Cancer Investigation, 10(5), 443-454 (1992)
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Ductal Carcinoma In Situ Sandra M. Swain, M.D. Comprehensive Breast Center Vincent T. Lombardi Cancer Research Center Georgetown University Medical Center Podium Level-Corridor B 3800 Reservoir Road PI.W. Washington, 0.C. 20007
INTRODUCTION
Wellings and Jensen have provided evidence for the location of most benign and malignant proliferative lesions of the breast (3,4). The method for characterizing these lesions was subgross examination correlated with histopathology . They hypothesize that the terminal ductal lobular unit (TDLU) is the origin of most pathologic breast lesions, including both ductal and lobular carcinoma in situ. Ductal carcinoma in situ was seen as dilatation and unfolding of the lobules with lobular coalescence. The lesions of lobular carcinoma in situ appeared as large, poorly defined ductules. Their studies also showed a markedly increased incidence of atypical and in situ lesions in cancer-associated breasts compared with random breasts at autopsy. Theories of the development of invasive cancer include progression from normal to epithelial hyperplasia to atypical hyperplasia to ductal carcinoma in situ to invasive ductal cancer. Gallagher has done whole organ sectioning of the breast and clearly feels that epithelial hyperplasia is a nonobligate preneoplastic lesion (5). He supports this statement with the evidence from whole organ sectioning in which breasts with an invasive cancer present almost universally contained proliferative ductal
The concept of carcinoma in situ was introduced by Broders in 1932 (1). He described carcinoma in situ as ‘‘a condition in which malignant epithelial cells and their progeny are found in or near positions occupied by their ancestors before the ancestors underwent malignant transformation. At least they have not migrated beyond the juncture of the epithelium and connective tissue or the so-called basement membrane. The normal anatomy of the breast has been studied in detail ( 2 ) . The breast contains 12 to 24 lobes, each supplied by a lactiferous duct. The lactiferous ducts dilate, forming a lactiferous sinus which opens in the nipple. Lactiferous ducts branch in the breast to form intralobar ducts. These branch to form the terminal ductal lobular unit. This unit consists of the extralobular terminal duct and the lobule. The extralobular terminal duct is surrounded by elastic tissue and lined by columnar epithelial cells. The lobule is formed by the intralobular terminal duct and two to six ductules or acini. The intralobular terminal duct is not surrounded by elastic tissue and is lined by cuboidal cells. ”
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Copyright 0 1992 by Marcel Dekker, Inc.
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epithelium. Also, within most breasts, a spectrum of disease was seen including atypical hyperplasia and ductal carcinoma in situ. More recently, investigators have looked at oncogene expression in various lesions of the breast. Expression of the erbB-2 oncogene protein 'product has been found to be present in a majority of comedo DCIS with reports of positivity ranging from 42-100% (6-8). A much lower proportion, or 14-28% of infiltrating ductal carcinomas, express erbB-2 (6,9,10). This suggests that either (i) not all noninvasive comedo DCIS become invasive, (ii) the majority of invasive cancers originate from a different process, or (iii) that the expression of oncogene erbB-2 is an early event and is lost during malignant progression and invasion. It is probable that the epithelial cells of ductal carcinoma in situ have already been affected by multiple genetic and epigenetic events. The susceptible cells then gain a selective growth advantage leading to malignant tumor progression, invasion, and eventually metastasis. Supporting the hypothesis that ductal carcinoma in situ is capable of progressing to invasive cancer is evidence that basement membranes are either altered focally or totally missing in all DCIS lesions when stained with periodic acid-Schiff (PAS) ( 1 1). DCIS by definition has intact basement membranes by light microscopy. Infiltrating tumors lack basement membranes. Ozzello studied DClS by PAS staining and found defective basal laminae in almost all cases ( 1 1). This ranged from variations in thickness to areas of discontinuity of the basement membrane. Ozzello also studied DCIS by electron microscopy ( I I). In many cases of DCIS, gaps were present and cells protruded through the gap into the surrounding stroma, indicating invasiveness. These abnormalities of basement membranes are not observed by light microscopy. Exciting work in the area of invasion and metastases is currently underway (Table I). Clearly defining the role of various growth factors, proteinases, and basement membrane components in invasion will lead to more directed therapeutic options. Barsky et al. found that the basement membrane components, type IV collagen and laminin, were lost in invasive breast tumors but not in DCIS or benign breast lesions ( 12). Also, when studying DCIS with microinvasion by light microscopy, there was disruption of the basement membrane with loss of type IV collagen and laminin in the areas of microinvasion only. Tenascin is an extracellular matrix glycoprotein which is important in tissue development. It reduces cell-to-
Swain
matrix adhesion and promotes cell movement. It has been found to be a part of the development of the normal mammary gland. Ferguson et al. have found that the distribution and quality of tenascin changes during the menstrual cycle (13). Also, it was found that tenascin is present in the basement membrane of DCIS and the stroma of invasive cancer. The epithelial-stromal junction of tumors contains large amounts of tenascin, suggesting that tenascin may promote decreased adhesiveness, therefore facilitating detachment and invasion of the stroma by neoplastic cells. More recently, Monteagudo et al. have found that type IV collagenase, a metalloproteinase enzyme which degrades type IV collagen, was present in myoepithelial cells of normal and hyperplastic tissues, and in the myoepithelial cells of DCIS (14). Normal terminal duct and hyperplastic epithelium also contained this enzyme, but not large or medium-sized ducts. The enzyme was found in epithelial cells of DCIS (20 of 23 cases), invasive carcinomas (36 or 40 cases), and in lymph node metastases in 10 of 12 cases. The investigators concluded first that myoepithelial cells were a source of enzymatic activity, resulting in basement membrane remodeling of the normal breast. Their second conclusion was that tumor cells were the source of the enzyme in invasive carcinoma, which could be responsible for invasion and metastasis. Basset et al. have identified a gene that is expressed exclusively in stromal cells surrounding invasive breast carcinomas (15). The product of the gene is stromelysin3 (ST-3), a metalloproteinase enzyme. Gene expression does not occur in the in situ component of invasive breast carcinomas. The conclusion was that this gene was linked somehow to tumor progression. ST-3 was stimulated by several growth factors including platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and most strongly by basic fibroblast growth factor (bFGF). The authors proposed that ST-3, a protease which can break down basement membranes, acts in conjunction with tenascin to decrease attachment during invasion. Gomm et al. have evaluated the distribution of basic fibroblast growth factor and transforming growth factor B (TGF p l ) in breast tissues (16). Basic fibroblast growth factor (bFGF) has been shown to stimulate tumor growth, while TGF pl inhibits some epithelial cell growth. It was found that bFGF was present in the myoepithelial cells of normal breast tissue. In in situ carcinoma, bFGF was found around the enlarged ducts, but in invasive disease it was present only in areas of residual benign elements. TGF p l was localized in the stroma in both
Ductal Carcinoma In Situ
445
Table I Factors Involved in Invasion and Metastasis
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Investigator
Factor
Normal Tissue
DCIS
Invasive Ductal Carcinoma
Barsky et al."
