lntraductal Carcinoma of the Breast:

Follow-up After Biopsy Only

DAVID L. PAGE, MD,' WILLIAM D. DUPONT, PHD,t LOWELL W. ROGERS, MD,' AND MARIE LANDENBERGER, RN'

Twenty-eight women with ductal carcinoma in situ (DCIS) of the breast treated by biopsy only were identified in a histologic review of 11,760 biopsies performed between 1950 and 1968. Seven of the 25 women followed for more than three years developed invasive breast carcinoma, all in the same breast with a previously detected DCIS. Average follow-up interval for the 18 women not developing invasive carcinoma was 16 years. The invasive carcinomas presented clinically from three to ten years (average, 6.1) after the biopsies demonstrating DCIS. Four women with invasive carcinoma developed distant metastases following mastectomy. This study suggests that 28% of women treated with biopsy only for DCIS presenting as an incidental histologic finding will develop invasive carcinoma in a follow-up period of approximately 15 years.

Cancer 49:751-758, 1982.

NOWLEDGE OF THE natural history of mammary K carcinoma in situ (CIS) is the basis of prognos- tication and therapeutic recommendation. The diag- nosis cannot be established without first removing a portion of breast for microscopic examination. Accept- ing that this procedure will alter the natural history by removing some or all of the cancer, the nearest we can come to predicting clinical outcome of patients with CIS is to follow women after biopsy. This will not reveal the unaltered natural history of these lesions, but will serve to answer the practical question of what will hap- pen if further therapy is not performed following iden- tification of CIS at biopsy.

The present study was undertaken in order to deter- mine the natural history of intraductal carcinoma of the breast (DCIS) following treatment by biopsy only. There are few reports in the literature concerning ductal carcinoma in situ treated by biopsy only, and most of these contain small numbers of cases in series primarily devoted to patients treated by mastectomy. The study of Betsill et al.,' updated recenty by Rosen et a1.,2 is

From the Departments of Pathology* and Preventive Medicine,?

Supported by NCI Contract no. N01-CB-74098. Address for reprints: David L. Page, MD, Department of Pathology,

Vanderbili University, Nashville, T N 37232. The authors thank Marcia Freudenthal, Luana Settle, Julia Hudg-

ins, Kay Covington, and Annelle Johnson for skilled and dedicated attention to obtaining follow-up information and sixty Nashville sur- geons and their office staffs for their cooperation and aid in clinical follow-up. The Medical Records Departments of Baptist, St. Thomas, and Vanderbilt Hospitals provided vital support.

Accepted for publication January 1, 1981.

Vanderbilt University Medical School, Nashville, Tennessee.

the only one presenting a series of patients similar to those reported here.

Materials and Methods

The surgical pathology diagnoses at Vanderbilt and Baptist Hospitals in Nashville, Tennessee were reviewed from 1952 to 1968, inclusive. All breast biopsies with diagnoses other than malignancy, fibroadenoma, or ab- scess were reviewed histologically for the presence of epithelial proliferative disease. There were 3,607 biop- sies reviewed at Baptist Hospital (after exclusion of 3 1 cases in which slides were missing from the file), and 2,449 biopsies reviewed from Vanderbilt Hospital (after exclusion of 29 cases in which slides and blocks were missing). Similarly, all breast biopsies performed at the St. Thomas Hospital during the years 1950 through 1968 were histologically reviewed, producing an addi- tional 5,704 biopsies containing breast tissue. A total of 21 cases were missing from the files at this hospital. Review of microscopic notes and the diagnoses of cases missing from the file contained no indication that the missing cases were a selected or biased group containing a greater number of atypical epithelial lesions than the cases reviewed.

Initial histologic review of all available slides was carried out by one of the authors (DLP). At this time, diagnoses of CIS or atypical hyperplasia were recorded, and slides of these cases were submitted to the second pathologist (LWR), who reviewed the slides and as- signed diagnoses to individual cases without knowledge of the diagnoses recorded previously. Differences of

0008-543X/82/02 15/0751 $0.90 0 American Cancer Society

7 5 1

1 5 2 CANCER February 15 1982 Vol. 49

FIG. 1. Ductal carcinoma in siru with typical cribriform pattern. In- traglandular lumina have smooth bor- ders and nuclei are small, dark, and of relatively uniform ovoid shape (H & E X 400).

opinion were then resolved by a simultaneous review of the slides. There was initial disagreement in four of the 28 biopsies which were finally assigned to the category of ductal carcinoma in situ.

