Breast Cancer Vol. 12 No. 2 April 2005 Original Article Rie Horii 1, 3, Futoshi Akiyama 1, Fujio Kasumi 2, Morio Koike 3, and Goi Sakamoto 1 1 Department of Breast Pathology, the Cancer Institute of the Japanese Foundation for Cancer Research, 2 Department of Breast Surgery, the Cancer Institute Hospital, 3 Department of Human Pathology, Tokyo Medical and Dental University Graduate School. Background: Healing is a phenomenon by which the intraductal component of breast cancer disappears and is replaced by fibrous tissue. Focally localized healing often prevents confirmation of the continuity of intraductal carcinoma. Objective: To clarify the clinicopathological characteristics of breast cancer with healing. Patients and Methods: At our hospital, 308 patients (311 breasts) underwent breast conservation therapy without neoadjuvant chemotherapy for breast cancer in 2000. These surgical specimens were histopathologically investigated with 5 mm serial sections. We assessed the proportion and the characteristics of breast cancer with healing. Results: (1) The proportion of breast cancer with healing was 7% (21/311). (2) In the 21 patients, the mean age was 59.2 years, and the mean diameter was 2.8 cm. (3) The histological type of the breast cancer varied: noninvasive ductal carcinoma in 2 cases, papillotubular carcinoma in 5, solid-tubular carcinoma in 8, scirrhous carcinoma in 5, invasive lobular carcinoma in 1, and Paget s disease in 1. However in all cases, the histologic type of the intraductal carcinoma foci was the comedo/solid type and the nuclear grade of cancer cells was high. (4) In cases with healing, areas of healing were seen in an average of 5 (1-26) blocks, compared with intraductal carcinoma foci in 13 blocks (2-40). Healing was located on the nipple side of the main lesion in 8 cases, the peripheral side in 9, and both sides in 4. In 3 cases, healing was seen at the surgical margin of the partial mastectomy specimen. Conclusion: The proportion of breast cancer cases with healing was 7% and these cases were intraductal carcinoma of the comedo/solid type, consisting of highly malignant cancer cells. Breast Cancer 12:140-144, 2005. Key words: Healing, Breast conservation therapy, Breast cancer, Accurate pathologic evaluation In breast cancer, the intraductal component can spontaneously disappear and be replaced by fibrous tissue. This phenomenon, known as healing, was reported by Muir et al. as early as 1934 1). However, the existence of healing has not previously exerted any influence on the pathological diagnosis of breast cancer. Consequently this phenomenon has attracted little attention and has not been reported in many cases. It is likely that few pathologists are aware of this phenomenon. At the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, we started Reprint requests to Rie Horii, Department of Breast Pathology, the Cancer Institute of the Japanese Foundation for Cancer Research, 3-10-6, Ariake, Koto-ku, Tokyo 135-8550, Japan. E-mail: rie.horii@jfcr.or.jp Received June 20, 2004; accepted November 29, 2004 breast conservation therapy for early breast cancer in 1986. Thereafter the number of such cases treated with this approach increased. In 2000, 311 (46%) of 670 primary breast cancer cases underwent breast conservation therapy. To accurately recognize the spread of intraductal carcinoma and determine the surgical margin status after partial mastectomy, surgical materials were histopathologically investigated with 5 mm serial sections. As a result, we noticed that focally localized healing often prevents confirmation of the continuity of intraductal carcinoma. We encountered a case of breast cancer, in which the surgical margin could not be accurately determined when performing partial mastectomy because of massive healing and in which recurrence occurred in the conserved breast very soon after partial mastectomy. This underscores the importance of paying atten- 140
Breast Cancer Vol. 12 No. 2 April 2005 a b c d Fig 1 Histology of healing (hematoxylin and eosin stain 100). 1a: Lymphocytes infiltrated around the intraductal carcinoma focus and the circular elastic fiber has become thick. 1b: Cancer cells gradually decrease from the marginal area of the duct and have been replaced by collagen fiber. 1c: Cancer nests have become diminished. There is a foreign body giant cell above the fibrosis. 1d: Cancer cells eventually completely disappeared and the ductal structure has changed into a round-to-oval scar consisting of concentric layers of collagen and elastic fibers. tion to the possibility of healing in determining the surgical margin status after partial mastectomy. Similarly, when making a diagnosis of multiple breast cancer, the recognition of the possibility of the discontinuity of the various carcinoma foci is necessary, and healing is therefore an important histological finding. When an area of healing is seen between two invasive carcinoma foci, even if no intraductal component is seen, we must consider these foci as one lesion connected by healing, not as multiple breast cancers. The current popularity of breast conservation therapy has necessitated judging the continuity of intraductal carcinoma in the pathological diagnosis of breast cancer. To accurately judge the continuity of intraductal carcinoma, the recognition of the possibility of healing is necessary. We think that healing is a clinicopathologically significant phenomenon. In this study, the objective is to clarify the clini- copathological characteristics of breast cancer with healing. Patients and Methods In the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 670 cases of primary breast cancer (680 breasts), underwent resection in 2000. Of these, 308 cases (311 breasts) underwent breast conservation therapy without neoadjuvant chemotherapy. Resected specimens were sectioned at 5 mm continuously and microscopically examined after hematoxylin-eosin staining. We evaluated the proportion and the characteristics of breast cancer with healing. By our definition, spontaneous healing occurred when intraductal carcinoma was completely replaced by fibrous tissue. The histological features that show change from an intraductal carcinoma focus into healing are as follows 141
