the demonstrated radiologically. In seven of the latter process of section cutting. cases the presence of calcification contributed to the 15

VOL.

49, No. 577 Rosemary R. Millis, R. Davis and A. J.'Stacey

(A and B) Calcification in infiltrating carcinoma as seen in preoperative mammogram and in surgical specimen (insert), (c) Calcification in a benign breast lesion (fibrocystic disease).

A (left)

c (below)

JANUARY

1976

The detection and significance of calcifications in the breast: a radiological and pathological study TABLE III CLINICAL AND RADIOLOGICAL FINDINGS OTHER THAN CALCIFICATION ON THE PRE-OPERATIVE MAMMOGRAMS OF PATIENTS WITH CARCINOMA AND BENIGN BREAST LESIONS

Radiological findings other than calcification Mass or disturbed architecture

Clinical findings

Benign lesions

Carcinomas Palpable mass

No other abnormality

Total

Carcinomas

Benign lesions

Carcinomas

Benign lesions

19

6

4

4

23

10

Palpable nodularity, no definite mass

0

2

6

8

6

10

Nipple discharge no palpable abnormality

0

0

0

1

0

1

Tenderness no palpable abnormality

0

1

0

0

0

1

No palpable or other abnormality

0

1

4

4

4

5

19

10

14

17

33

27

Total

TABLE IV

TABLE V

SPATIAL RELATIONSHIP OF CALCIFICATION TO OTHER RADIOLOGICAL ABNORMALITIES ON PRE-OPERATIVE MAMMOGRAMS OF PATIENTS WITH CARCINOMA AND BENIGN BREAST LESION

SIZE OF CALCIFICATIONS ON PRE-OPERATIVE MAMMOGRAMS OF PATIENTS WITH CARCINOMA AND BENIGN BREAST LESIONS

Site of calcification Calcification only within mass or area of disturbed architecture Calcification within mass or area of disturbed architecture and surrounding tissue Calcification seen only in surrounding tissue

Carcinoma Benign

11

9

Carcinomas

Benign lesions

1. Less than 500 /x.m

11

9

2. Between 500 pm and 900 /im

15*

12f

3. A mixture of 1 and 2 above

5

4

4. More than 1,000 //.m

2

2

33

27

Size of the majority of calcifications

7

2

Total 0

1

* 13 of these cases contained some fine calcification less than 500 fjLm.

Calcification unaccompanied by mass or area of disturbed architecture

13

17

Total

33

27

f 3 of these cases contained some fine calcification less than 500 fim.

In benign lesions there was a clinically palpable lump in only ten patients (Table III) and a mass was demonstrated radiologically in six of these. In four other cases without a definite clinical lump, mammograms revealed a mass in two and an area of disturbed architecture in two others. In the remaining 17 cases calcification was the only radiological abnormality. Where another radiological abnormality was present, the calcification was seen within the area of the abnormality in seven cases, and it was also deposited in the surrounding tissue in two other cases, but calcification was only in the surrounding tissue in one case (Table IV).

radiological diagnosis of carcinoma; in five the appearance of the mass was equivocal; in two the mass alone would have been considered benign. In 12 cases the radiological appearance of the mass was diagnostic of a carcinoma, the presence of calcification being merely confirmatory. The spatial relationship of calcification to the mass when present is shown in Table IV. Where a mass was visible, the calcification was always found within the mass, as well as being present in the surrounding tissue in some cases (Fig. 3). This latter feature was clearly demonstrated in the stereoscopic projections. 17

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49, No. 577 Rosemary R. Millis, R. Davis and A. J. Stacey

f&SF^y^''''

FIG. 3. Obvious infiltrating carcinoma with calcification within the mass and surrounding tissue extending towards the nipple.

2. Size of calcification

TABLE VI

The size of the particles of calcification is shown in Table V. Usually a range of sizes was found (Fig. 4), and the predominant size range was recorded. In those cases where the particles were more numerous, the range of size was wider. In both malignant and benign lesions particles varied from approximately 100 fim to 1,500 /xm with an occasional larger particle. In only two carcinomas, both containing less than five calcifications, did all the particles measure over 1,000 fim across. One carcinoma contained a single 6 x 2 mm bilobed calcification; this patient had been treated with radiotherapy prior to mastectomy (Fig. 5).