We also reviewed slides from cases diagnosed as Pa- get’s disease and carcinoma in situ during the same periods from each hospital. Fifty-two cases of ductal carcinoma in situ, with or without Paget’s disease, were

FIG. 2. Delicate arcades of cells with slightly eosinophilic cytoplasm and ovoid nuclei are present without visible fibrovascular support. Luminal bor- ders are smooth and the elongated pa- pillations suggest an intermediate form between micropapillary and the cri- briform pattern of intraductal carci- noma ( H & E X 400).

No. 4 INTRADUCTAL CARCINOMA OF THE BREAST . Page et al. 753

FIG. 3. Extensive in situ micropapillary carcinoma. Note the thin elongated fronds with somewhat bulbous tips comprised of small dark nuclei with scant cytoplasm. I t is likely that some of the islands of cells apparently floating in the lumen are, in fact, attached to elongated fronds not in the plane of section. Although the pattern is predominantly micropapillary, a cribriform arcade is developing to the right emphasizing that the patterns of in situ carcinoma may be somewhat heterogeneous (H & E X 160).

treated by mastectomy during the period reviewed. These were included in the 2,404 breast carcinomas diagnosed and treated in the same time.

Follow-up information was obtained by contacting patients o r relatives using information available in the hospital records and surgeons’ office records.

Anatomic Findings

Review of the histologic slides identified 28 cases of ductal carcinoma in situ (DCIS) which were treated by biopsy only. The number of histologic slides available for review in these cases of DCIS ranged from 1-4 for each individual biopsy, averaging 2 slides for each woman. A n average of 4.5 cm2 of tissue was available for review in each case.

The observed carcinomas in the study population displayed the breadth of histologic change currently accepted as ductal carcinoma in situ (Figs. 1-5). Typ- ical cribriform patterns, micropapillary carcinomas, and intermediate forms were all noted.3 Presence of cellular necrosis was never a prominent feature of any of these lesions, but was seen in some cases (Fig. 5) . Therefore, none of these lesions would have qualified for the designation of comedo carcinoma which is char-

acterized by marked atypia of nuclear cytology and extensive cellular necro~is .~

Consistency of diagnosis through this review was fos- tered by following a few simple rules. We required that at least two spaces be completely involved by a char- acteristic population of cells without the presence of a second cell type anywhere in these spaces. Twenty-six cases had involvement of more than two spaces, leaving only two cases included in the study group because of meeting the minimal criterion of involvement of two spaces by characteristic cells and cellular patterns. Al- though this criterion is arbitrary, it was found helpful in allowing initial agreement in diagnoses between the two reviewing pathologists. The bulbous projections characteristic of micropapillary carcinoma had to be present throughout or intermixed with the cribriform pattern consisting of “punched out” neatly rounded spaces between the neoplastic cells. The nuclei needed to be evenly placed, monotonously similar to each other, hyperchromatic, and rounded or oblong, the only ex- ception being if there was extreme nuclear atypia seen in comedo carcinoma present throughout the entire cell population. Only two cases met our diagnostic criteria for ductal carcinoma in situ on these grounds.

Two of the cases had lobular carcinoma in situ

754 CANCER February 15 1982 Vol. 49

present in addition to DCIS. These cases were in- cluded in this study group following the reasoning of Betsill et al.’

Clinical Features

The 28 women with DCIS were treated with biopsy only. One woman was black, the remainder were white. They ranged in age from 33 to 80 (average, 52 years at time of biopsy) (see Table 1). Areas of irregularity or lumpiness in the breast were detected by the patients themselves in the majority of cases (22); four were de- tected by a physician, and two unknown. The interval between detection and biopsy was between one to 12 weeks for 22 women (average, three weeks). The five remaining women had detected abnormalities from one to ten years prior to biopsy, averaging a five-year in- terval before biopsy. Three of these five women were in the group who subsequently developed invasive car- cinoma. A history of breast carcinoma in a sister and/ or mother was revealed in six of the 28 women, but was unknown for six of the patients. Only one of the women subsequently developing invasive carcinoma had a pos- itive family history, with the other six family histories known to be negative for breast cancer.