Type IV collagen and laminin
Basement membrane
Basement membrane
Absent
Ferguson et
Tenascin
Basement and subbasement membrane and stroma (small amount)
Basement and subbasement membrane zone around ductules and stroma
Intralobular and interlobular stroma, negative in basement membranes
Monteagudo et a1.I4
Type IV collagenase
Myoepithelial cells around terminal ducts and hyperplasia Negative in medium and large ducts
Discontinuous staining in myoepithelial cells and in epithelial cells (20/23)
Epithelial cells
Basset et al."
Stromelysin-3
Eight-week human embryo interdigital region of limb bud
Negative in stromal cells
Stromal cells
Gomm et al.I6
bFGF
Myoepithelial cells
In myoepithelial cells around DCIS
Negative except in around benign tissues
Periductal and intralobular stroma
benign and malignant breast tissues. The change in secretion or activity of these and other growth factors could lead to tumor progression and invasion. The development of malignant progression, invasion, and metastasis most likely is linked to a cascade of events, with an interaction between various enzymes, growth factors, and genes. This is certainly a very exciting area in breast cancer research today.
HISTOLOGY More attention has been paid in recent times to the histologic subtypes of ductal carcinoma in situ. These include micropapillary, comedo carcinoma, cribriform, solid, and papillary. There also are unusual variants which include intracystic and intraductal mucinous carcinoma (17). About one third of patients will have two or more patterns ( 18). Eusebi et a]. also describe a clinging type which actually is a description of a specific pattern of comedo DCIS (19).
Periductal and intraductal stroma associated with epithelial elements
Periductal and intraductal stroma and epithelial cells
The features of comedo DCIS include a layer of cells surrounding a central area of necrosis (uncommon in micropapillary or cribriform) (17). The cells themselves may be uniform and only slightly larger than normal, or very large with a high nuclear to cytoplasmic ratio. The cytoplasm is usually eosinophilic. The clinging form of comedo DCIS refers to a pattern in which the presence of only a thin layer of neoplastic cells is present and necrosis may only focally denude the lining. Micropapillary DCIS appears as the formation of small, broad papillations which are devoid of a fibrovascular core (17). They may also form looping arches or Roman bridges. The cells usually are a monomorphic population of small cells. A variant of micropapillary DCIS has been described by Rosen and Scott which is called cystic hypersecretory carcinoma (20). Many of the ducts in this variant have dense luminal secretions. The features of papillary DCIS include an epithelium which lines branching, fibrovascular stalks (17). The cells themselves range from small and uniform to large and pleo-
Swain
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focal invasion indicates a risk for metastases and systemic disease rather than a discrete localized lesion. Microinvasion is defined by Fechner and Mills as nests of cells immediately adjacent to ducts with DCIS which do not extend more than 0.1 mm. from the duct (17). Attempts have also been made to categorize DCIS based on microscopic features. The European Organization for the Treatment of Cancer (EORTC) held a consensus meeting on in situ breast cancer in 1988 (21). They suggested that DCIS be divided on the basis of biological variables such as the expression of the protein product of erbB-2. The expression of this protein in DCIS is correlated with large nuclear size, poor nuclear grade, and a high mitotic rate. Those types of DCIS with small monomorphic cells usually are negative for this expression. Therefore, DCIS would be classified as either large polymorphic cells (erbB-2 ) or small monomorphic cells (erbB-2 - ). Meyer has evaluated the cell kinetics of in situ breast carcinoma. He found that the median thymidine labeling index (TLI) for cribriform-papillary DCIS was 1.3%, solid DCIS was 2.45%, and comedo DCIS was 4.4% (22). His data also show that when both noninvasive and invasive cancer were present, the TLI of each was similar. This indicated that the proliferative rates of cells did not change with invasion.