NUMBER OF CALCIFICATIONS ON PRE-OPERATIVE MAMMOGRAMS OF PATIENTS WITH CARCINOMA AND BENIGN BREAST LESIONS

3. Number of calcifications The total number of calcifications seen within the area of the lesion is shown in Table VI. In only six carcinomas were there less than five particles, while in 16 the particles were too numerous to count. In six cases of benign disease the particles were also very numerous, but usually there were fewer than commonly seen in association with carcinoma.

problem, but often although the particles were densely packed and often uncountable, they extended over a considerable area of the mammogram. In the carcinomas this usually occurred when there was widespread intraduct change either confined to the ducts or associated with infiltration. A not uncommon pattern consisted of a dense cluster of calcifications extending to the sub-areolar region. In two of the cases of carcinoma and two of the benign lesions the calcification was truly widespread; one of the carcinomas was multifocal and the other a case of in-situ lobulaf carcinoma with associated fibrocystic disease. Both the patients with benign

Carcinomas

Benign lesions

Less than 5 particles

6

5

5-9 particles

6

6

10-30 particles

5

10

Uncountable

16

6

Total

33

27

Number of calcifications

4. Distribution of calcification The spatial distribution of the calcification on the mammograms is shown in Table VII and was sometimes difficult to classify. Localized clusters were no 18

JANUARY 1976

The detection and significance of calcifications in the breast: a radiological and pathological study

^PS Infiltrating carcinoma of breast containing a large area of numerous clustered calcifications with a wide range of size and no obvious mass.

disease were thought to have carcinoma on clinical grounds. One elderly patient with a blood-stained nipple discharge had widespread duct papillomatosis and the other with contralateral in-situ lobular carcinoma had fibrocystic disease. In patients with carcinoma and mammary dysplasia of the remaining breast, there were sparse widely scattered particles elsewhere on the mammogram, in addition to the calcification associated with the carcinoma.

A single bilobed calcification occurring in a carcinoma treated with radiotherapy.

1. Type of carcinoma Tables VIII-XI give an analysis of the histological type of the carcinomas, the grade of the carcinomas (Bloom and Richardson, 1957), the pathological size of the tumours, and the number of involved lymph-nodes, comparing those with and Pathological features of carcinomas (both with and without calcification on the pre-operative mammowithout calcification) and of benign breast lesions with grams. The ten cases in which scant calcification calcification on pre-operative mammograms was seen on histology, but not on mammography, 19

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49, No. 577 Rosemary R. Millis, R. Davis and A. jf. Stacey

are included with the carcinomas in which calcification was not found on mammograms. It will be seen that the two groups contain similar tumours. The histology in the benign breasts showed a variety of disorders including fibroadenosis, cystic

TABLE IX GRADE OF CARCINOMAS BOTH WITH AND WITHOUT CALCIFICATION ON PRE-OPERATIVE MAMMOGRAMS

Grade of carcinoma (Bloom and Richardson, 1957)

With calcification

Grade I TABLE VII SPATIAL DISTRIBUTION OF CALCIFICATION ON PRE-OPERATIVE MAMMOGRAMS OF PATIENTS WITH CARCINOMA AND BENIGN BREAST LESIONS

Spatial distribution

Carcinoma

Benign

25

16

Closely packed over large area

5

6

Diffusely and evenly scattered throughout breast

2

2

Closely packed over localized area

Without calcification

5

4

Grade II

13

18

Grade III

6

9

In situ carcinoma

9

4

33

35

Total

TABLE X PATHOLOGICAL SIZE OF CARCINOMAS BOTH WITH AND WITHOUT CALCIFICATION ON PRE-OPERATIVE MAMMOGRAMS

Diffusely scattered throughout breast with one localized cluster Total

1

3

33

27

Pathological size of tumour

TABLE VIII HlSTOLOGICAL TYPE OF ALL CARCINOMAS BOTH WITH AND WITHOUT CALCIFICATION ON PRE-OPERATIVE MAMMOGRAMS

Type of carcinoma

With* calcification

Withoutf calcification

Infiltrating duct carcinoma with associated in-situ duct change

18

24

In-situ intraduct carcinoma

8

3

Infiltrating tubular carcinoma

3

1

Infiltrating carcinoma with no in-situ change

1

5

Infiltrating carcinoma with in-situ lobular change

1

1

Mucoid carcinoma

1

0

Intracystic papillary carcinoma

0

1

In-situ lobular carcinoma

1

0

Total

33

35

With calcification

Without calcification

In situ

9

3

Infiltrating carcinoma up to 1 cm

2

5

Infiltrating carcinoma 1 1 2 cm

12

17

Infiltrating carcinoma 2-1-5 cm

10

10

0

0

33

35

Infiltrating carcinoma over 5 cm Total

TABLE XI NUMBER OF LYMPH-NODES CONTAINING METASTASES IN PATIENTS WITH AND WITHOUT CALCIFICATION ON PREOPERATIVE MAMMOGRAMS

