Japanese Journal of Clinical Oncology 33:161-166 (2003)
© 2003 Foundation for Promotion of Cancer Research
Pathological Assessment of Intraductal Spread of Carcinoma in Relation to Surgical Margin State in Breast-conserving Surgery
1 Division of Surgical Oncology, Tohoku University School of Medicine, Sendai, 2 Department of Pathology, Institute for Differentiation, Aging and Cancer, Tohoku University, Sendai and 3 Department of Pathology, Tohoku University Hospital, Sendai, Japan
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Background: Spreading of carcinoma has been considered to be a prognostic factor for local failure after breast-conserving therapy. The extensive intraductal component (EIC) was defined as when the component of intraductal carcinoma constitutes more than 25% of the primary tumor with intraductal foci. However, the definition of EIC was based on the predominance of intraductal component surrounding the invasive lesions and not on the segmental anatomy. We designated carcinoma extension as the intraductal spread of carcinoma (ISC) along with the duct–lobular system by three-dimensional (3-D) reconstruction analysis. This study was initiated to simplify the method of two-dimensional (2-D) pathological examination based on 3-D mapping.
Methods: Thirty-four specimens from breast cancer patients were subjected to 3-D reconstruction. We investigated the correlation between actual extension of intraductal carcinoma and EIC defined by 2-D examination or ISC grading defined by 3-D reconstruction. Furthermore, using another 62 histological mappings, we investigated how correctly the simplified 2-D method using several paraffin blocks reflected the actual carcinoma spread and margin state.
Results: Carcinoma extension over 2 cm was observed in 64% specimens that were EIC positive and 26% specimens that were EIC negative. In contrast, according to the ISC grading defined by 3-D reconstruction, none of the specimens with a low grade of ISC demonstrated carcinoma extension over 2 cm. Carcinoma extension over 2 cm was observed in 71% of specimens with a high grade of ISC, thus demonstrating a correlation between carcinoma extension and ISC grading. In addition, the simplified 2-D method using only several blocks reflected both the 3-D ISC grading and surgical margin state.
Conclusions: We conclude that ISC grading correlates with carcinoma extension and surgical margin state. From a clinical point of view, the simplified 2-D examination using paraffin blocks may contribute to routine surgical pathology in evaluating the degree of carcinoma extension in breast-conserving therapy.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Breast-conserving treatment has become one of the standard therapies for early breast cancer. The results of several randomized prospective trials such as the Milan trial (1,2) and NSABP trial (3,4) have demonstrated that no detrimental effects in terms of survival and distant metastasis rates were observed in patients treated by breast-conserving surgery and radiation compared with those treated by modified radical mastectomy. The cosmetic effect is well evaluated as it improves the quality of life in breast-conserving therapy. The extension of carcinoma component, however, is occasionally higher than the preoperative prediction. Several groups have noted that a high degree of intraductal carcinoma extension and multicentricity are due to cancer residues after breast-conserving therapy (5–11). Not only survival issues but also cosmetic, economic and psychological demerit from the local recurrence within the breast occur.
Schnitt and co-workers (12,13) designated intraductal extension of carcinoma as extensive intraductal component (EIC) when intraductal carcinoma occupies more than 25% of the primary tumor with intraductal foci separate from the main tumor mass. EIC is a very simple and easy detection method by two-dimensional (2-D) pathological examination to identify the intraductal carcinoma extension. It is based, however, on the predominance of intraductal component in the main tumor associated with invasive component and not on the segmental anatomy. We think that it is necessary to define the intraductal carcinoma extension based on the segmental anatomy, proposing the term intraductal spread of carcinoma (ISC) (14,15). ISC was defined as a state in which ductal carcinoma in situ (DCIS) extends beyond the terminal duct–lobular unit (TDLU) and into large ducts. We classified four ISC grades based on the extent in the duct–lobular system and showed how closely it correlated with carcinoma residues after breast-conserving treatment (14,15).