morphic. lntracystic DCIS is usually of the papillary type and involves a dilated, grossly visible duct. Mucinous DCIS is rare and is associated with abundant mucin formation. The features of cribriform DCIS include duct lumina which are partially or completely filled with neoplastic cells (17). The cells are radially oriented around spaces forming true glandular lumina. The salient feature of solid DCIS is ducts filled partially or completely with neoplastic cells in no specific pattern (17). There may be rare areas of microscopic necrosis. The cells are atypical and pleomorphic. Patchefsky et al. have analyzed various aspects of DCIS in 51 women with 55 cancers, either DCIS alone or with microinvasion (18). These patients were all treated with mastectomy, and this was a retrospective review. Ninety percent of micropapillary lesions were clinically detectable at presentation, while 74% of comedo DCIS lesions were detected by mammography alone. Table 2 illustrates the features associated with each histologic subtype. Multicentricity is defined as tumor present in any zone outside the biopsy site. The important findings were that the majority of comedo DCIS lesions were of high nuclear grade and were associated with microinvasion, and the majority of micropapillary lesions were multicentric with a large number of ducts involved. However, conclusions from this study are interesting but limited, since it was not a prospective study. Prospective studies executed in the future will be able to answer the question of whether histologic subtype can predict which patients are more likely to have invasive or multicentric disease and develop recurrence. These .issues have implications for determining local treatment options. DCIS with microinvasion is being more commonly diagnosed. It is frequently difficult to determine whether focal invasion is present. Clinically and prognostically
+
INCIDENCE In 1978, a survey by the American College of Surgeons of patients with histologically proven breast carcinoma revealed a 1.4% incidence of in situ cancers (23). In 1975, the Surveillance, Epidemiology, and End Results (SEER) program which collects cancer statistics in 10% of the population found that, of all breast cancers
Table 2 Histologic Subtypes of DCIS
' Histology Micropapillary Papillary
Comedo carcinoma Solid
+
cribriform Adapted from Ref. 18.
High Nuclear
Mean Duct Involvement
Microinvasion
Grade (%)
(%I
Multicentric
20
198
30
80
7
I12
7
40
89
78
63
37
0
20
0
27
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Ductal Carcinoma In Situ
reported, 5.1% were in situ disease (24). Large-scale screening programs have led to an increase in the number of noninvasive cancers that are diagnosed. Screening studies such as the Health Insurance Plan (HIP) of New York study found in situ cancers in 12% of the cancers diagnosed in the screened group versus 8.4% in the control group (25). The randomized Swedish study found 9.2% of screened cancers to be in situ versus 2.5% of the cancers in the control group (26). The Edinburgh Breast Screening Project revealed in situ cancers in 16% of screened cancers (27), and the Guilford Breast Screening Project had a 10.3% incidence of in situ cancers (28). The Breast Cancer Detection Demonstration Project (BCDDP), a nonrandomized study that screened 280,000 women, detected 4,240 cancers (29). Seventeen percent of these cancers were noninvasive. In situ carcinomas made up 20% of cancers diagnosed in women under 50 years of age, and 16% in women older than 50 years of age. The recent results collected by the SEER group for 1985 reveal an increase in incidence of in situ cancers compared with 1975 (30). There were 1,187 in situ cancers of 12,935 total cancers (9%). This extrapolates to a diagnosis of 11- 12,000 noninvasive cancers a year in the United States. This increase of 4.1% in 10 years is felt to be due to increasing numbers of women undergoing screening mammography, and more sensitive mammographic techniques. While the diagnosis of noninvasive breast carcinoma is being made more often, it is unfortunate that treatment options in this disease are based largely on retrospective studies with the natural history being obscured. The National Surgical Adjuvant Breast and Bowel Project (NSABP) has recently closed a prospective randomized trial (December 1990) which investigated the optimal treatment for ductal carcinoma in situ. The average age range at diagnosis of ductal carcinoma in situ is 51-59 years (31). This is similar to the age range at diagnosis of invasive ductal cancer in the United States, which is 50-60 years of age (32,33). The older literature reports that the majority of cases of ductal carcinoma in situ present with a palpable mass (31). However, it is now much more common for these lesions to be nonpalpable and to be found by routine screening mammography. The Breast Cancer Detection Demonstration Project study reported that 67% of the cases of ductal carcinoma in situ were detected by mammography alone (34). Gump et al. feel that DCIS treatment options should be determined individually, depending on the presence of gross or microscopic disease (35). Also, Andersen et
447
al. have prospectively evaluated 27 cases of ductal carcinoma in situ and divided the disease into three subgroups on which they base treatment (36). The first group consists of microfocal lesions or lesions that are less than 5 mm in size and were accidental findings. The second type is composed of tumor-forming lesions greater than 5 mm in diameter. The last group includes diffuse lesions which require a microscopic diagnosis. Again, these were usually accidental findings. Andersen recommends excision alone for the first two groups, and mastectomy for the latter.
MULTICENTRICITY Multicentricity is defined differently by various pathologists. The general definition given by McDivitt is “the presence of two or more separate foci of carcinoma within the breast which are thought to have arisen independently in response to the same carcinogenic stimulus’’ (37). Multicentricity has been reported to occur in 19-76% of patients with the diagnosis of ductal carcinoma in situ (31). The most carefully reported studies reveal a 33% incidence by Brown et al. (38), 38% by von Reuden and Wilson (39), 36% by Nielsen et a1 (40), 41% by Schwartz et al. (41), 18% by Schuh et al. (also 13% lobular carcinoma in situ) (42), and 40% by Tinnemans et al. (one case was also lobular carcinoma in situ) (43). Nielsen et al. describes multicentric foci of ductal carcinoma in situ in 47% of autopsy cases containing previously undiagnosed ductal carcinoma in situ (bilaterally 33%) (40). Lagios defined multicentricity as a lesion 5 cm distant from the primary tumor (44). Using whole organ sectioning, he found multicentricity in 14% of lesions less than 2.5 cm in diameter, and in 54% of those 2.5 cm or greater. Gump et al. reviewed 70 patients with ductal carcinoma in situ and found disease elsewhere in the breast in 25% of patients presenting with microscopic ductal carcinoma in situ, and 37% of those presenting with gross ductal carcinoma in situ (35). These researchers believe that this is an underestimate, since only random sections were taken from each quadrant. One report disputing the incidence of multicentricity in ductal carcinoma in situ is that of Fisher et al. (45). They found no cases of multicentricity in 27 cases treated by mastectomy with an average size of 2.2 cm. In summary, evidence from meticulously done studies using whole organ sectioning, and from careful review of the literature reveals about a 35% incidence of mul-
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448
ticentricity of ductal carcinoma in situ in all but one report. This chance of multicentricity must be taken into consideration when treatment options are considered.