Number of involved axillary lymph-nodes

With calcification

Without calcification

11

15

One tofivenodes involved

4

11

More than five nodes involved

7

2

Nodes not removed

11

7

Total

33

35

All nodes negative

*The two cases with calcification on pre-operative mammography and not on histology were both infiltratingcarcinomas with intraduct change. •f" The cases with calcification on histology but not on preoperative mammograms consisted of six infiltrating carcinomas with intraduct change and four infiltrating carcinomas with no in-situ change. 20

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1976

The detection and significance of calcifications in the breast: a radiological and pathological study disease, sclerosing adenosis, pink cell metaplasia, duct ectasia, duct papillomatosis and epithelial hyperplasia. 2. Histological site of calcification in carcinomas In nearly all cases the calcification was present within malignant tissue. In all cases of in-situ duct, and in most cases of infiltrating duct, carcinoma with in-situ change, calcification was present in the necrotic debris in the centre of the malignant ducts. These were frequently located around the edge of the main infiltrating tumour mass, thus giving the appearance on the mammogram of calcification outside the carcinoma (Fig. 3). In some cases, calcification was also found in benign ducts within and around the carcinoma as well as among the malignant cells and in a few cases (four) calcification was found only in benign ducts within and around the carcinoma. In the one mucoid carcinoma studied, calcification was seen within the mucoid stroma and in the irradiated carcinoma a large area of calcification similar in type to that often seen in fibroadenomas was present in the collagenous stroma. Large calcifications have since been seen in two more irradiated carcinomas.

both within tubules, among solid islands of malignant cells and within stroma, and in benign ducts and acini, the calcium particles were usually small, round, homogeneous or laminated, sometimes resembling psammoma bodies, occurring either singly, or in small groups (Fig. 7A and B). These latter calcifications sometimes appeared to be deposited within mucin present within the tissue. The calcification seen in areas of sclerosing adenosis nearly always consisted of small laminated particles (Fig. 8), but often larger round or irregular particles were seen in dilated benign ducts.

3. Histological site of calcification in benign breast lesions In benign breast disease, calcification was seen in the lumen of ducts and acini, in the wall of ectatic ducts, in areas of pink cell metaplasia, and in stroma. 4. Histological size and appearance of calcification The individual particle size in both malignant and benign lesions ranged from less than 10 yu,m to 500 fxm with aggregates of many particles measuring up to 1,500 ju.m. The microscopic appearances of the particles varied. The largest collections were seen within the necrotic material in the centre of malignant ducts (Fig. 6A and B) where the calcification appeared granular and was composed of numerous particles varying in size, usually irregular and angular in shape, but sometimes rounded or laminated. The overall texture of the calcification resembled that of the rather granular necrotic material in which it was deposited. This appearance was enhanced by the shattering of the calcium particles when sectioned. Frequently, calcification was seen only in the central portion of the necrotic material, but sometimes it was deposited around the periphery or was randomly distributed. This type of calcification was also seen in infiltrating areas of carcinoma and in benign tissue. However, in areas of infiltrating carcinoma



'

/

FIG. 6. (A) Calcification in the centre of malignant ducts in an infiltrating and intraduct carcinoma. (Haematoxylin and eosin X12-8.) (B) High-power view of the clustersof irregular calcification in the centre of the malignant ducts. (Haematoxylin and eosin x 80.)

VOL.

49, No. 577 Rosemary R. Millis, R. Davis and A. J. Stacey DISCUSSION

B

7. (A) Calcification in infiltrating carcinoma both within tubules and stroma. (Haematoxylin and eosin X 32.) (B) High-power view of rounded laminated calcification in an infiltrating carcinoma. (Haematoxylin and eosin X 128.) FIG.

FIG. 8. Calcification in sclerosing adenosis. (Haematoxylin and eosin X 32.)