The definition of ISC is based on 3-D pathological examination. Serial slices 5 µm thick were made of the specimens from breast cancer patients receiving quadrantectomy and computer-assisted 3-D mapping of the tumors was constructed along with the duct–lobular system. This 3-D examination can detect the detail of carcinoma extension and the surgical margin state. It is very difficult, however, to do the 3-D pathological examination in all patients receiving breast-conserving surgery because about 2500–5000 hematoxylin and eosin-stained preparations are needed for one patient. This study was initiated to simplify the method of 2-D pathological examination based on 3-D pathological mapping. First, we investigated how correctly the EIC judgement accepted as an easy method by 2-D examination and ISC grading by 3-D examination show the actual carcinoma spread. Then the same was done with simulation based on the simplified 2-D method using several paraffin blocks.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Materials
Investigation of Correlation Between Actual Intraductal Carcinoma Extension and EIC Judgement by 2-D Examination or ISC Grading by 3-D Examination
Thirty-four specimens from stage I and II breast cancer patients receiving quadrantectomy in Tohoku University Hospital from 1990 to 1994 were fixed in 10% formalin neutral buffer solution and embedded in paraffin. The patients ranged in age from 25 to 73 years (median, 54 years). The histopathology of all the cases was invasive ductal carcinoma (IDC) and included IDC with predominant intraductal component cases.
Simplified Method for Detecting ISC Grading by 2-D Pathological Examination Using Several Paraffin Blocks
Sixty-two specimens from stage I and II breast cancer patients receiving quadrantectomy in Tohoku University Hospital from 1990 to 1996 were fixed in 10% formalin neutral buffer solution and embedded in paraffin. The patients ranged in age from 29 to 83 years (median, 52 years). The histopathology of all the cases was invasive ductal carcinoma (IDC) and included IDC with predominant intraductal component cases.
Methods
Investigation of Correlation Between Actual Intraductal Carcinoma Extension and EIC Judgement by 2-D Examination or ISC Grading by 3-D Examination
The tissues were subjected to serial sectioning and 3-D reconstruction using a workstation. First, the specimens were sequentially sliced to 3 mm thickness using a ham slicer and made into 5 µm thick sections. Sections 100 µm thick were stained with hematoxylin and eosin. From these, graphic 3-D reconstruction was performed with the aid of a computer system developed on a workstation (Hewlett-Packard, Model 300) and OZ software (Rise, Sendai, Japan).
In this study, we defined the high degree of intraductal carcinoma extension group as when the intraductal carcinoma component exists more than 2 cm distant from the edge of invasive lesions. We investigated how the EIC judgment by 2-D or ISC grading by 3-D examination method can determine the spread of intraductal carcinoma lesions.
EIC judgement
Schnitt and co-workers (12,13) designated intraductal extension of carcinoma as EIC when intraductal carcinoma constitutes more than 25% of the primary tumor with intraductal foci separate from the main tumor mass.
ISC definition and classification
We designated intraductal extension as intraductal spread of carcinoma (ISC) and classified ISC into four grades, i.e., grade 0–3 based on the extent of carcinoma along with the duct–lobular system (15) (Fig. 1).
|
ISC was defined as the state in which DCIS was present clearly extending beyond the TDLU or present prominently within the large ducts. The predominance of an invasive or an intraductal component was not considered (15). A photomicrograph of an ISC grade 1 case is presented in Fig. 2.
|
Simplified Method for Detecting ISC Grading by 2-D Pathological Examination Using Several Paraffin Blocks
Serial slices 5 mm thick were made from the specimens and used to map the pathological results. We then tried to establish a simplified 2-D pathological examination method using several pathological paraffin blocks (Fig. 3). We simulated the several paraffin blocks such as 4 cm long, 5 mm thick, parallel to the nipple-tumor line and chose the main tumor site, both bilateral 10 mm sites. For example, the main tumor site was by two paraffin blocks when the tumor size was 1 cm and two sets of bilateral blocks, total six blocks.
|
We then investigated how the simplified 2-D pathological examination method using several paraffin blocks can correctly determine the intraductal carcinoma extension and the surgical margin status.