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RESIDUAL DISEASE AFTER EXCISIONAL BIOPSY Since local excision alone has been suggested as a treatment modality for ductal carcinoma in situ, it is important to evaluate the adequacy of removal of the lesion after biopsy alone. This is done by reviewing cases in which a mastectomy has been performed after biopsy. Rosen described 53 cases of ductal carcinoma in situ in which 57% had residual ductal carcinoma in situ alone at mastectomy (38% had residual disease only in the original biopsy site and the remainder extended to another quadrant) (46). Contesso et al. reported residual disease in 76% of patients (47), Carter and Smith in 66% (48), and Wanebo et al. in 60% (49). Tinnemans studied residual ductal carcinoma in situ in the area of the biopsy site in 60% of 25 patients treated by mastectomy (43). His patients had nonpalpable lesions biopsied by needle localization. Gump reported residual disease after biopsy in 31% of patients presenting with microscopic ductal carcinoma in situ, and 76% of patients presenting with gross ductal carcinoma in situ (35). Fisher found residual ductal carcinoma in situ in 54% of 28 patients at mastectomy (45). Five of these had only had needle biopsies, suggesting that this number would have been lower after an excisional biopsy. These studies all suggest a very high incidence of residual disease after biopsy alone. However, it is not known if attempts were made to obtain negative margins in these patients. Wide local excision may remove most of the residual disease, but may still be inadequate if no further treatment is done. This issue has to be addressed in carefully executed prospective studies.
INCIDENCE OF INVASIVE DISEASE A substantial number of patients originally diagnosed as having ductal carcinoma in situ have been found to have areas of invasion when reviewed by another pathologist. Gillis et al. cut new blocks in 50 cases of ductal carcinoma in situ to look for evidence of invasion (50). Twenty-eight percent of these cases contained areas of invasion. Brown et al. reviewed 52 cases of ductal carcinoma in situ and found that 15% actually had areas of invasion disease (38). These studies stress the importance
of a thorough and extensive review of specimens. The recommendation is that at least 8- 10 slides be cut and examined. The frequency of finding invasive disease at mastectomy in patients with a biopsy diagnosis of ductal carcinoma in situ ranges from 2 to 21% (31). Lagios, using whole organ section of 115 mastectomy specimens, found an incidence of invasive disease of 42% in lesions 4.5 cm or greater in diameter, and 0% in lesions less than 4.5 cm (5132). This excluded four patients who had initial inadequate excisions with tumors 25 mm
SM f RT SM -+ RT or Mastectomy
20
5 ) UK-UKCCCR/BCTCS
DCIS 2 LCIS Screen Detected Negative Margins
SM SM SM SM
-
6) Norway NBCG-4
DCIS > 5 rnm < 30 mm
SM
7) Denmark DBCG 89-1s
DCIS f LCIS Negative Margins
SM 2 RT (register ineligible patients)
8) NSABP B-24
DCIS
SM
SM = Segmental mastectomy or wide excision. RT = Radiation therapy. Tam = Tamoxifen. Source: From Ref. 74.
5 5
cm
f
+ Tam
+ RT
+ RT + Tam
f
RT
+ RT ;f: Tam
-
-
Ductal Carcinoma In Situ
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therapy. The question of whether radiation therapy following excision is necessary or effective in these cases is an important one and cannot be answered at the present time. Patients with tumors with a diffuse intraductal pattern are difficult to excise entirely with negative margins, and these patients are best treated with mastectomy. An axillary nodal dissection is not necessary for prognostic purposes in most patients with ductal carcinoma in situ. However, if larger lesions are present, nodal dissection should be performed since the incidence of microinvasion is higher in larger lesions.
ACKNOWLEDGMENTS My thanks to Ms. Barbara Berman for her superb secretarial support in the preparation of the manuscript.
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54. Rosen P P Lobular carcinoma in situ and intraductal carcinoma of the breast. In The Breast. Edited by RW McDivitt, HA Oberman, L Ozzello. Williams & Wilkins, Baltimore, 1984. 55. Page DL, Dupont WD, Rogers LW et al: Intraductal carcinoma of the breast: Follow-up after biopsy only. Cancer 49:751-758, 1982. 56. Farrow JH: The James Ewing lecture: Current concepts in the detection and treatment of the earliest of the breast cancers. Cancer 25:468-477, 1970. 57. Bedwani R, Vana I , Rosner D et al: Management and survival of female patients with “minimal” breast cancer: As observed in the long-term and short-term surveys of the American College of Surgeons. Cancer 47:2769-2778, 1981. 5 8 . Fisher ER, Leeming R, Anderson S et al: Conservative management of intraductal carcinoma (DCIS) of the breast. J Surg Oncol 471139-147, 1991. 59. Baird RM; Worth A, Hislop G: Recurrence after lumpectomy for comedo-type intraductal carcinoma of the breast. Am J Surg 159:479-481, 1990. 