In the detection of fine calcifications it has been shown that xeroradiography has advantages over the conventional method, and, in many cases, provides additional radiological detail under the exposure conditions described. Although the quality of the PE 4006 and Medichrome films were found to be comparable to each other, the Medichrome film, used with an intensifying screen, has obvious advantages in sensitivity, whilst its specially designed viewing system affords a facility often neglected in radiology. The deterioration of the image on film as the X-ray beam is hardened imposes restrictions on the conditions of use which are not experienced in xeroradiography. In all of the techniques it was found that fine particles were more easily detected when they were located in groups of varying sizes; this would suggest that the presence of the larger particles provokes closer local scrutiny. No attempt has been made to illustrate the comparative appearance of calcification shown by the various recording media, as it will be appreciated that detail in conventional radiographs does not reproduce well and would be shown to disadvantage. The importance of detecting fine particles is emphasized in the above study since 11 of the carcinomas contained predominantly fine calcification, and some fine particles were found in the majority of the other carcinomas (Table V). Benign lesions containing a wide range of particle size generally exhibited less fine calcification. However, the proportion of lesions containing predominantly fine calcification was similar in both malignant and benign breast disease. Since completing this work, several more carcinomas containing only fine calcification have been seen and in at least two of these cases, the tumour was detected solely by the presence of calcification on the mammogram in the absence of any clinical or other radiological abnormality (Fig. 9). The results in Part I of this report indicate that such cases may well be missed by mammography using film techniques. When choosing a radiological technique, factors other than discrimination must of course be considered. Patient exposure is particularly important, and it is appreciated that conventional film techniques using an intensifying screen will result in a reduction in patient exposure when compared with xeroradiography. This rather complex subject is discussed in detail in another paper shortly to appear in this Journal. 22

JANUARY

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The detection and significance of calcifications in the breast: a radiological and pathological study

3

An impalpable infiltrating carcinoma found by a small cluster of fine calcification (arrowed and insert).

certainly at this hospital differentiation is still considered a distinct problem. Although the results of this study confirm that malignant calcification is more frequently associated with a mass, more numerous and closely packed, and usually includes finer particles, none of these features are definitive and none can be taken in isolation. On many occasions malignant and benign lesions are indistinguishable, as illustrated in Figs. 2A and B and 10A and B. This agrees with the findings of Fisher, Dow and Posado (1973) who, after radiological examination of breast tissue slices containing malignant and benign lesions, concluded "that there is no distinctive pattern of calcification which per se is pathognomonic of mammary carcinoma". The radiological density and shape of the particles of calcification is not recorded in this study as these

The problem of establishing characteristic patterns of calcification in malignant and benign breast lesions has been the subject of several papers (Levitan et al., 1964; Gershon-Cohen, Berger and Curcio, 1966; Wolfe, 1966; Egan, 1969; Minagi, 1969; Koehl et al., 1970; Rogers and Powell, 1972). In the past most authors seem to have minimized the difficulty in distinguishing between the two. However, with increasing experience, there is a growing awareness that there is no definitive pattern that is pathognomonic of either condition, and 23

Rosemary R. Millis, R. Davis and A. J. Stacey

FIG. 10A.

Fairly widespread calcification in a case of infiltrating carcinoma with in-situ intraduct change.

features have not been found helpful in distinguishing between malignant and benign lesions (apart from the obvious coarse "benign" calcifications of a fibroadenoma or duct ectasia). It was also found impractical to determine the shape of fine particles. Reports on the incidence of calcification in carcinoma of the breast in pre-operative mammograms using conventional film, range from approximately 30-40 per cent. When tissue blocks or slices of specimens are examined, higher percentages are reported, usually ranging from approximately 40 to 60 per cent (Leborgne, 1953; Shepherd, Crile and Strittmatter, 1962; Levitan et ai, 1964; Black and Young, 1965; Gershon-Cohen et ah, 1966; Egan, 1969; Koehl et al, 1970; Rosen, Snyder, Foote and Wallace, 1970), although an incidence as high as 86 per cent has been found by one group of workers (Fisher et ah, 1974). Calcification was demonstrated on pre-operative mammography in 48-5 per cent of patients with carcinoma in this study. This slightly higher incidence may largely be accounted for by the easier visualization of fine particles by xeroradiography. There were, however, some cases in which occasional small calcifications seen on histology, were not demonstrated on the pre-operative mammogram. For the purposes of this study, these were grouped with the cases in which calcification was not

seen either on radiology or histology since it is considered that multiple sections of any carcinoma may well reveal many more small foci of calcification. Such small particles can be detected on the preoperative mammogram only when they are more numerous and close together. Radiological examination of surgical specimens of breast lesions did not reveal significant additional amounts of calcification in this study in contrast to the findings of other workers using conventional film (Bauermeister and Hall, 1973; Egan, 1969; Rosen et al., 1970). This is consistent with the results in Part I which showed that fine calcification within mastectomy specimen and in phantoms is more easily demonstrated by xeroradiography. There are few reports on the incidence of calcification in benign breast disease in pre-operative mammograms. An incidence of 23 per cent has been reported (Rosen et al., 1970; Koehl et al., 1970) based on specimen radiography using film. The 20 per cent incidence in this series seen on pre-operative mammograms compares extremely favourably with this figure. The histological size of the majority of the calcifications appeared smaller than the radiological size. To clarify this, selected thin 0-5 cm slices of breast tissue containing many calcifications of various sizes were cleared with xylene and the calcifications 24