Definition of ISC high degree group by simplified 2-D pathological examination method
The correlation between the distance of intraductal spread of carcinoma from the edge of the invasive lesion and ISC grading by 3-D examination is shown in Table 1. The distances were 0–2 mm in ISC grade 0 group, 0–4 mm in ISC grade 1 group, 6–27 mm in ISC grade 2 group and 24–53 mm in ISC grade 3 group. The distances of intraductal spread of carcinoma from the edge of invasive lesion were all less than 4 mm in ISC grade 0 and 1 groups and all more than 6 mm in ISC grade 2 and 3 groups. In this study, we defined the ISC high degree group by the simplified 2-D pathological examination method when the intraductal carcinoma component existed more than 5 mm distant from the edge of the invasive lesions.
|
Judgement of positive surgical margin
Quadrantectomy and complete axillary dissection (levels I and II with or without level III) were performed in all breast-conserving therapy patients. The surgical margin was judged positive when the carcinoma component existed within 5 mm from the stump.
Pathological judgement
Two pathologists performed the pathological judgment, one from the Department of Pathology, Tohoku University Hospital and the other from the Department of Pathology, Institute for Differentiation, Aging and Cancer, Tohoku University.
Statistics
Results were compared by the chi-squared test. Differences were considered statistically significant when the P value was <0.05.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Investigation of Correlation Between Actual Intraductal Carcinoma Extension and EIC Judgement by 2-D Examination or ISC Grading by 3-D Examination
The results of the correlation between actual intraductal carcinoma extension and EIC judgement by 2-D examination or ISC grading by 3-D examination are presented in Table 2. Intraductal carcinoma extension over 2 cm from the edge of the invasive lesion was observed in seven of 11 (64%) specimens that were EIC positive and in six of 23 (26%) specimens that were EIC negative. On the other hand, intraductal carcinoma extension less than 2 cm was observed in 17 of 23 (74%) specimens that were EIC negative and in four of 11 (36%) specimens that were EIC positive. The difference in intraductal carcinoma extension between the EIC positive and negative groups was statistically significant (P < 0.05). EIC judgement by 2-D examination is able to detect a high degree of intraductal carcinoma extension in the EIC positive group, but it also appeared that a high degree of intraductal carcinoma extension was observed in 26% of the EIC negative group.
|
In contrast, according to the ISC grading defined by 3-D reconstruction, none of 17 specimens with low grade (0, 1) ISC demonstrated carcinoma extension over 2 cm and in 12 of 17 (71%) specimens that were high grade (2, 3) ISC. Intraductal carcinoma extension less than 2 cm was observed in five of 17 (29%) specimens that were high grade ISC, but in 17 of 17 (100%) specimens that were low grade ISC. The difference in intraductal carcinoma extension between ISC grade 0, 1 group and ISC grade 2, 3 group was statistically significant (P < 0.001). Furthermore, all of the ISC grade 0, 1 group actually showed intraductal carcinoma extension less than 2 cm. ISC grading by 3-D examination was able to detect a high degree of intraductal carcinoma extension in the grade 2, 3 group, but there were no false negatives in the grade 0, 1 group.
There was no significant relationship between ISC grade and clinicopathological findings, such as invasive tumor size, histological grade, hormone receptor status or lymph node metastasis.
Simplified Method for Detecting ISC Grading by 2-D Pathological Examination Using Several Paraffin Blocks
One case of histopathological cancer mapping of a quadrantectomy specimen is presented in Fig. 4. The results of correlation between ISC judgement by simplified 2-D examination and actual distance of intraductal carcinoma extension, positive rate of surgical margin are presented in Table 3. Intraductal carcinoma extension over 2 cm was observed in 26 of 34 (76%) specimens that were in the ISC high degree group and 18 of 34 (53%) specimens appeared to be surgical margin positive. On the other hand, one of 28 (4%) specimens that were in the ISC low degree group demonstrated intraductal carcinoma extension over 2 cm and none of this group appeared to be surgical margin positive. The differences in intraductal spreading of carcinoma, positive rate of surgical margin between ISC low degree group and ISC high degree group were statistically significant (P < 0.001). The simplified method for detecting ISC grading by 2-D pathological examination using several paraffin blocks was able to detect correctly a high degree of intraductal carcinoma extension and positive surgical margin in the ISC high degree group and a high degree of intraductal carcinoma extension and surgical margin positive case is rarely observed in the ISC low degree group.
