- Email: [email protected]
histological correlations of breast ductal carcinoma in situ
519
l’enfant.
parturient women in a high-risk population. N Engl J Med 1988; 318:
Paris, Nov 27-30, 1989: 141 (abstr). 8. Novick LF, Bems D, Stricof R, Stevens R, Pass K, Wethers J. HIV seroprevalence in newborns in New York State. JAMA 1989; 261:
185. 13. Hull HF, Bettinger CJ, Gallaher MM, Keller NM, Wilson J, Mertz GJ. Comparison of HIV-antibody prevalence in patients consenting to and declining HIV-antibody testing in an STD clinic. JAMA 1988; 260:
Italian hospitals. Les
implications
du SIDA pour la
mere et
1745-50. 9. Gill ON, Adler MW, Day NE. Br Med J 1989; 299: 1295-98.
Monitoring the prevalence of HIV.
10. Grant DB, Smith I. Survey of neonatal screening for primary hypothyroidism in England, Wales and Northern Ireland 1982-4. Br Med J 1988; 296: 1355-58. 11. Minkoff HL, Holman S, Beller E, Delke I, Fishbone A, Landesman S. SUNY Health Science Center routinely offered prenatal HIV testing.
N Engl J Med 1988; 319: 1018. 12. Krasinski K, Borrowsky W, Bebenroth D, Moore T. Failure of voluntary testing for human immunodeficiency virus to identify infected
935-38. 14. Landesman S, Minkoff H, Helman S, McCalla S, Syn O. Serosurvey of human immunodeficiency virus infection in parturients. JAMA 1987; 258: 2701-03. 15. Evans BA, McCormack SM, Bond RA, MacRae KD, Thorp RW. Human immunodeficiency virus infection, hepatitis B virus infection and sexual behaviour of women attending a genitourinary clinic. Br Med J 1988; 296: 473-75. 16. Royal College of Obstetricians and Gynaecologists. Report of the RCOG sub-committee on problems associated with AIDS in relation to obstetrics and gynaecology. London: RCOG, 1987.
CLINICAL PRACTICE Extent, distribution, and mammographic/
histological
To
correlations of breast ductal carcinoma in situ
potential of breast-conserving (DCIS), 82 mastectomy specimens were studied by Egan’s serial subgross method. 42 (51%) of the tumours were larger than 50 mm and only 12 (15%) were assess
the
treatment for ductal carcinoma in situ
smaller than 20 mm; the size distribution was not affected by the mode of detection (mammography 52 cases, clinical examination 30). All but 1 case showed only 1 region of tumour. 66% of tumours involved one breast quadrant, 23% extended over more than one quadrant, and 11% were centrally located. Mammographic estimates, based on the extent of microcalcifications, frequently underestimated the histological size of tumours, the extent of the discrepancy being related to the histological type—8/50 predominantly comedo DCIS showed a discrepancy greater than 20 mm with 15/32 compared predominantly micropapillary/cribriform. In view of the frequently large size, adequate excision of many DCIS will require a wide excision involving up to a whole quadrant.
Introduction Until now the standard treatment for ductal carcinoma in situ of the breast (DCIS, intraductal carcinoma) has been ablative surgery, with a cure rate of nearly 100%. However,
the results of breast-conserving treatment rather than mastectomy for the management of early invasive breast cancer are promising. This development has created controversy, in that mastectomy is still recommended for patients with non-invasive intraductal cancers (ie, at an earlier stage than any invasive cancer), whereas many patients with invasive cancers are offered breast-conserving treatment. The increasing use of mammography in routine diagnosis of breast disorders and the introduction of mammographic mass screening programmes1 have expanded the scale of the problem by raising the rate of detection of DCIS three or four fold to as much as 15-20% of all mammographically detected cancers .1,3 The main reservation about conservative treatment of DCIS is that its distribution in the breast is assumed to be multicentric. In patients with DCIS, treated by lumpectomy and subsequent mastectomy, residual tumour was found in 30-60% of mastectomy specimens 4 The effect of radiotherapy on this residual DCIS is not yet clear.6,7 Therefore, the surgeon should ideally make every attempt to resect all disease, with histologically adequate margins, ADDRESSES: Departments of Pathology Schuurmans Stekhoven, PhD), Radiology (J and Epidemiology (A. L. M. Verbeek, MD), Hospital, and Department of Pathology,
(R. Holland, MD, J. H. H. C. L Hendriks, MD), Radboud University Canisius Wilhelmina Hospital (M. Mravunac, MD), Nijmegen, the Netherlands. Correspondence to Dr R. Holland, Department of Pathology, Radboud University Hospital, 6500 HB Nijmegen, the Netherlands.