JANUARY 1976

The detection and significance of calcifications in the breast: a radiological and pathological study (2) the irregular shape of the calcifications which are only occasionally sectioned across their greatest diameter; (3) the fact that several small particles in close proximity appear as a single calcification radiologically. This technique using cleared specimens has also proved valuable in some of the subsequent work, which includes the evaluation of image quality under other film-screen combinations, and the investigation of the effect of exposure parameters (including patient movement) on the apparent radiological density and shape of particles. The histological site and appearance of calcifications described above is similar to findings by other workers (Levxtan et al., 1964; Patton et al., 1966; Gershon-Cohen et al., 1966; Hassler, 1969; Koehl et al., 1970). However, although the appearances of the particles varied, no one type was peculiar to either malignant or benign lesions. The appearance of the calcification is possibly determined by the nature of the tissue in which it is deposited rather than the histological type of the surrounding cells. The irregular calcification typically seen in the centre of malignant ducts seems to be deposited in degenerating and necrotic cells. The round or laminated particles usually seen amongst infiltrating tumours or in benign ducts are often deposited among mucinous secretions. When located in the stroma, the calcification has presumably remained trapped after the original surrounding epithelial cells have degenerated and disappeared. Comparison of carcinomas containing calcification and those in which calcification was not demonstrated in pre-operative mammography shows that the tumours are similar in respect of their histological type, grade (Bloom and Richardson, 1957), pathological size and the number of involved axillary lymph-nodes. CONCLUSIONS

Smaller particles of calcification have been detected within breast tissue using xeroradiography than were demonstrated using conventional film techniques. Visualization of all fine calcification is enhanced by the use of this technique. These advantages maybe attributed to the "edge effect" combined with the wide exposure latitude of the xeroradiographic process. This technique may also be used with radiation beams of harder quality which are generally considered unacceptable for use with film techniques. Calcifications of varying size are found in many carcinomas. The detection of fine particles is particularly important when they are the only indication

FIG. 10B.

Similar widespread calcification in benign breast disease (fibrocystic disease).

stained using alazarin red. The calcifications in the cleared tissue were then measured microscopically, photographed, radiographed within a fat-equivalent phantom using both film and xeroradiography, and the specimen finally processed histologically. The particles were measured on each occasion. This showed that the discrepancy in size was due to a number of factors including: (1) the edge effect of xeroradiography; 25

VOL.

49, No. 577 Rosemary R. Millis, R. Davis and A. J. Stacey

1972. Mammography, 2nd ed. (Thomas, Chicago). of an occult carcinoma. No definitive features are E. R., DOW, W. A., and POSADA, H., 1973. Correlafound distinguishing between calcification occurring FISHER, tions between specimen roentgenograms (mammograms) in malignant and benign breast lesions. No difference and pathologic findings in breast disease. In Pathology Annual, edited by Sheldon C. Somers, pp. 453-472 is found in the pathology of carcinomas containing (Appleton-Century-Crofts, New York). calcification and those without calcification. The FISHER, E. R., POSADA, H., and RAMOS, H., 1974. Evaluation incidence of calcification recorded on the pre- of mammography based upon correlation of specimen mammograms and histopathologic findings. The American operative mammograms in cases of carcinoma of the Journal of Clinical Pathology, 62, 60-72. breast in this series is 48-5 per cent. This relatively GILLBE, P., 1973. Xeroradiography of the breast. Radihigh incidence is attributed to the easier visualography 39,127'-13 5. GERSHON-COHEN, J., YUI, Lorna S., and BERGER, S. M., ization of fine particles using xeroradiography. ACKNOWLEDGMENTS