The average volume of breast tissue removed at time of biopsy was 22 ccm in 25 women (range, 1-50 cm). Three women, all in the group who did not develop invasive carcinoma, had an average biopsy volume of 190 ccm. Grossly evident cysts in 14 of the biopsy spec- imens, ranging from 1-6 cm in size, averaged 2 cm in

FIG. 4. Micropapillary carci- noma in situ. Papillary projections from the dilated glandular space exhibit bridging pattern with other papillations. As is typical with mi- cropapillary carcinoma, the nuclei are large, and in this case exhibit prominent nucleoli. A more solid pattern of growth with superim- posed papillations is noted on the left of the illustration ( H & E X 400).

dimension. Smaller cysts of 1-5 mm in greatest di- mension were evident histologically in four other biop- sies. The reason for the presence of a palpable irregu- larity in the breast was not evident in the remaining cases, and may have been due to local variation in the amount of fibrous tissue. In none of the cases could the local textural or palpable abnormality be ascribed to the epithelial changes diagnosed as carcinoma in situ. Presence of a mass lesion with the form of a papilloma was seen in only two cases. Each of these was less than 1 cm, and although there was significant atypia within the epithelium covering fibrovascular papillary stalks, there was also diagnostic ductal carcinoma in situ in breast adjacent to these lesions.

Results

Twenty-eight patients were determined to have DCIS on histologic review of biopsies originally diagnosed as benign (0.24% of the biopsies reviewed). Follow-up in- formation was obtained on all 28 patients (Fig. 6 ) , seven of whom subsequently developed invasive breast cancer. The incidence of invasive carcinoma is eleven times that expected from the age-matched experience of The Third National Cancer Survey for White Women in Atlanta, Georgia3 P < 0.00005). Three of these 28 women were followed for less than three years. Two died of unrelated cause within two years, and the third had bilateral mastectomy revealing extensive epithelial proliferative disease without carcinoma. The remaining 18 women who did not develop subsequent carcinoma were fol-

No. 4 INTRADUCTAL CARCINOMA OF THE BREAST - Page et al. 7 5 5

FIG. 5. ,Cystic space lined by short papillations with small in- traglandular lumina. The nuclei are usually large and have more prominent nucleoli than is ordi- narily seen in intraductal carci- noma. Cytoplasm is somewhat acidophilic. Nuclear variation and atypia approaches that seen in co- medo carcinoma. Debris of cellular necrosis is present ( H & E X 400).

lowed from 8-27 years (average, 16.25 years). Fourteen were alive and well when contacted; four died of un- related diseases. The seven women who developed sub- sequent invasive carcinoma within 3- 10 years after ini- tial biopsy (average, 6.1) were all treated by mastectomy (Table 1 ) . The histologic pattern of the invasive car- cinoma in six women was that of solid islands and oc- casional poorly formed glandular formations charac- teristic of infiltrating ductal carcinoma. The sixth patient had a mucinous carcinoma and died of lym- phoma 15 years after mastectomy. Four of the seven developed distant metastases; three of these died of breast carcinoma. Another women had a mastectomy scar recurrence of carcinoma one year after mastec- tomy, and died one year later of cardiovascular disease without further evidence of breast cancer.

All seven invasive carcinomas developed in the same breast bhich had demonstrated DCIS on biopsy (Table 1 ). Five were in the same quadrant, one presented with a massive lesion thought probably to arise in the same quadrant, and the sixth patient presented with carci- noma in an adjacent quadrant. All original biopsies were from the upper, outer quadrants.