520
treating DCIS conservatively. Since histological of the margins is not fully reliable, subsequent radiotherapy will be necessary in many cases to eliminate
DCIS-predominantly comedo type (50 cases) and predominantly micropapillary/cribriform type (32 cases). Predominantly comedo carcinoma comprised comedo
any residual tumour. For this type of management detailed
carcinoma alone in 34 cases, combined with cribriform and/or large papillary pattern but with no difference in cytology in 9 cases, and combined with micropapillary/ cribriform pattern and with different cytology in 7 cases. The comedo type of tumour typically had a moderate to high nuclear grade and substantial necrosis. The microcalcifications usually lay within the necrotic debris and were amorphous. The mammographic equivalent of these microcalcifications was the so-called casting type of microcalcification, with a linear or branching aspect, and the coarse granular type, with irregular shapeSIO-12 (see
when
assessment
information must be available on the distribution of DCIS in the breast and the accuracy of mammography in assessing the extent of the tumour. Since few intraductal cancers are palpable, the mammographic estimate is the sole guide for resection. We have carried out a study on 82 mastectomy specimens from patients with DCIS, using the Egan method of serial subgross and correlated radiographic examination.
Patients and methods Of 91 consecutive patients treated for DCI S between 1980 and 1987 in two hospitals in Nijmegen, we excluded from the study 6 patients treated with less than a mastectomy and 3 patients with noninvasive intracystic carcinoma. Thus, the study group consisted of 82 women with DCIS who underwent mastectomy. In 47 cases the cancer was detected within a mammographic screening programme and 35 cases were derived from an outpatient population. 52 cancers were discovered by means of mammography, and 30 were detected
clinically by means of a palpable mass, nipple discharge, or Paget’s disease. Substantial microcalcifications were seen on the mammograms of 16 of these 30 patients but 14 had no mammographic signs at all. All mastectomy specimens were examined in one laboratory by the serial subgross and correlated radiographic-histological method (Egan method8) described in detail previously.9 Whole organ sections of the chilled breast are taken every 5 mm, and each one is radiographed. Tissue blocks for paraffin sections are taken from radiologically suspicious lesions (ie, those with microcalcifications or architectural distortions) and from areas showing grossly suspicious changes. In any breast specimen, an average of 25 tissue blocks were taken from the quadrant containing the index lesion, plus random samples from other quadrants, the nipple, and the central area beneath the nippleareolar complex. Both the precise site of the blocks taken and the microscopically verified extension of each lesion were indicated on the specimen X-ray. This method allows detailed reconstruction of the site, the extent, and the distribution of the tumour foci in the breast. All preoperative mammograms, including magnification views of each patient, were reviewed to assess the extent of the tumour, based on the distribution of substantial microcalcifications. For each patient, at least two mammograms, a mediolateral oblique and a craniocaudal view, were available. The mammograms were done with a ’Senograph 600T’ (General Electric/Compagnie General de Radiologie) with ’Min R’ screens and ’OM-1’ film (Kodak). The magnification views were carried out with an 0 1 mm focus. The mammographic extent of a DCIS was defined as the greatest distance between the most peripherally located clusters of suspicious microcalcifications, and the histological extent as the greatest distance between the most peripherally located, histologically verified, DCIS foci. Only foci with distinct histological features of DCIS were assessed for involvement; foci of atypical ductal hyperplasia were not. The mammographic estimates were compared with the histologically confirmed sizes of the tumours. A DCIS was considered to be confined to one quadrant when the cancer could be encompassed within a pair of perpendicular axes meeting at the nipple.
Results
Histological subtypes and their microcalcifications The 82 cases of DCIS were subclassified histologically according to their architectural pattern, nuclear grade (low, intermediate, high), and the presence or absence of substantial necrosis. We observed
two
main groups of
accompanying figure, a, b).
Micropapillary/cribriform carcinoma occurred alone in 18 cases, combined with solid pattern but with no difference in cytology in 3 cases, and combined with comedo pattern with different cytology in 11 cases. The micropapillary/ cribriform type was characterised by a low to moderate nuclear grade and absence of substantial necrosis. The microcalcifications, if present, were of a crystalline type with oval or circular shapes, and many had a laminated aspect. They typically lay in the alcian-blue-positive secretion produced by the tumour cells. The mammographic equivalent of these microcalcifications was multiple clusters of very fine granular deposits, with irregular or more or less regular oval or circular forms (figure, c, d). visible microlinear-type Mammographically calcifications were present alone or mixed with granular type in 40 of 50 (80%) predominantly comedo DCIS compared with only 5 of 32 (16%) predominantly micropapillary/ cribriform
tumours.