This project would not have been possible without the co-operation and advice of many of our colleagues in various departments of the Royal Marsden Hospital and the Institute of Cancer Research. We would first like to thank Dr. Iris M. E. Hamlin (Consultant Pathologist) for her continued interest and useful discussion. Encouragement and advice was also received from Professor J. W. Boag, Director of the Division of Physics. Our thanks are further extended to Mr. W. P. Greening and Mr. J. A. McKinna (Breast Unit and Department of Surgery), Dr. J. J. Stevenson, Dr. K. A. Tonge (Department of Diagnostic Radiology), the staff of the Diagnostic Radiology Department and the histopathology technicians for their help. It is a pleasure to record our debt to Miss Ann V. Casey of the Ravenor Park Clinic for assistance with the use of the Medichrome film. Finally we gratefully acknowledge both the Medical Art and Photographic Departments for assistance with the diagram and figures in the text. One of the authors, Dr. R. Millis, is a research assistant on a grant from the Eranda Trust of the Breast Unit, Royal Marsden Hospital.

1962. The diagnostic importance of calcereous patterns in roentgenography of breast cancer. American Journal of Roentgenology, Radium Therapy and Nuclear Medicine, 88, 1117-1125.

GERSHON-COHEN, J., BERGER, S. M., and CURCIO, B. M.

1966. Breast cancer with microcalcifications: Diagnostic difficulties. Radiology 87, 613-622. HASSLER, O., 1969. Microradiographic investigations of calcifications of the female breast. Cancer, 23, 1103-1109. KOEHL, R. H., SNYDER, Ruth E., HUTTER, R. P., and FOOTE,

F. W., 1970. The incidence and significance of calcifications within operative breast specimens. The American Journal of Clinical Pathology, 53, 3-14. LEBORGNE, R., 1949. Diagnostico de los tumores de la mama por la radiographia simple. Boletin de la Sociedad de Cirurgia de Uruguay, 20, 407-422. 1953. The Breast in roentgen diagnosis, pp. 124 (Impresora Uruguaya S.A., Montevideo, Uruguay,). LEVITAN, L. H., WITTEN, D. M., and HARRISON, E. G.,

1964. Calcification in breast disease, mammographic— pathologic correlation. American Journal of Roentgenology, Radium Therapy and Nuclear Medicine, 92, 29-39. MINAGI, H. 1969. Sources of error in mammography. Oncology, 23,164-166. PATTON, R. B., POZNANSKI, A. K., and ZYLACK, C. J., 1966.

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Pathologic examination of specimens containing nonpalpable breast cancers discovered by radiography. American Journal of Clinical Pathology, 46, 330-334.

BAUERMEISTER, D. E., and HALL MCLURE, H., 1973. Speci-

men radiography—a mandatory adjunct to mammography. American Journal of Clinical Pathology, 59, 782-783.

ROGERS, J. V., and POWELL, R. W., 1972. Mammographic

indications for biopsy of clinically normal breasts: correlation with pathological findings in 72 cases. American Journal of Roentgenology, Radium Therapy and Nuclear Medicine, 115, 794-800.

BLACK, J. W., and YOUNG, B., 1965. A radiological and

pathological study of the incidence of calcification in diseases of the breast and neoplasms of other tissues. The British Journal of Radiology, 38, 596-598.

ROSEN, P., SNYDER, Ruth E., FOOTE, F. W., and WALLACE,

Thelma, 1970. Detection of occult carcinoma in the apparently benign breast biopsy through specimen radiography. Cancer, 26, 944-952.

BLOOM, H. J. G., and RICHARDSON, W. W., 1957. Histo-

logical grading and prognosis in breast cancer. British Journal of Cancer, 11, 359-377. BOAG, J. W., STACEY, A. J., and DAVIS, R., 1971. Some

SHEPHERD, T. J. CRILE, G., and STRITTMATTER, W. C ,

clinical and experimental applications of xeroradi1962. Roentgenographic evaluation of calcifications seen ography. Journal of Photographic Science, 19, 45-48. in paraffin block specimens of mammary tumours. 1972. Xeroradiographic recording of mammograms. Radiology, 78, 967-969. British Journal of Radiology, 45, 633-640. WOLFE, J. N., 1966. Mammography: errors in diagnosis. EGAN, R. L., 1969. Fundamentals of mammographic diagRadiology, 87, 214-219. nosis of benign and malignant diseases. Oncology, 23, Xeroradiography of the Breast (Charles C. Thomas, 126-148. Springfield, Illinois).

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The detection and significance of calcifications in the breast: a radiological and pathological study.

The radiological detection of calcification is compared using xeroradiography, non-screen film and a film-screen combination. The "threshold" values o...
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