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Breast-conserving treatment has become a standard therapy for early breast cancer with the aim of improving the quality of life of the patient. However, the problem of local failure in the operated breast still remains unresolved. Several groups have noted that invasive cancers accompanied by EIC positive features are associated with higher local recurrence rates within the breast after breast-conserving therapy than EIC negative invasive cancers (16–20). The definition of EIC is very simple and it is easy to presume the existence of intraductal carcinoma extension. However, it is not based on the segmental anatomy, which we think is necessary to define the intraductal carcinoma extension. Wellings et al. proposed the use of anatomical terms, the duct–lobular system (21). Large ducts and TDLU comprise a duct–lobular system. Large ducts include collecting duct, lactiferous sinus, segmental duct and subsegmental duct. TDLU consists of an extralobular terminal duct, intralobular terminal ducts and ductules. We have conducted 3-D reconstruction analyses of breast tissue using subserial sections. The studies demonstrated that breast carcinoma and peripheral papilloma originated from the TDLU (14,15,22).
We proposed the name ISC and classified ISC into four grades (15). ISC was defined as the state in which DCIS extends beyond TDLU and into large ducts. In our previous study, all EIC positive cases showed a high degree of ISC; however, 28% of EIC negative cases also showed a high degree of ISC. We proposed ISC grades based on its extent in ductal anatomy and showed how closely it correlated with carcinoma residues after breast-conserving surgery (15).
In this study, it was demonstrated that ISC grading by 3-D pathological examination is able to detect a high degree of intraductal carcinoma extension and surgical margin positive cases correctly. The definition of ISC by 3-D pathological examination appears to be correct for detecting a high degree of intraductal carcinoma extension without false negatives because no cases with a high degree of intraductal carcinoma extension were found in the ISC grade 0, 1 group. The definition of EIC is able to presume intraductal carcinoma extension from 1–3 hematoxylin and eosin-stained preparations for one patient; however, for ISC definition with serial slices 50–100 µm thick and computer-assisted 3-D mapping a total of about 2500–5000 hematoxylin and eosin-stained preparations are necessary for one patient. Hence it is very difficult to do this 3-D pathological examination for all patients receiving breast-conserving surgery. Therefore, in this study, we tried to define the simplified 2-D pathological examination method using several paraffin blocks for detecting a high degree of intraductal carcinoma extension based on 3-D examination.
In this simplified method for detecting ISC grading by 2-D pathological examination, we can presume a high degree of intraductal carcinoma extension and surgical margin status using the following blocks with each main tumor size: 6 to 1 cm, 8 to 2 cm and 10 to 3 cm. In our previous study, it needed 30–93 blocks (average 52.5 blocks) for one patient receiving breast-conserving surgery to make serial slices 5 mm thick. In this simplified method, the number of examination blocks was able to be reduced to 1/5–1/8. We made blocks 4 cm long, 5 mm thick parallel to the nipple-tumor line. In the blocks across this line, the duct is cut into round slices and its level is almost indiscernible. However, in the blocks parallel to this line, one can easily observe how cancer grows in the periphery spread towards large ducts (13–15,21–24). At first fearing that many high degree ISC might be missed with slices 5 mm thick, we began with slices 2 mm thick. As in fact, however, ISC did not always follow parallel to the nipple-tumor line, almost all ISC could be detectable with slices 5 mm thick.