The linear type of microcalcification
appeared invariably in the comedo component of the mixed type tumours, whereas the micropapillary or cribriform component showed fine granular microcalcifications or none at all. 7 (14%) predominantly comedo tumours and 12 (37%) predominantly micropapillary/cribriform tumours had granular microcalcifications alone. Remarkably, there were no detectable microcalcifications in 15 (47%) of the tumours predominantly micropapillary/cribriform compared with only 3 (6%) of the predominantly comedo type. The difference in distribution of type of microcalcification was significant (p < 0-001; chi-square test). 11 of the 14 mammographically occult intraductal cancers of the predominantly micropapillary/ were cribriform type with a median size of 50 mm (range 2-120 mm), whereas only 3 were of the predominantly comedo type, with a median size of 15 mm (range 15-30 mm). The latter 3 were located in the subareolar region and were associated with Paget’s disease of the nipple.
Mammographic-histological correlation 51 % of the cancers were 50 mm or larger and 15 % were smaller than 20 mm; this size distribution was independent of the mode of detection (p 0-16; chi-square test; table I) or the histological type of the tumour. 26 (52%) of the predominantly comedo tumours and 16 (50%) of the predominantly micropapillary/cribriform tumours were larger than 50 mm (p = 0-26). The tumour size assessed by mammography, on the basis of the extent of microcalcifications or soft tissue density (4 cases), was smaller than that assessed by histology in many cases. The extent of the discrepancy was clearly related to the histological type of the DCIS; only 8 (16%) of the =
521
Mammographic images and histology of the two main types of DCIS. Linear and coarse granular microcalcifications, characteristic of comedo type DCIS (a); with significant necrosis and amorphous calcium deposits (b); fine granular microcalcifications in multiple cluster arrangement, characteristic of micropapillary type DCIS (c); with a laminated crystalline calcium deposit and without significant necrosis (d).
predominantly comedo carcinomas showed a discrepancy between mammographic and histological estimates of more than 20 mm compared with 15 (47%) of the predominantly micropapillary/cribriform carcinomas (p < 0-001). Analysis of the subsets of pure comedo and pure micropapillary// cribriform carcinomas showed that the striking differences between the mammographic and histological estimates could be ascribed to the micropapillary/cribriform types. The discrepancy was more than 20 mm in 8 (44%) of the pure micropapillary/cribriform tumours compared with only 5 (12%) of the pure comedo type. However, when the comedo type occurred together with the micropapillary// cribriform type, the discrepancy was substantial; it was more
quadrant. The other 27, measuring 40 mm or less and occupying less than a whole quadrant, could have been removed completely, with histologically tumour-free margins, by a quadrantectomy. In 81 of the 82 cancers the tumour involved only one region of the breast without substantial areas of uninvolved
54 of the 82 DCIS were confined to one quadrant, 19 extended over more than one quadrant, and 9 were centrally located (table 11). 27 of the one-quadrant tumours measured more than 40 mm and extended almost over the whole
breast tissue between the groups of DCIS foci. There was multicentric distribution in only 1 case; the tumour affected opposite quadrants but not the neighbouring quadrants. In 28 cases of pure comedo type DCIS, contiguous and three-dimensional sampling of the tissue blocks from the centre to the periphery of the tumour allowed us to assess whether the clusters of intraductal foci were independent sites of tumour development or the product of contiguous growth along the ductal system. Tumour growth was considered to be contiguous if histological examination of sequential tissue blocks in two or three dimensions showed that the ducts were affected. 26 of the 28 comedo type carcinomas showed such contiguous spread but it could not be proved in the other 2 cases.