60. Millis RR, Thynne GSJ: In situ intraductal carcinoma of the breast: A long term follow-up study. Br J Surg 62:957-962, 1975. 61. Ashikari R, Hajdu SI, Robbins GF: Intraductal carcinoma of the breast (1960-1969). Cancer 28:1182-1187, 1971. 62. Recht A, Danoff BS, Solin LJ et al: Intraductal carcinoma of the breast: Results of treatment with excisional biopsy and irradiation. J Clin Oncol 3:1339-1343, 1985. 63. Solin LJ, Fowble BL, Schultz DJ et al: Definitive irradiation for intraductal carcinoma of the breast. Int J Radiat Oncol Biol Phys 19:843-850, 1990. 64. Zafrani B, Fourquet A, Vilcoq JR et a!: Conservative management of intraductal breast carcinoma with tumorectomy and radiation therapy. Cancer 57: 1299-1301, 1986. 65. Kurtz JM, Jacquemier J, Torhorst J et al: Conservation therapy for breast cancers other than infiltrating ductal carcinoma. Cancer 63: 1630- 1635, 1989. 66. Fowble B: Intraductal noninvasive breast cancer: A comparison of three local treatments. Oncology 3(6):5 1-66, 1989. 67. Silverstein MH, Waisman JR. Gamagami P et al: Intraductal carcinoma of the breast (208 cases): Clinical factors influencing treatment choice. Cancer 66( 1):102-108, 1990. 68. McCormick B, Rose PP, Kinne D et al: Duct carcinoma in-situ of the breast: Does conservation surgery and radiotherapy provide acceptable local control after conservation surgery and radiotherapy. Int J Radiat Oncol Biol Phys 21:289-292, 1991. 69. Stotter AT, McNeese M, Oswald MJ et al: The role of limited surgery with irradiation in primary treatment of ductal in situ breast cancer. Int J Radiat Oncol Biol Phys 18:283-287, 1990. 70. Haffty BG, Peschel RE, Papadopoulous D et al: Radiation therapy for ductal carcinoma in situ of the brease. Conn Med 54(9):482484, 1990. 71. Ciatto S, Bonardi R, Cataliotti L et al: Intraductal breast carcinoma. Review of a multicenter series of 3.50 cases. Tumori 76:552-554, 1990. 72. Wecksell A, Altkiss MJ, Shahamatpour M: Recurrent intraductal breast carcinoma following radiation therapy: A case report. Breast 8:13-15, 1982. 73. Mayr NA, Staples JJ, Robinson RA, VanMetre JE: lntraductal breast carcinoma: Initial results of a morphometric study using computerized digital image analysis. Clin Oncol 2:66-70, 1990. 74. Fisher B, from protocol NSABP-B 17, personal communication.
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Ductal Carcinoma In Situ Sandra M. Swain, M.D. Comprehensive Breast Center Vincent T. Lombardi Cancer Research Center Georgetown University Medical Center Podium Level-Corridor B 3800 Reservoir Road PI.W. Washington, 0.C. 20007
INTRODUCTION
Wellings and Jensen have provided evidence for the location of most benign and malignant proliferative lesions of the breast (3,4). The method for characterizing these lesions was subgross examination correlated with histopathology . They hypothesize that the terminal ductal lobular unit (TDLU) is the origin of most pathologic breast lesions, including both ductal and lobular carcinoma in situ. Ductal carcinoma in situ was seen as dilatation and unfolding of the lobules with lobular coalescence. The lesions of lobular carcinoma in situ appeared as large, poorly defined ductules. Their studies also showed a markedly increased incidence of atypical and in situ lesions in cancer-associated breasts compared with random breasts at autopsy. Theories of the development of invasive cancer include progression from normal to epithelial hyperplasia to atypical hyperplasia to ductal carcinoma in situ to invasive ductal cancer. Gallagher has done whole organ sectioning of the breast and clearly feels that epithelial hyperplasia is a nonobligate preneoplastic lesion (5). He supports this statement with the evidence from whole organ sectioning in which breasts with an invasive cancer present almost universally contained proliferative ductal
The concept of carcinoma in situ was introduced by Broders in 1932 (1). He described carcinoma in situ as ‘‘a condition in which malignant epithelial cells and their progeny are found in or near positions occupied by their ancestors before the ancestors underwent malignant transformation. At least they have not migrated beyond the juncture of the epithelium and connective tissue or the so-called basement membrane. The normal anatomy of the breast has been studied in detail ( 2 ) . The breast contains 12 to 24 lobes, each supplied by a lactiferous duct. The lactiferous ducts dilate, forming a lactiferous sinus which opens in the nipple. Lactiferous ducts branch in the breast to form intralobar ducts. These branch to form the terminal ductal lobular unit. This unit consists of the extralobular terminal duct and the lobule. The extralobular terminal duct is surrounded by elastic tissue and lined by columnar epithelial cells. The lobule is formed by the intralobular terminal duct and two to six ductules or acini. The intralobular terminal duct is not surrounded by elastic tissue and is lined by cuboidal cells. ”
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Copyright 0 1992 by Marcel Dekker, Inc.