From our 3-D pathological examination, it was proved that the higher the degree of intraductal carcinoma extension, the greater is the multicentricity. The frequencies of multiplicity were 0% in ISC grade 0, 11% in grade 1, 54% in grade 2 and 100% in grade 3 (15) defined by 3-D reconstruction. The co-existence of a high degree of intraductal carcinoma extension and multicentricity is an important factor for cancer residues after breast-conserving therapy. Six of 62 cases that were examined by the simplified method subsequently developed ipsilateral breast cancer. Three of six cases were positive for surgical margin and five were patients with high ISC grade. There may be greater benefit of ISC assessment for predicting ipsilateral breast cancer recurrence. The extension of carcinoma component correctly and easily obtained from resected specimens is of use in deciding adjuvant therapy including postoperative radiotherapy and predicting ipsilateral breast recurrence after breast-conserving therapy.
If the patient has a tumor with high ISC grade, without positive surgical margin status, irradiation is adopted in our hospital to prevent local recurrence. Endocrine therapy should also be adopted for patients with ER and/or PgR positive tumors.
Furthermore, to evaluate ultrasonography, 3-D MRI and helical CT as preoperative approaches, a careful comparative study with pathological data is needed. From these data, we have to evaluate the entry criteria and adequate resection range of breast-conserving therapy individually.
We conclude that ISC grading correlates with carcinoma extension and surgical margin state. From a clinical point of view, the simplified 2-D examination using paraffin blocks may contribute to routine surgical pathology in evaluating the degree of carcinoma extension in breast-conserving therapy.
|
FOOTNOTES |
|---|
+ For reprints and all correspondence: Noriaki Ohuchi, Division of Surgical Oncology, Tohoku University School of Medicine, 1–1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. E-mail: noriaki{at}mail.cc.tohoku.ac.jp
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1 Veronesi U, Saccozzi R, Del Vecchio M, Banfi A, Clemente C, De Lena M, et al. Comparing radical mastectomy with quadrantectomy, axillary dissection and radiotherapy in patients with small cancers of the breast. N Engl J Med 1981;305:6–11.[Abstract]
2 Veronesi U, Banfi A, Del Vecchio M, Saccozzi R, Clemente C, Greco M, et al. Comparison of Halsted mastectomy with quadrantectomy, axillar dissection and radiotherapy in early breast cancer: long-term results. Eur J Cancer Clin Oncol 1986;22:1085–9.[CrossRef][Web of Science][Medline]
3 Fisher ER, Sass RF, Fisher B, Wickerham L, Paik SM. Pathologic findings from the National Surgical Adjuvant Breast Project (Protocol No. 6), I. Intraductal carcinoma (DCIS). Cancer 1986;57:197–208.[CrossRef][Web of Science][Medline]
4 Fisher B, Redmond C, Poisson R, Margolese R, Wolmark N, Wicherham L, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989;320:822–8.[Abstract]
5 Holland R, Connolly JL, Gelman R, Mravunac M, Hendriks JHCL, Verbeek ALM, et al. The presence of an intraductal component following a limited excision correlates with prominent residual disease in the remainder of the breast. J Clin Oncol 1990;8:113–8.
6 Eberlein TJ, Connoly JL, Schnitt SJ, Recht A, Osteen RT, Harris JR. Predictors of local recurrence following conservative breast surgery and radiation therapy: the influence of tumor size. Arch Surg 1990;125:771–7.