TABLE)—H!STOLOG!CALTUMOURS!ZEBYMODEOFDETECT!ON
TABLE II-HISTOLOGICALLY VERIFIED QUADRANT INVOLVEMENT
than 20 mm in 50% of these cases. Pattern of tumour distribution
——————————————————————————"——’——’————————
522
In 52% of tumours (43 of
82) an intraductal tumour focus
lie in the nipple/subareolar region. The likelihood that this region would be involved was clearly related to the histological type (32/50 [64%] predominantly comedo vs 11/32 [34%] predominantly micropapillary / cribriform showed nipple/subareolar involvement). The tumour focus was in the nipple itself in 22 of the 43 cases (51 %) and a manifestation of Paget’s disease in 9 of these. Nipple/subareolar involvement was seen in 70% of the tumours measuring more than 40 mm but in only 15% of those smaller than 40 mm. Of the 43 cases with nipple/subareolar involvement 13 (30%) had substantial microcalcifications on mammography but 30 (70%) had no mammographic abnormalities. was
shown
by histology
to
Discussion We have shown that DCIS are rarely small tumours at the time of detection and that the size distribution is not related to the mode of detection. The widespread use of mammography is generally believed to be causing a shift in the size distribution of tumours detected towards smaller cancers. Though this shift has been proved for invasive cancers, 2,13,14 it has not yet been shown for the non-invasive intraductal cancers. Previous studies have focused on the multicentric and multifocal distribution of DCIS rather than on the size of the tumours. Size has been estimated mainly on the basis of microcalcifications on routine mammograms and/or standard pathological examination of the diagnostic biopsy sample. Residual tumour foci in tissue later obtained at mastectomy were considered as separate foci. However, we have found that DCIS typically does not have a multicentric distribution. This finding is very important, since it means that a "one piece" complete resection of the tumour should be possible. However, about 25% of the tumours in our series were very large. Because they extended over two or more quadrants, breast-conserving treatment would not have been possible (table n). In general, cancers of 40 mm or less seem to be most suitable for conservative treatment. Even these tumours will probably need a wide excision involving up to a whole quadrant to facilitate both complete resection and meticulous histological examination of the margins. Taking account of the high frequency of nipple and subareolar involvement, the resection should include an extension in the direction of the nipple, the margin of which should also be carefully studied for possible involvement. We have found that the reliability of mammography in assessing tumour size is related to both the histological type of the DCIS and the type of microcalcifications seen by mammography. Mammographic estimates of the predominantly comedo type of DCIS closely approximate the histologically confirmed size of the tumour. These cancers can be recognised on the mammogram by their typical linear, branching, or coarse granular microcalcifications. In contrast, mammographic estimates of the predominantly micropapillary/cribriform types correlate poorly with the histological sizes. Some of these tumours show clusters of fme granular microcalcifications on the mammogram, but others show no microcalcifications at all. The major consequence of our findings is that the surgeon can rely on the mammographic estimate if the mammogram shows the linear or coarse granular calcifications of comedo
type DCIS. However, estimates based on the fine granular calcifications of a micropapillary/cribriform type cancer cannot be fully trusted. In many of the latter type of tumours the microcalcifications indicate only a small part of the whole tumour. Besides, they may be completely occult on mammography even in patients with symptoms. Since the effect of radiotherapy on a large residual tumour burden of DCIS is still unsettled, any surgical approach should satisfy the main aim of removing the disease entirely. Because of large size at detection, few DCIS are candidates for breast-conserving therapy. Tumours estimated by mammography to measure up to 40 mm, which show the typical linear or branching microcalcifications of the comedo type, can safely be treated with a wide excision involving up to a whole quadrant, provided that the resection margins are tumour-free on histology. Since histological assessment of the margins is not fully reliable, subsequent radiotherapy will be necessary to eliminate any residual tumour. Management of tumours with clusters of fine granular mammographic microcalcifications and with micropapillary or cribriform histology should take into account that the mammographic estimate based on the microcalcifications is likely to under-represent the extent of the tumour. A postoperative mammogram is required to confirm the completeness of resection. We thank Dr Jay R. Harris, Dr Laszlo Tabar, and Barbara Silver for helpful suggestions in the preparation of this article; and Gerry Prinsen and Henny Rijken for helping to prepare the typescript.