Discussion

The 28 cases of DCIS reported here represent 2.4 per 1,000 of the benign breast biopsies reviewed. They are

all examples of incidental histologic findings which did not produce grossly identifiable lesions. Of the patients followed over three years (seven of 25) , 28% developed invasive carcinoma in the same breast as the biopsy showing in siru disease. Only a single previously pub- lished study has been conducted similarly to our own: Betsill er a/.' reviewed 8,609 breast biopsies originally interpreted as benign, and identified 25 women with

FIG. 6 . Age at biopsy and subsequent invasive cancer development in the 28 women.

756 CANCER February 1.5 1982 Vol. 49

TABLE I . Patients with Subsequent Invasive Carcinoma

Age at Location of Location of infiltrating Interval to Size of Status of axillary lymph biopsy biopsy cancer invasive cancer cancer nodes Survival

33 Left UOQ* Massive in left

38 Right UOQ Right UOQ

44 Left UOQ Left UOQ in old incision

53 Right UOQ Right UOQ

60 Right UOQ Right LOQt

63 Left UOQ Left UOQ in same incision

74 Right UOQ Right UOQ

3 years

7 years

10 years

4 years

3 years

6 years

10 years

* UOQ = Upper outer quadrant.

DCIS treated by biopsy only. Follow-up information was available for only ten of these women, but six of these had developed invasive mammary carcinoma. They concluded that their series in combination with other studies supported a 39% subsequent incidence of clinically evident carcinoma. Some of the cited series included cases of more extensive disease than those pre- sented in their own series. For example, the study of Lewis and Geschickter,’ included only cases diagnosed as comedo carcinoma. Most of these lesions produced palpable masses and microinvasion may well have been present, inasmuch as the histologic definition of their series states “invasion of fat or fibrous tissue is incon- spicuous or absent.” Moreover, six of eight women de- veloped subsequent carcinoma within four years. Two series cited by Betsill et a/.’ primarily reported papillary lesions presenting as mass lesions in the breast. It is debatable whether these lesions, despite similar histo- logic patterns, are comparable to the less conspicuous intraductal lesions of the type presented in our study and the study by Betsill et a1.l However, Betsill et al.’ analyzed their own study by including all patients in the denominator including those not followed up; this gave them an incidence of subsequent carcinomas of 2870, including in the numerator one patient who was treated by mastectomy 12 years later when another biopsy showed DCIS. This percentage is reduced to 24% if only the subsequent invasive carcinomas are included. The interval to subsequent carcinoma averaged 9.7 years.

Massive Carcinoma Dead of disease two years after mastectomy

metastasis six years after mastectomy

3 cm Positive Dead of disease three years after mastectomy

Unknown Carcinoma Dead of disease one year after mastectomy

2 cm Negative Died of lymphoma 15 years after mastectomy

2 cm Carcinoma Dead of cerebrovascular accident 20 years after mastectomy

Simple mastectomy only Dead of heart disease two years after mastectomy with recurrence in the operative mastectomy scar one year after mastectomy

2.5 cm Negative Living with bone marrow

2.5 cm

~ ~~ ~

t LOQ = Lower outer quadrant.

One further series is valuable in attempting to resolve the question of magnitude of risk for subsequent car- cinoma in women with DCIS discovered at biopsy. The series presented by Farrow6 reviewed cases of DCIS as routinely reported from the Pathology Service of the Memorial Hospital in New York. The histologic criteria for diagnosis are probably similar to those employed by Betsill et a1.I and ourselves. The later invasive lesions were described as being “within or nearby the previous local excisional site,” with carcinoma developing within an interval of 1-8 years. Of the 25 patients, 20% de- veloped invasive carcinoma in the follow-up period, al- though the total number of patients for which follow- up had been successful is not reported.

Consistency of histologic diagnosis in our own series, as well as that of Betsill et a/.,’ was assured in that all cases were reviewed by the same pathologists at the same time. We believe that our cases are comparable. The similarity of incidence of DCIS in these compar- ably conducted studies supports this conclusion (2.4 per 1,000 biopsies in our study; 2.9 per 1,000 in the Betsill et a1.l study). Apparently most of the cases in the latter study had the histologic pattern of ductal carcinoma in situ confined to ducts and lobules without the for- mation of a papillary mass. Only two of our cases were associated with the formation of a papillary mass lesion (originally diagnosed as papilloma), and neither of these cases went on to develop invasive carcinoma. Each of these two cases also exhibited involvement of ducts and lobules outside the mass lesion. Two patients in the

No. 4 INTRADUCTAL CARCINOMA OF THE BREAST - Page et U l . 757

series of Betsill et a.' as well as two patients in our own series also had lobular carcinoma in situ in other areas of the sarne biopsy.