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epithelium. Also, within most breasts, a spectrum of disease was seen including atypical hyperplasia and ductal carcinoma in situ. More recently, investigators have looked at oncogene expression in various lesions of the breast. Expression of the erbB-2 oncogene protein 'product has been found to be present in a majority of comedo DCIS with reports of positivity ranging from 42-100% (6-8). A much lower proportion, or 14-28% of infiltrating ductal carcinomas, express erbB-2 (6,9,10). This suggests that either (i) not all noninvasive comedo DCIS become invasive, (ii) the majority of invasive cancers originate from a different process, or (iii) that the expression of oncogene erbB-2 is an early event and is lost during malignant progression and invasion. It is probable that the epithelial cells of ductal carcinoma in situ have already been affected by multiple genetic and epigenetic events. The susceptible cells then gain a selective growth advantage leading to malignant tumor progression, invasion, and eventually metastasis. Supporting the hypothesis that ductal carcinoma in situ is capable of progressing to invasive cancer is evidence that basement membranes are either altered focally or totally missing in all DCIS lesions when stained with periodic acid-Schiff (PAS) ( 1 1). DCIS by definition has intact basement membranes by light microscopy. Infiltrating tumors lack basement membranes. Ozzello studied DClS by PAS staining and found defective basal laminae in almost all cases ( 1 1). This ranged from variations in thickness to areas of discontinuity of the basement membrane. Ozzello also studied DCIS by electron microscopy ( I I). In many cases of DCIS, gaps were present and cells protruded through the gap into the surrounding stroma, indicating invasiveness. These abnormalities of basement membranes are not observed by light microscopy. Exciting work in the area of invasion and metastases is currently underway (Table I). Clearly defining the role of various growth factors, proteinases, and basement membrane components in invasion will lead to more directed therapeutic options. Barsky et al. found that the basement membrane components, type IV collagen and laminin, were lost in invasive breast tumors but not in DCIS or benign breast lesions ( 12). Also, when studying DCIS with microinvasion by light microscopy, there was disruption of the basement membrane with loss of type IV collagen and laminin in the areas of microinvasion only. Tenascin is an extracellular matrix glycoprotein which is important in tissue development. It reduces cell-to-
Swain
matrix adhesion and promotes cell movement. It has been found to be a part of the development of the normal mammary gland. Ferguson et al. have found that the distribution and quality of tenascin changes during the menstrual cycle (13). Also, it was found that tenascin is present in the basement membrane of DCIS and the stroma of invasive cancer. The epithelial-stromal junction of tumors contains large amounts of tenascin, suggesting that tenascin may promote decreased adhesiveness, therefore facilitating detachment and invasion of the stroma by neoplastic cells. More recently, Monteagudo et al. have found that type IV collagenase, a metalloproteinase enzyme which degrades type IV collagen, was present in myoepithelial cells of normal and hyperplastic tissues, and in the myoepithelial cells of DCIS (14). Normal terminal duct and hyperplastic epithelium also contained this enzyme, but not large or medium-sized ducts. The enzyme was found in epithelial cells of DCIS (20 of 23 cases), invasive carcinomas (36 or 40 cases), and in lymph node metastases in 10 of 12 cases. The investigators concluded first that myoepithelial cells were a source of enzymatic activity, resulting in basement membrane remodeling of the normal breast. Their second conclusion was that tumor cells were the source of the enzyme in invasive carcinoma, which could be responsible for invasion and metastasis. Basset et al. have identified a gene that is expressed exclusively in stromal cells surrounding invasive breast carcinomas (15). The product of the gene is stromelysin3 (ST-3), a metalloproteinase enzyme. Gene expression does not occur in the in situ component of invasive breast carcinomas. The conclusion was that this gene was linked somehow to tumor progression. ST-3 was stimulated by several growth factors including platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and most strongly by basic fibroblast growth factor (bFGF). The authors proposed that ST-3, a protease which can break down basement membranes, acts in conjunction with tenascin to decrease attachment during invasion. Gomm et al. have evaluated the distribution of basic fibroblast growth factor and transforming growth factor B (TGF p l ) in breast tissues (16). Basic fibroblast growth factor (bFGF) has been shown to stimulate tumor growth, while TGF pl inhibits some epithelial cell growth. It was found that bFGF was present in the myoepithelial cells of normal breast tissue. In in situ carcinoma, bFGF was found around the enlarged ducts, but in invasive disease it was present only in areas of residual benign elements. TGF p l was localized in the stroma in both
Ductal Carcinoma In Situ
445
Table I Factors Involved in Invasion and Metastasis
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Investigator
Factor
Normal Tissue
DCIS
Invasive Ductal Carcinoma
Barsky et al."
Type IV collagen and laminin
Basement membrane
Basement membrane
Absent
Ferguson et
Tenascin
Basement and subbasement membrane and stroma (small amount)
Basement and subbasement membrane zone around ductules and stroma
Intralobular and interlobular stroma, negative in basement membranes
Monteagudo et a1.I4
Type IV collagenase
Myoepithelial cells around terminal ducts and hyperplasia Negative in medium and large ducts
Discontinuous staining in myoepithelial cells and in epithelial cells (20/23)
Epithelial cells
Basset et al."
Stromelysin-3
Eight-week human embryo interdigital region of limb bud
Negative in stromal cells
Stromal cells
Gomm et al.I6
bFGF
Myoepithelial cells
In myoepithelial cells around DCIS
Negative except in around benign tissues
Periductal and intralobular stroma
benign and malignant breast tissues. The change in secretion or activity of these and other growth factors could lead to tumor progression and invasion. The development of malignant progression, invasion, and metastasis most likely is linked to a cascade of events, with an interaction between various enzymes, growth factors, and genes. This is certainly a very exciting area in breast cancer research today.
HISTOLOGY More attention has been paid in recent times to the histologic subtypes of ductal carcinoma in situ. These include micropapillary, comedo carcinoma, cribriform, solid, and papillary. There also are unusual variants which include intracystic and intraductal mucinous carcinoma (17). About one third of patients will have two or more patterns ( 18). Eusebi et a]. also describe a clinging type which actually is a description of a specific pattern of comedo DCIS (19).
Periductal and intraductal stroma associated with epithelial elements
Periductal and intraductal stroma and epithelial cells
The features of comedo DCIS include a layer of cells surrounding a central area of necrosis (uncommon in micropapillary or cribriform) (17). The cells themselves may be uniform and only slightly larger than normal, or very large with a high nuclear to cytoplasmic ratio. The cytoplasm is usually eosinophilic. The clinging form of comedo DCIS refers to a pattern in which the presence of only a thin layer of neoplastic cells is present and necrosis may only focally denude the lining. Micropapillary DCIS appears as the formation of small, broad papillations which are devoid of a fibrovascular core (17). They may also form looping arches or Roman bridges. The cells usually are a monomorphic population of small cells. A variant of micropapillary DCIS has been described by Rosen and Scott which is called cystic hypersecretory carcinoma (20). Many of the ducts in this variant have dense luminal secretions. The features of papillary DCIS include an epithelium which lines branching, fibrovascular stalks (17). The cells themselves range from small and uniform to large and pleo-
Swain
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focal invasion indicates a risk for metastases and systemic disease rather than a discrete localized lesion. Microinvasion is defined by Fechner and Mills as nests of cells immediately adjacent to ducts with DCIS which do not extend more than 0.1 mm. from the duct (17). Attempts have also been made to categorize DCIS based on microscopic features. The European Organization for the Treatment of Cancer (EORTC) held a consensus meeting on in situ breast cancer in 1988 (21). They suggested that DCIS be divided on the basis of biological variables such as the expression of the protein product of erbB-2. The expression of this protein in DCIS is correlated with large nuclear size, poor nuclear grade, and a high mitotic rate. Those types of DCIS with small monomorphic cells usually are negative for this expression. Therefore, DCIS would be classified as either large polymorphic cells (erbB-2 ) or small monomorphic cells (erbB-2 - ). Meyer has evaluated the cell kinetics of in situ breast carcinoma. He found that the median thymidine labeling index (TLI) for cribriform-papillary DCIS was 1.3%, solid DCIS was 2.45%, and comedo DCIS was 4.4% (22). His data also show that when both noninvasive and invasive cancer were present, the TLI of each was similar. This indicated that the proliferative rates of cells did not change with invasion.