REFERENCES 1. Schnitt SJ, Silen N, Sadowsky NL, Connolly JL, Harris JR. Ductal carcinoma in situ (intraductal carcinoma) of the breast. N Engl J Med 1988; 318: 898-903 2. Baker LH. Breast Cancer Detection Demonstration Project: five-year summary report. CA 1982; 32: 194-225. 3. Peeters PHM, Verbeek ALM, Straatman H, et al. Evaluation of overdiagnosis of breast cancer in screening with mammography. Int J Epidermiol 1989; 18: 295-99. 4. Lagios MD, Westdahl PR, Margolin FR, Rose MR. Duct carcinoma in situ: relationship of extent of noninvasive diseases to the frequency of occult invasion, multicentricity, lymph node metastases, and shortterm treatment failures. Cancer 1982; 50: 1309-14. 5. Rosen PP, Senie R, Schottenfeld D, Ashikari R. Noninvasive breast carcinoma. Ann Surg 1979; 189: 377-82. 6. Fisher ER, Sass R, Fisher B, et al. Pathologic findings from the National Surgical Adjuvant Breast Project (Protocol 6). I. Intraductal carcinoma (DCIS). Cancer 1986; 57: 197-208. 7. Holland R, Connolly JL, Gelman R, et al. The presence of an extensive intraductal component (EIC) following a limited excision predicts for prominent residual disease in the remainder of the breast. J Clin Oncol
1990; 8: 113-18. 8. Egan RL. Multicentric breast carcinomas; clinical-radiographicpathologic whole organ studies and 10-year survival. Cancer 1982; 49: 1123-30. 9. Holland R, Veling SHJ, Mravunac M, et al. Histologic multifocality of Tis, T1-2 breast carcinoma. Implications for clinical trials of breast-conserving surgery. Cancer 1985; 56: 979-90. 10. Tabár L, Dean PB. Teaching atlas of mammography. New York: Thieme-Stratton, 1983; 138-203. 11. Sickles EA. Breast calcifications: mammographic evaluation. Radiology 1986; 160: 289-93. 12. Lanyi M. Diagnosis and differential diagnosis of breast calcifications. Berlin: Springer Verlag, 1986. 13. Fagerberg CJG, Tabár L. The results of periodic one-view mammography screening in a randomized, controlled trial in Sweden. Part 1. In: Day NE, Miller AB, eds. Screening for breast cancer. Toronto: Hans Hubner, 1988: 33-38. 14. Peeters PHM, Verbeek ALM, Hendriks JHCL, van Bon MJH. Screening for breast cancer in Nijmegen, report of 6 screening rounds, 1975-1986. Int J Cancer 1989; 43: 226-30.
l’enfant.
parturient women in a high-risk population. N Engl J Med 1988; 318:
Paris, Nov 27-30, 1989: 141 (abstr). 8. Novick LF, Bems D, Stricof R, Stevens R, Pass K, Wethers J. HIV seroprevalence in newborns in New York State. JAMA 1989; 261:
185. 13. Hull HF, Bettinger CJ, Gallaher MM, Keller NM, Wilson J, Mertz GJ. Comparison of HIV-antibody prevalence in patients consenting to and declining HIV-antibody testing in an STD clinic. JAMA 1988; 260:
Italian hospitals. Les
implications
du SIDA pour la
mere et
1745-50. 9. Gill ON, Adler MW, Day NE. Br Med J 1989; 299: 1295-98.
Monitoring the prevalence of HIV.
10. Grant DB, Smith I. Survey of neonatal screening for primary hypothyroidism in England, Wales and Northern Ireland 1982-4. Br Med J 1988; 296: 1355-58. 11. Minkoff HL, Holman S, Beller E, Delke I, Fishbone A, Landesman S. SUNY Health Science Center routinely offered prenatal HIV testing.
N Engl J Med 1988; 319: 1018. 12. Krasinski K, Borrowsky W, Bebenroth D, Moore T. Failure of voluntary testing for human immunodeficiency virus to identify infected
935-38. 14. Landesman S, Minkoff H, Helman S, McCalla S, Syn O. Serosurvey of human immunodeficiency virus infection in parturients. JAMA 1987; 258: 2701-03. 15. Evans BA, McCormack SM, Bond RA, MacRae KD, Thorp RW. Human immunodeficiency virus infection, hepatitis B virus infection and sexual behaviour of women attending a genitourinary clinic. Br Med J 1988; 296: 473-75. 16. Royal College of Obstetricians and Gynaecologists. Report of the RCOG sub-committee on problems associated with AIDS in relation to obstetrics and gynaecology. London: RCOG, 1987.
CLINICAL PRACTICE Extent, distribution, and mammographic/
histological
To
correlations of breast ductal carcinoma in situ
potential of breast-conserving (DCIS), 82 mastectomy specimens were studied by Egan’s serial subgross method. 42 (51%) of the tumours were larger than 50 mm and only 12 (15%) were assess
the
treatment for ductal carcinoma in situ
smaller than 20 mm; the size distribution was not affected by the mode of detection (mammography 52 cases, clinical examination 30). All but 1 case showed only 1 region of tumour. 66% of tumours involved one breast quadrant, 23% extended over more than one quadrant, and 11% were centrally located. Mammographic estimates, based on the extent of microcalcifications, frequently underestimated the histological size of tumours, the extent of the discrepancy being related to the histological type—8/50 predominantly comedo DCIS showed a discrepancy greater than 20 mm with 15/32 compared predominantly micropapillary/cribriform. In view of the frequently large size, adequate excision of many DCIS will require a wide excision involving up to a whole quadrant.