Horii R, et al (Fig 1a-d): 1. Lymphocytes infiltrated around the intraductal carcinoma lesion and the circular elastic fiber was thickened. 2. Cancer cells gradually decreased forward from the marginal area of the duct, and were replaced by collagen fiber. 3. Finally cancer cells completely disappeared and the ductal structure changed into a round-to-oval scar consisting of concentric layers of collagen and elastic fibers. Results Proportion Out of 308 cases (311 breasts), healing was seen histopathologically in 21 cases (21 breasts). The proportion of breast cancer with healing was 7% (21/311). Clinical Characteristics In these 21 cases, the mean age was 59.2 (46-86) years, compared with 53.3 (26-86) years in the overall breast conservation surgery group and the mean tumor diameter was 2.8 (1.2-6.0) cm, compared with 2.1 (non-palpable-7.0) cm in the 308 cases. Pathological Characteristics The histological type 2) of the 21 cases of breast cancer broadly varied: noninvasive ductal carcinoma in 2 cases, papillotubular carcinoma in 5, solidtubular carcinoma in 8, scirrhous carcinoma in 5, invasive lobular carcinoma in 1 and Paget s disease in 1. The proportion of cases in which healing was recognized for each histological type was as follows: 4% (2/46) in noninvasive ductal carcinoma, 9% (5/57) in papillotubular carcinoma, 14% (8/58) in solid-tubular carcinoma, 3% (4/125) in scirrhous carcinoma, 13% (1/8) in invasive lobular carcinoma and 50% (1/2) in Paget s disease (Table 1). In all cases, the histologic type of the intraductal carcinoma foci was the comedo/solid type and the nuclear grade of cancer cells was high, Grade 3 by Nuclear Grading 2) (Fig 1). In cases with healing, areas of healing were seen in an average of 5 (1-26) blocks, compared with intraductal carcinoma foci in 13 (2-40) blocks. In the 21 cases with healing, healing was located on the nipple side of the main lesion in 8 cases (38%), the peripheral side in 9 (43%) and both sides in 4 (19%). In 3 cases (14%), healing was Table 1 The Proportion of Breast Cancer Cases with Healing Among all breast cancer The proportion for each histological type Noninvasive ductal carcinoma Papillotubular carcinoma Solid-tubular carcinoma Schirrous carcinoma Invasive lobular carcinoma Paget s disease seen at the surgical margin of the partial mastectomy specimen. Discussion 7% (21/311) 4% (2/46) 9% (5/57) 14% (8/58) 3% (4/125) 13% (1/8) 50% (1/2) Spontaneous healing is a phenomenon by which the intraductal component of breast cancer disappears and is replaced by fibrous tissue. In 1934, Muir et al. reported this histopathological phenomenon for the first time 1). The cause of the periductal fibrosis in breast cancer, which includes healing, is not clear. Some papers reported that the cause of the periductal fibrosis may be a biological reaction to the basal membrane invasion of cancer cells or the carcinoma producing material 3, 4). Therefore, periductal fibrosis has been studied as a predictive factor of the survival of noninvasive ductal carcinoma 3-5). Most such healing is focally localized in intraductal carcinoma, and often breaks up the continuous ductal spread of breast cancer cells. If healing, although present, is not recognized, there is the possibility of misjudging the continuity of intraductal carcinoma. When multiple breast cancer is diagnosed or when deciding the surgical margin status after partial mastectomy, accurate assessment of the continuity of intraductal carcinoma is necessary and healing is an important histological finding. The current popularity of breast conservation therapy has given healing new clinicopathological significance. The proportion of breast cancers with healing was 7%. There is no report about the proportion of breast cancer with healing defined as intraductal carcinoma being completely replaced by fibrous tissue. Fisher et al. reported that periductal fibrosis was seen in 58% of 78 noninvasive ductal carcinoma cases which were registered for National Surgical Adjuvant Breast and Bowel Project Protocol 6 4). In that series, we noted the histologic 142