morphic. lntracystic DCIS is usually of the papillary type and involves a dilated, grossly visible duct. Mucinous DCIS is rare and is associated with abundant mucin formation. The features of cribriform DCIS include duct lumina which are partially or completely filled with neoplastic cells (17). The cells are radially oriented around spaces forming true glandular lumina. The salient feature of solid DCIS is ducts filled partially or completely with neoplastic cells in no specific pattern (17). There may be rare areas of microscopic necrosis. The cells are atypical and pleomorphic. Patchefsky et al. have analyzed various aspects of DCIS in 51 women with 55 cancers, either DCIS alone or with microinvasion (18). These patients were all treated with mastectomy, and this was a retrospective review. Ninety percent of micropapillary lesions were clinically detectable at presentation, while 74% of comedo DCIS lesions were detected by mammography alone. Table 2 illustrates the features associated with each histologic subtype. Multicentricity is defined as tumor present in any zone outside the biopsy site. The important findings were that the majority of comedo DCIS lesions were of high nuclear grade and were associated with microinvasion, and the majority of micropapillary lesions were multicentric with a large number of ducts involved. However, conclusions from this study are interesting but limited, since it was not a prospective study. Prospective studies executed in the future will be able to answer the question of whether histologic subtype can predict which patients are more likely to have invasive or multicentric disease and develop recurrence. These .issues have implications for determining local treatment options. DCIS with microinvasion is being more commonly diagnosed. It is frequently difficult to determine whether focal invasion is present. Clinically and prognostically
+
INCIDENCE In 1978, a survey by the American College of Surgeons of patients with histologically proven breast carcinoma revealed a 1.4% incidence of in situ cancers (23). In 1975, the Surveillance, Epidemiology, and End Results (SEER) program which collects cancer statistics in 10% of the population found that, of all breast cancers
Table 2 Histologic Subtypes of DCIS
' Histology Micropapillary Papillary
Comedo carcinoma Solid
+
cribriform Adapted from Ref. 18.
High Nuclear
Mean Duct Involvement
Microinvasion
Grade (%)
(%I
Multicentric
20
198
30
80
7
I12
7
40
89
78
63
37
0
20
0
27
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Ductal Carcinoma In Situ
reported, 5.1% were in situ disease (24). Large-scale screening programs have led to an increase in the number of noninvasive cancers that are diagnosed. Screening studies such as the Health Insurance Plan (HIP) of New York study found in situ cancers in 12% of the cancers diagnosed in the screened group versus 8.4% in the control group (25). The randomized Swedish study found 9.2% of screened cancers to be in situ versus 2.5% of the cancers in the control group (26). The Edinburgh Breast Screening Project revealed in situ cancers in 16% of screened cancers (27), and the Guilford Breast Screening Project had a 10.3% incidence of in situ cancers (28). The Breast Cancer Detection Demonstration Project (BCDDP), a nonrandomized study that screened 280,000 women, detected 4,240 cancers (29). Seventeen percent of these cancers were noninvasive. In situ carcinomas made up 20% of cancers diagnosed in women under 50 years of age, and 16% in women older than 50 years of age. The recent results collected by the SEER group for 1985 reveal an increase in incidence of in situ cancers compared with 1975 (30). There were 1,187 in situ cancers of 12,935 total cancers (9%). This extrapolates to a diagnosis of 11- 12,000 noninvasive cancers a year in the United States. This increase of 4.1% in 10 years is felt to be due to increasing numbers of women undergoing screening mammography, and more sensitive mammographic techniques. While the diagnosis of noninvasive breast carcinoma is being made more often, it is unfortunate that treatment options in this disease are based largely on retrospective studies with the natural history being obscured. The National Surgical Adjuvant Breast and Bowel Project (NSABP) has recently closed a prospective randomized trial (December 1990) which investigated the optimal treatment for ductal carcinoma in situ. The average age range at diagnosis of ductal carcinoma in situ is 51-59 years (31). This is similar to the age range at diagnosis of invasive ductal cancer in the United States, which is 50-60 years of age (32,33). The older literature reports that the majority of cases of ductal carcinoma in situ present with a palpable mass (31). However, it is now much more common for these lesions to be nonpalpable and to be found by routine screening mammography. The Breast Cancer Detection Demonstration Project study reported that 67% of the cases of ductal carcinoma in situ were detected by mammography alone (34). Gump et al. feel that DCIS treatment options should be determined individually, depending on the presence of gross or microscopic disease (35). Also, Andersen et
447
al. have prospectively evaluated 27 cases of ductal carcinoma in situ and divided the disease into three subgroups on which they base treatment (36). The first group consists of microfocal lesions or lesions that are less than 5 mm in size and were accidental findings. The second type is composed of tumor-forming lesions greater than 5 mm in diameter. The last group includes diffuse lesions which require a microscopic diagnosis. Again, these were usually accidental findings. Andersen recommends excision alone for the first two groups, and mastectomy for the latter.