Introduction Until now the standard treatment for ductal carcinoma in situ of the breast (DCIS, intraductal carcinoma) has been ablative surgery, with a cure rate of nearly 100%. However,
the results of breast-conserving treatment rather than mastectomy for the management of early invasive breast cancer are promising. This development has created controversy, in that mastectomy is still recommended for patients with non-invasive intraductal cancers (ie, at an earlier stage than any invasive cancer), whereas many patients with invasive cancers are offered breast-conserving treatment. The increasing use of mammography in routine diagnosis of breast disorders and the introduction of mammographic mass screening programmes1 have expanded the scale of the problem by raising the rate of detection of DCIS three or four fold to as much as 15-20% of all mammographically detected cancers .1,3 The main reservation about conservative treatment of DCIS is that its distribution in the breast is assumed to be multicentric. In patients with DCIS, treated by lumpectomy and subsequent mastectomy, residual tumour was found in 30-60% of mastectomy specimens 4 The effect of radiotherapy on this residual DCIS is not yet clear.6,7 Therefore, the surgeon should ideally make every attempt to resect all disease, with histologically adequate margins, ADDRESSES: Departments of Pathology Schuurmans Stekhoven, PhD), Radiology (J and Epidemiology (A. L. M. Verbeek, MD), Hospital, and Department of Pathology,
(R. Holland, MD, J. H. H. C. L Hendriks, MD), Radboud University Canisius Wilhelmina Hospital (M. Mravunac, MD), Nijmegen, the Netherlands. Correspondence to Dr R. Holland, Department of Pathology, Radboud University Hospital, 6500 HB Nijmegen, the Netherlands.
520
treating DCIS conservatively. Since histological of the margins is not fully reliable, subsequent radiotherapy will be necessary in many cases to eliminate
DCIS-predominantly comedo type (50 cases) and predominantly micropapillary/cribriform type (32 cases). Predominantly comedo carcinoma comprised comedo
any residual tumour. For this type of management detailed
carcinoma alone in 34 cases, combined with cribriform and/or large papillary pattern but with no difference in cytology in 9 cases, and combined with micropapillary/ cribriform pattern and with different cytology in 7 cases. The comedo type of tumour typically had a moderate to high nuclear grade and substantial necrosis. The microcalcifications usually lay within the necrotic debris and were amorphous. The mammographic equivalent of these microcalcifications was the so-called casting type of microcalcification, with a linear or branching aspect, and the coarse granular type, with irregular shapeSIO-12 (see
when
assessment
information must be available on the distribution of DCIS in the breast and the accuracy of mammography in assessing the extent of the tumour. Since few intraductal cancers are palpable, the mammographic estimate is the sole guide for resection. We have carried out a study on 82 mastectomy specimens from patients with DCIS, using the Egan method of serial subgross and correlated radiographic examination.
Patients and methods Of 91 consecutive patients treated for DCI S between 1980 and 1987 in two hospitals in Nijmegen, we excluded from the study 6 patients treated with less than a mastectomy and 3 patients with noninvasive intracystic carcinoma. Thus, the study group consisted of 82 women with DCIS who underwent mastectomy. In 47 cases the cancer was detected within a mammographic screening programme and 35 cases were derived from an outpatient population. 52 cancers were discovered by means of mammography, and 30 were detected
clinically by means of a palpable mass, nipple discharge, or Paget’s disease. Substantial microcalcifications were seen on the mammograms of 16 of these 30 patients but 14 had no mammographic signs at all. All mastectomy specimens were examined in one laboratory by the serial subgross and correlated radiographic-histological method (Egan method8) described in detail previously.9 Whole organ sections of the chilled breast are taken every 5 mm, and each one is radiographed. Tissue blocks for paraffin sections are taken from radiologically suspicious lesions (ie, those with microcalcifications or architectural distortions) and from areas showing grossly suspicious changes. In any breast specimen, an average of 25 tissue blocks were taken from the quadrant containing the index lesion, plus random samples from other quadrants, the nipple, and the central area beneath the nippleareolar complex. Both the precise site of the blocks taken and the microscopically verified extension of each lesion were indicated on the specimen X-ray. This method allows detailed reconstruction of the site, the extent, and the distribution of the tumour foci in the breast. All preoperative mammograms, including magnification views of each patient, were reviewed to assess the extent of the tumour, based on the distribution of substantial microcalcifications. For each patient, at least two mammograms, a mediolateral oblique and a craniocaudal view, were available. The mammograms were done with a ’Senograph 600T’ (General Electric/Compagnie General de Radiologie) with ’Min R’ screens and ’OM-1’ film (Kodak). The magnification views were carried out with an 0 1 mm focus. The mammographic extent of a DCIS was defined as the greatest distance between the most peripherally located clusters of suspicious microcalcifications, and the histological extent as the greatest distance between the most peripherally located, histologically verified, DCIS foci. Only foci with distinct histological features of DCIS were assessed for involvement; foci of atypical ductal hyperplasia were not. The mammographic estimates were compared with the histologically confirmed sizes of the tumours. A DCIS was considered to be confined to one quadrant when the cancer could be encompassed within a pair of perpendicular axes meeting at the nipple.