The subsequently developing invasive carcinoma is probably the result of evolution of a focus of residual intraductal carcinoma into invasive cancer. Careful his- topathologic studies of mastectomy specimens per- formed soon after the diagnosis of ductal carcinoma in situ at biopsy support this conclusion. When mastec- tomy is done within six months after the identification of ductal carcinoma in situ by biopsy, the incidence of invasive carcinoma in the mastectomy specimen has been reported at 6% in one series7 and 18% in another.n Thus, while some of the cases subsequently developing clinically invasive carcinomas may be the result of in- vasive carcinoma present and undetected at the time of original biopsy, at least one-half of the subsequently developing invasive carcinomas can best be ascribed to evolution from residual noninvasive carcinoma left after biopsy. Rosen et ~ 1 . ~ demonstrated residual noninvasive carcinoma in 60% of their mastectomy specimens per- formed soon after the biopsy had revealed ductal car- cinoma in situ, with only 33% of these presenting dis- ease outside the original quadrant demonstrating DCIS. Carter and Smith* demonstrated that 66% of subse- quent mastectomy specimens had ductal carcinoma in silu. Thus, if the true risk of subsequent invasive car- cinoma development is in the range of 30%, and 60% of the breasts have residual ductal carcinoma in situ after biopsy, our best estimate as to the percentage of DCIS lesions evolving into invasive carcinoma is ap- proximately 50%. Schwartz et ~ 1 . ~ found five of 1 1 cases with DCIS had DCIS (four cases) or noninvasive lob- ular carcinoma (one case) outside the quadrant origi- nally shown to contain DCIS. This finding is consistent with those cited above.

As emphasized by Betsill et al.,' we believe it is im- portant for physicians treating breast disease to keep firmly in mind that carcinoma in situ of the breast is not one disease process. The different histologic patterns of disease diagnosed as ductal carcinoma in siru differ in several significant respects from those called lobular carcinoma in silu. Although the level of risk of sub- sequent invasive carcinoma may be similar in these two diseases, the subsequently developing invasive carci- nomas with lobular carcinoma in situ are almost equally distributed between each breast."." Lobular carcinoma in situ is characterized by a much greater degree of multifocality and bilaterality than ductal carcinoma in situ. I n our own series, there were no cases of women developing carcinoma in the contralateral breast.

None of the women in the current series had mam- mography. It is unknown how many of the lesions re- ported here would have been detectable by mammog-

raphy; considering the subtlety of the histologic pattern and lack of evident calcifications at least within the lesion itself, it is probable that many of the lesions re- ported here would not have been detectable by mam- mogr a ph y .