MULTICENTRICITY Multicentricity is defined differently by various pathologists. The general definition given by McDivitt is “the presence of two or more separate foci of carcinoma within the breast which are thought to have arisen independently in response to the same carcinogenic stimulus’’ (37). Multicentricity has been reported to occur in 19-76% of patients with the diagnosis of ductal carcinoma in situ (31). The most carefully reported studies reveal a 33% incidence by Brown et al. (38), 38% by von Reuden and Wilson (39), 36% by Nielsen et a1 (40), 41% by Schwartz et al. (41), 18% by Schuh et al. (also 13% lobular carcinoma in situ) (42), and 40% by Tinnemans et al. (one case was also lobular carcinoma in situ) (43). Nielsen et al. describes multicentric foci of ductal carcinoma in situ in 47% of autopsy cases containing previously undiagnosed ductal carcinoma in situ (bilaterally 33%) (40). Lagios defined multicentricity as a lesion 5 cm distant from the primary tumor (44). Using whole organ sectioning, he found multicentricity in 14% of lesions less than 2.5 cm in diameter, and in 54% of those 2.5 cm or greater. Gump et al. reviewed 70 patients with ductal carcinoma in situ and found disease elsewhere in the breast in 25% of patients presenting with microscopic ductal carcinoma in situ, and 37% of those presenting with gross ductal carcinoma in situ (35). These researchers believe that this is an underestimate, since only random sections were taken from each quadrant. One report disputing the incidence of multicentricity in ductal carcinoma in situ is that of Fisher et al. (45). They found no cases of multicentricity in 27 cases treated by mastectomy with an average size of 2.2 cm. In summary, evidence from meticulously done studies using whole organ sectioning, and from careful review of the literature reveals about a 35% incidence of mul-
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ticentricity of ductal carcinoma in situ in all but one report. This chance of multicentricity must be taken into consideration when treatment options are considered.
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RESIDUAL DISEASE AFTER EXCISIONAL BIOPSY Since local excision alone has been suggested as a treatment modality for ductal carcinoma in situ, it is important to evaluate the adequacy of removal of the lesion after biopsy alone. This is done by reviewing cases in which a mastectomy has been performed after biopsy. Rosen described 53 cases of ductal carcinoma in situ in which 57% had residual ductal carcinoma in situ alone at mastectomy (38% had residual disease only in the original biopsy site and the remainder extended to another quadrant) (46). Contesso et al. reported residual disease in 76% of patients (47), Carter and Smith in 66% (48), and Wanebo et al. in 60% (49). Tinnemans studied residual ductal carcinoma in situ in the area of the biopsy site in 60% of 25 patients treated by mastectomy (43). His patients had nonpalpable lesions biopsied by needle localization. Gump reported residual disease after biopsy in 31% of patients presenting with microscopic ductal carcinoma in situ, and 76% of patients presenting with gross ductal carcinoma in situ (35). Fisher found residual ductal carcinoma in situ in 54% of 28 patients at mastectomy (45). Five of these had only had needle biopsies, suggesting that this number would have been lower after an excisional biopsy. These studies all suggest a very high incidence of residual disease after biopsy alone. However, it is not known if attempts were made to obtain negative margins in these patients. Wide local excision may remove most of the residual disease, but may still be inadequate if no further treatment is done. This issue has to be addressed in carefully executed prospective studies.
INCIDENCE OF INVASIVE DISEASE A substantial number of patients originally diagnosed as having ductal carcinoma in situ have been found to have areas of invasion when reviewed by another pathologist. Gillis et al. cut new blocks in 50 cases of ductal carcinoma in situ to look for evidence of invasion (50). Twenty-eight percent of these cases contained areas of invasion. Brown et al. reviewed 52 cases of ductal carcinoma in situ and found that 15% actually had areas of invasion disease (38). These studies stress the importance
of a thorough and extensive review of specimens. The recommendation is that at least 8- 10 slides be cut and examined. The frequency of finding invasive disease at mastectomy in patients with a biopsy diagnosis of ductal carcinoma in situ ranges from 2 to 21% (31). Lagios, using whole organ section of 115 mastectomy specimens, found an incidence of invasive disease of 42% in lesions 4.5 cm or greater in diameter, and 0% in lesions less than 4.5 cm (5132). This excluded four patients who had initial inadequate excisions with tumors 25 mm
SM f RT SM -+ RT or Mastectomy
20
5 ) UK-UKCCCR/BCTCS
DCIS 2 LCIS Screen Detected Negative Margins
SM SM SM SM
-
6) Norway NBCG-4
DCIS > 5 rnm < 30 mm
SM
7) Denmark DBCG 89-1s
DCIS f LCIS Negative Margins
SM 2 RT (register ineligible patients)
8) NSABP B-24
DCIS
SM
SM = Segmental mastectomy or wide excision. RT = Radiation therapy. Tam = Tamoxifen. Source: From Ref. 74.
5 5
cm
f
+ Tam
+ RT
+ RT + Tam
f
RT
+ RT ;f: Tam
-
-
Ductal Carcinoma In Situ
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therapy. The question of whether radiation therapy following excision is necessary or effective in these cases is an important one and cannot be answered at the present time. Patients with tumors with a diffuse intraductal pattern are difficult to excise entirely with negative margins, and these patients are best treated with mastectomy. An axillary nodal dissection is not necessary for prognostic purposes in most patients with ductal carcinoma in situ. However, if larger lesions are present, nodal dissection should be performed since the incidence of microinvasion is higher in larger lesions.
ACKNOWLEDGMENTS My thanks to Ms. Barbara Berman for her superb secretarial support in the preparation of the manuscript.
REFERENCES I. 2.
3.
4.
5.
6. 7.
8.
9.
10.
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