Results
Histological subtypes and their microcalcifications The 82 cases of DCIS were subclassified histologically according to their architectural pattern, nuclear grade (low, intermediate, high), and the presence or absence of substantial necrosis. We observed
two
main groups of
accompanying figure, a, b).
Micropapillary/cribriform carcinoma occurred alone in 18 cases, combined with solid pattern but with no difference in cytology in 3 cases, and combined with comedo pattern with different cytology in 11 cases. The micropapillary/ cribriform type was characterised by a low to moderate nuclear grade and absence of substantial necrosis. The microcalcifications, if present, were of a crystalline type with oval or circular shapes, and many had a laminated aspect. They typically lay in the alcian-blue-positive secretion produced by the tumour cells. The mammographic equivalent of these microcalcifications was multiple clusters of very fine granular deposits, with irregular or more or less regular oval or circular forms (figure, c, d). visible microlinear-type Mammographically calcifications were present alone or mixed with granular type in 40 of 50 (80%) predominantly comedo DCIS compared with only 5 of 32 (16%) predominantly micropapillary/ cribriform
tumours.
The linear type of microcalcification
appeared invariably in the comedo component of the mixed type tumours, whereas the micropapillary or cribriform component showed fine granular microcalcifications or none at all. 7 (14%) predominantly comedo tumours and 12 (37%) predominantly micropapillary/cribriform tumours had granular microcalcifications alone. Remarkably, there were no detectable microcalcifications in 15 (47%) of the tumours predominantly micropapillary/cribriform compared with only 3 (6%) of the predominantly comedo type. The difference in distribution of type of microcalcification was significant (p < 0-001; chi-square test). 11 of the 14 mammographically occult intraductal cancers of the predominantly micropapillary/ were cribriform type with a median size of 50 mm (range 2-120 mm), whereas only 3 were of the predominantly comedo type, with a median size of 15 mm (range 15-30 mm). The latter 3 were located in the subareolar region and were associated with Paget’s disease of the nipple.
Mammographic-histological correlation 51 % of the cancers were 50 mm or larger and 15 % were smaller than 20 mm; this size distribution was independent of the mode of detection (p 0-16; chi-square test; table I) or the histological type of the tumour. 26 (52%) of the predominantly comedo tumours and 16 (50%) of the predominantly micropapillary/cribriform tumours were larger than 50 mm (p = 0-26). The tumour size assessed by mammography, on the basis of the extent of microcalcifications or soft tissue density (4 cases), was smaller than that assessed by histology in many cases. The extent of the discrepancy was clearly related to the histological type of the DCIS; only 8 (16%) of the =
521
Mammographic images and histology of the two main types of DCIS. Linear and coarse granular microcalcifications, characteristic of comedo type DCIS (a); with significant necrosis and amorphous calcium deposits (b); fine granular microcalcifications in multiple cluster arrangement, characteristic of micropapillary type DCIS (c); with a laminated crystalline calcium deposit and without significant necrosis (d).
predominantly comedo carcinomas showed a discrepancy between mammographic and histological estimates of more than 20 mm compared with 15 (47%) of the predominantly micropapillary/cribriform carcinomas (p < 0-001). Analysis of the subsets of pure comedo and pure micropapillary// cribriform carcinomas showed that the striking differences between the mammographic and histological estimates could be ascribed to the micropapillary/cribriform types. The discrepancy was more than 20 mm in 8 (44%) of the pure micropapillary/cribriform tumours compared with only 5 (12%) of the pure comedo type. However, when the comedo type occurred together with the micropapillary// cribriform type, the discrepancy was substantial; it was more
quadrant. The other 27, measuring 40 mm or less and occupying less than a whole quadrant, could have been removed completely, with histologically tumour-free margins, by a quadrantectomy. In 81 of the 82 cancers the tumour involved only one region of the breast without substantial areas of uninvolved
54 of the 82 DCIS were confined to one quadrant, 19 extended over more than one quadrant, and 9 were centrally located (table 11). 27 of the one-quadrant tumours measured more than 40 mm and extended almost over the whole
breast tissue between the groups of DCIS foci. There was multicentric distribution in only 1 case; the tumour affected opposite quadrants but not the neighbouring quadrants. In 28 cases of pure comedo type DCIS, contiguous and three-dimensional sampling of the tissue blocks from the centre to the periphery of the tumour allowed us to assess whether the clusters of intraductal foci were independent sites of tumour development or the product of contiguous growth along the ductal system. Tumour growth was considered to be contiguous if histological examination of sequential tissue blocks in two or three dimensions showed that the ducts were affected. 26 of the 28 comedo type carcinomas showed such contiguous spread but it could not be proved in the other 2 cases.