7 Anscher MS, Jones P, Prosnitz LR, Blackstock W, Hebert M, Reddick R, et al. Local failure and margin status in early-stage breast carcinoma treated with conservation surgery and radiation therapy. Ann Surg 1993;218:22–8.[Web of Science][Medline]
8 Kurtz JM, Amalric R, Brandone H, Ayme Y, Jacquemier J, Pietra J, et al. Local recurrence after breast-conserving surgery and radiotherapy: frequency, time course and prognosis. Cancer 1989;63:1912–7.[CrossRef][Web of Science][Medline]
9 Boyages J, Abram R, Connolly JL. Early breast cancer: predictors of breast recurrence for patients treated with conservative surgery and radiation therapy. Radiother Oncol 1990;19:29–41.[CrossRef][Web of Science][Medline]
10 Johnson JE, Page DL, Winfield AC, Reynolds VH, Sawyers JL. Recurrent mammary carcinoma after local excision. Cancer 1995;75:1612–8.[CrossRef][Web of Science][Medline]
11 Recht A, Silen W, Schnitt SJ, Connolly JL, Gelman RS, Rose MA, et al. Time-course of local recurrence following conservative surgery and radiotherapy for early stage breast cancer. Int J Radiat Oncol Biol Phys 1988;15:255–61.[CrossRef][Web of Science][Medline]
12 Schnitt SJ, Connolly JL, Harris JR, Hellman S, Cohen RB. Pathologic predictors of early local recurrence in stage I and II breast cancer treated by primary radiation therapy. Cancer 1984;53:1049–57.[CrossRef][Web of Science][Medline]
13 Schnitt SJ, Connolly JL, Khettry U, Mazoujian G, Brenner M, Silver B, et al. Pathologic findings on re-excision of the primary site in breast cancer patients considered for treatment by primary radiation therapy. Cancer 1987;59:675–81.[CrossRef][Web of Science][Medline]
14 Ohuchi N, Furuta A, Mori S. Management of ductal carcinoma in situ with nipple discharge. Cancer 1994;74:1294–302.[CrossRef][Web of Science][Medline]
15 Ohuchi N. Breast-conserving surgery for invasive cancer: a principle based on segmental anatomy. Tohoku J Exp Med 1999;108:103–18.[CrossRef]
16 Bartelink H, Borger JH, Van Dongen JA, Peterse JL. The impact of tumor size and histology on local control after breast-conserving therapy. Radiother Oncol 1988;11:297–303.[CrossRef][Web of Science][Medline]
17 Lindley R, Bulman A, Parsons P, Phillips R, Henry K, Ellis H. Histologic features predictive of an increased risk of early local recurrence after treatment of breast cancer by local tumor excision and radical radio-therapy. Surgery 1989;105:13–20.[Web of Science][Medline]
18 Harris JR, Connolly JL, Schnitt SJ, Cohen RB, Hellman S. Clinical–pathologic study of early breast cancer treated by primary radiation therapy. J Clin Oncol 1983;1:184–9.[Abstract]
19 Kurtz JM, Jacquemier J, Amalric R, Brandone H, Ayme Y, Hans D, et al. Risk factor for breast recurrence in pre- and post-menopausal women with infiltrating ductal cancer treated by conservation therapy. Cancer 1990;65:1867–78.[CrossRef][Web of Science][Medline]
20 Beron PJ, Horwitz EM, Martinez AA, Wimbish KJ, Levine AJ, Gustafson G, et al. Pathologic and mammographic findings predicting the adequacy of tumor excision before breast-conserving therapy. Am J Roentgenol 1996;6:1409–14.
21 Wellings SR, Jensen HM, Marcum RG. An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions. J Natl Cancer Inst 1975;55:231–73.[Web of Science][Medline]
22 Ohuchi N, Abe R, Kasai M. Possible cancerous change of intraductal papillomas of the breast: a 3-D reconstruction of 25 cases. Cancer 1984;54:605–11.[CrossRef][Web of Science][Medline]
23 Page DL, Rogers LM. Epithelial hyperplasia. In: Page DL, Anderson TJ, editors. Diagnostic Histopathology of the Breast. Edinburgh: Churchill Livingstone 1987;120–56.
24 Ohuchi N, Harada Y, Ishida T, Satomi S. Breast-conserving surgery for primary breast cancer: immediate volume replacement using lateral tissue flap. Breast Cancer 1997;4:135–41.[Medline]
Received December 13, 2002; accepted February 7, 2003
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Shimauchi, T. Yamada, A. Sato, K. Takase, S. Usami, T. Ishida, T. Moriya, and S. Takahashi Comparison of MDCT and MRI for evaluating the intraductal component of breast cancer. Am. J. Roentgenol., August 1, 2006; 187(2): 322 - 329. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||