Although the apparent multicentric nature of histo- logic mammary carcinoma in situ has been noted by many s t u d i e ~ ~ ~ ~ ~ ~ ~ l ~ ~ ' ~ and has been used as support for total mastectomy as the best therapeutic measure for most patients, we feel it is important for empiricism rather than a priori reasoning to prevail. We therefore feel it important to use available information on patients with specific therapeutic interventions for DCIS, to more fully understand its clinical significance. Specif- ically, what is the experience of women treated by wide local excision as opposed to biopsy only? It is clear that the risk of subsequent invasive carcinoma development after DCIS treated only by biopsy is medically signif- icant, and is probably in the range of 25%, with most cases occurring within a ten-year period after biopsy. Furthermore, this study, as well as that of Betsill et al.,' has demonstrated that clinically significant ( i n - vasive) carcinoma is overwhelmingly likely to occur in the region of the original biopsy than in some other quadrant. The next relevant question is, what is the risk of subsequent invasive carcinoma after a planned wide or segmental excision of the area harboring ductal car- cinoma in situ? Millis and ThynneI4 presented a series of patients diagnosed as having in situ intraduct car- cinoma at the Royal Marsden Hospital in London dur- ing the period from 1948 to 1968. Eight patients were treated by wide local excision. This study demonstrated no difference in survival between patients treated by wide local excision and those treated by mastectomy. Two patients were alive and well after over 15 years, one at 10-14 years, and four at 5-9 years (one of these patients had mastectomy after recurrence within the breast seven years following initial biopsy). No patient had developed a metastasis, including a ninth patient who was well more than 15 years after a local recur- rence at six months was treated by radical mastectomy. A national survey by the American College of Surgeons showed no difference in 5-year cure or recurrence rates in patients with DCIS whether treated by total mas- tectomy or wedge exc i~ ion . '~ The appearance of sub- sequent invasive carcinoma in proximity to the area with DCIS, as well as the apparent good prognosis at- tending wide local excision of DCIS, would seem to support the performance of wide local excision in se- lected cases in which conservation of the breast is strongly desired. These patients will require close clin- ical follow-up. Further studies of planned wide local or segmental excision are indicated in patients with a strong desire for breast conservation. Careful docu-

758 CANCER February 15 1982 Vol. 49

mentation of the extent of disease will be essential in order to determine prognostic indicators of subsequent morbidity.

REFERENCES

I . Betsill W L Jr. Rosen PP, Lieberman PH, Robbins GF. Intra- ductal carcinoma. Long-term follow-up after treatment by biopsy alone. J A M A 1978; 239: 1863- 1867.

2. Rosen PP, Braun DW Jr , Kinne DE. The clinical significance of preinvasive breast carcinomas. Cancer 1980; 46:9 19-925.

3. McDivitt RW, Stewart FW, Berg JW. Tumors of the breast. In: Atlas of tumor pathology, 2nd series, pt. 2. Armed Forces Institute of Pathology, 1968; 29-49.

4. The third national cancer survey--advanced three year report: 1969-1971 incidence. Bethesda, Md: Natl Inst Health, 1974. U. S. DHEW Publication no. ( N I H ) 74-646.

5. Lewis D. Geschickter CF. Comedo carcinomas of the breast. Arch Surg 1938; 36:225-244.

6. Farrow JH. Current concepts in the detection and treatment of the earliest of the early breast cancers. Cancer 1970; a25:468-477.

7. Rosen PP, Senie R, Schottenfeld D, Ashikari R. Noninvasive breast carcinoma. Frequency of unsuspected invasion and implications for treatment. Ann Surg 1979; 189:377-382.

8. Carter D, Smith RRL. Carcinoma in situ of the breast. Cancer

9. Schwartz GF, Patchesfsky AS, Feig SA, Shaber GS, Schwartz AB. Multicentricity of nonpalpable breast cancer. Cancer 1980

10. Haagensen CD, Lane N, Lattes R. Bodian C. Lobular neoplasia (so-called lobular carcinoma in situ) of the breast. Cancer 1978; 421737-769.

I I . Rosen PP, Lieberman PH, Braun DW Jr, Kosloff C. Adair F. Lobular carcinoma in situ of the breast: Detailed analysis of 99 pa- tients with average follow-up of 24 years. Amer J S u r g Parhol 1978;

12. Fisher ER, Gregoria R, Redmond C, Vellios F. Sommers SC, Fisher B. Pathologic findings from the National Surgical Adjuvant Breast Project (Protocol no. 4): I. Observations concerning the mul- ticentricity of mammary cancer. Cancer 1975; 35247-253.

13. Gallager HS, Martin JE. The study of mammary carcinoma by mammography and whole organ sectioning. Cancer 1969; 23:855- 873.

14. Millis RR. Thynne GSJ. I n situ intraduct carcinoma of the breast: a long term follow-up study. Er J Surg 1975; 62:957-962.

15. Rosner D, Bedwani RN, Vana J, Baker HW, Murphy GP. Noninvasive breast carcinoma. Results of a national survey by the American College of Surgeons. Ann Surg 1980; I92:139- 147.

1977; 40:1189-1l93.

451291 3-2916.

21225-25 I .