TABLE)—H!STOLOG!CALTUMOURS!ZEBYMODEOFDETECT!ON
TABLE II-HISTOLOGICALLY VERIFIED QUADRANT INVOLVEMENT
than 20 mm in 50% of these cases. Pattern of tumour distribution
——————————————————————————"——’——’————————
522
In 52% of tumours (43 of
82) an intraductal tumour focus
lie in the nipple/subareolar region. The likelihood that this region would be involved was clearly related to the histological type (32/50 [64%] predominantly comedo vs 11/32 [34%] predominantly micropapillary / cribriform showed nipple/subareolar involvement). The tumour focus was in the nipple itself in 22 of the 43 cases (51 %) and a manifestation of Paget’s disease in 9 of these. Nipple/subareolar involvement was seen in 70% of the tumours measuring more than 40 mm but in only 15% of those smaller than 40 mm. Of the 43 cases with nipple/subareolar involvement 13 (30%) had substantial microcalcifications on mammography but 30 (70%) had no mammographic abnormalities. was
shown
by histology
to
Discussion We have shown that DCIS are rarely small tumours at the time of detection and that the size distribution is not related to the mode of detection. The widespread use of mammography is generally believed to be causing a shift in the size distribution of tumours detected towards smaller cancers. Though this shift has been proved for invasive cancers, 2,13,14 it has not yet been shown for the non-invasive intraductal cancers. Previous studies have focused on the multicentric and multifocal distribution of DCIS rather than on the size of the tumours. Size has been estimated mainly on the basis of microcalcifications on routine mammograms and/or standard pathological examination of the diagnostic biopsy sample. Residual tumour foci in tissue later obtained at mastectomy were considered as separate foci. However, we have found that DCIS typically does not have a multicentric distribution. This finding is very important, since it means that a "one piece" complete resection of the tumour should be possible. However, about 25% of the tumours in our series were very large. Because they extended over two or more quadrants, breast-conserving treatment would not have been possible (table n). In general, cancers of 40 mm or less seem to be most suitable for conservative treatment. Even these tumours will probably need a wide excision involving up to a whole quadrant to facilitate both complete resection and meticulous histological examination of the margins. Taking account of the high frequency of nipple and subareolar involvement, the resection should include an extension in the direction of the nipple, the margin of which should also be carefully studied for possible involvement. We have found that the reliability of mammography in assessing tumour size is related to both the histological type of the DCIS and the type of microcalcifications seen by mammography. Mammographic estimates of the predominantly comedo type of DCIS closely approximate the histologically confirmed size of the tumour. These cancers can be recognised on the mammogram by their typical linear, branching, or coarse granular microcalcifications. In contrast, mammographic estimates of the predominantly micropapillary/cribriform types correlate poorly with the histological sizes. Some of these tumours show clusters of fme granular microcalcifications on the mammogram, but others show no microcalcifications at all. The major consequence of our findings is that the surgeon can rely on the mammographic estimate if the mammogram shows the linear or coarse granular calcifications of comedo
type DCIS. However, estimates based on the fine granular calcifications of a micropapillary/cribriform type cancer cannot be fully trusted. In many of the latter type of tumours the microcalcifications indicate only a small part of the whole tumour. Besides, they may be completely occult on mammography even in patients with symptoms. Since the effect of radiotherapy on a large residual tumour burden of DCIS is still unsettled, any surgical approach should satisfy the main aim of removing the disease entirely. Because of large size at detection, few DCIS are candidates for breast-conserving therapy. Tumours estimated by mammography to measure up to 40 mm, which show the typical linear or branching microcalcifications of the comedo type, can safely be treated with a wide excision involving up to a whole quadrant, provided that the resection margins are tumour-free on histology. Since histological assessment of the margins is not fully reliable, subsequent radiotherapy will be necessary to eliminate any residual tumour. Management of tumours with clusters of fine granular mammographic microcalcifications and with micropapillary or cribriform histology should take into account that the mammographic estimate based on the microcalcifications is likely to under-represent the extent of the tumour. A postoperative mammogram is required to confirm the completeness of resection. We thank Dr Jay R. Harris, Dr Laszlo Tabar, and Barbara Silver for helpful suggestions in the preparation of this article; and Gerry Prinsen and Henny Rijken for helping to prepare the typescript.
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