Breast Cancer Vol. 12 No. 2 April 2005 appearance of healing seen in some of the figures showing periductal fibrosis, but the exact percentage of cases fitting our criteria of healing could not be calculated from the data presented. We observed an increase of thick elastic fibers with concomitant decrease and eventually disappearance of cancer cells, as healing. They reported that about 60% of breast cancers had thick elastic fibers around the intraductal carcinoma component. In our data, using the definition of healing as intraductal carcinoma completely replaced by fibrous tissue in a part of the lesion, healing was recognized in 7% of breast cancer cases. The proportion of cases showing healing was low in scirrhous carcinoma and high in solid-tubular carcinoma and Paget s disease. The first cases in which healing was reported by Muir et al., were 2 cases of Paget s disease 1). When Paget s disease, which is a rare histological type, is diagnosed, it is necessary to consider the possibility of healing. Healing in breast cancer cases was not related to age or tumor size. But in all breast cancer cases with healing, intraductal carcinoma foci were of the comedo/solid type and the nuclear grade of the cancer cells was high. These data suggest that healing is related to the histological type of intraductal carcinoma and the nuclear grade of cancer cells. Most breast cancer with periductal fibrosis has been reported to be the comedo type of intraductal carcinoma, consisting of highly malignant cancer cells 5-7). The fact that the characteristics of breast cancer with healing and with periductal fibrosis are similar, may suggest some relation to the cause of healing and periductal fibrosis. The spread and the location of healing were varied. In 3 cases, which accounted for 14% of cases of breast cancer with healing and 1% of all cases treated with breast conservation therapy, healing was seen at the surgical margin of the partial mastectomy specimen. We must consider the possibility that cancer cells might remain in the conserved breast when areas of healing are seen, even if no carcinoma is seen at the surgical margin after partial mastectomy. As pathologists, when healing is seen at the surgical margin we have to inform the clinician. When more than one invasive carcinoma lesion is seen in the same breast, it is important to judge whether the invasive carcinoma foci actually represent different portions of one lesion connected by some areas of healed intraductal carcinoma or not, to truly understand the condition of the patient. When multiple breast cancer is diagnosed, recognition of the discontinuity of each carcinoma lesion is necessary. If healing, although present, is not recognized, there is the danger of misdiagnosing multiple breast cancer. Breast cancer with healing is not a rare entity. Especially when intraductal carcinoma lesions are of the comedo/solid type consisting of highly malignant cancer cells, we must consider the possibility of healing when diagnosing multiple breast cancer. All previously recognized healing was focally localized in intraductal carcinoma, with intraductal carcinoma lesions adjacent to the healing. Breast imaging techniques are progressing. If smaller noninvasive ductal carcinomas can be detected by breast imaging, cancer nests which have been completely replaced by healing may be visualized. When biopsy is performed on a small target to diagnose intraductal carcinoma, only areas of healing may be obtained, showing no carcinoma lesion. We encountered one case of the comedo type noninvasive ductal carcinoma in which only findings of healing were seen in one of the needle biopsy specimens. When only areas of healing are seen in a small biopsy specimen, we must consider the possibility that there might be other areas of intraductal carcinoma consisting of highly malignant cancer cells around the areas of healing. The characteristic histological findings of healing are easily recognized on conventional hematoxylin and eosin stained specimens. However, to detect healing, it is necessary for pathologists to be aware of the concept and findings of healing. Healing is an interesting phenomenon by which the intraductal component of breast cancer spontaneously disappears. We consider that the elucidation of the mechanism of healing will provide hints leading to the development of new breast cancer treatments. Conclusion The proportion of breast cancer with healing was 7% and the characteristics of these cases were intraductal carcinoma of the comedo/solid type, consisting of highly malignant cancer cells. Therefore when determining the surgical margin status after partial mastectomy for breast cancer with these characteristics, we must be particularly aware of the concept of healing. 143
Horii R, et al Acknowledgement The authors are indebted to Prof. J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript. This study was supported by a grant -in-aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (No.13-9). References 1) Muir R, Aitkenhead AC: The healing of intra-duct carcinoma of the mamma. J Pathol Bacteriol 38:117-127, 1934. 2) The Japanese Breast Cancer Society: General Rules for Clinical and Pathological Recording of Breast Cancer, 15th ed, Kanehara shuppan, Tokyo, pp32-68 and 14-18, 2004 (in Japanese). 3) King TA, Farr GH, Cederbom GJ, Smetherman DH, Bolton JS, Stolier AN, Fuhrman GM: A mass on breast imaging predicts coexisting invasive carcinoma in patients with a core biopsy diagnosis of ductal carcinoma in situ. Am Surg 67:907-912, 2001. 4) Fisher ER, Sass R, Fisher B, Wickerham L, Paik SM, collaborating NSABP investigators: Pathologic findings from the National Surgical Adjuvant Breast Project (Protocol 6) 1. Intraductal Carcinoma (DCIS). Cancer 57:197-208, 1986. 5) Sneige N, McNeese MD, Atkinson EN, Ames FC, Kemp B, Sahin A, Ayala AG: Ductal carcinoma in situ treated with lumpectomy and irradiation: Histopathological analysis of 49 specimens with emphasis on risk factors and long term results. Hum Pathol 26:642-649, 1995. 6) Claus EB, Chu P, Howe CL, Davison TL, Stern DF, Carter D, DiGiovanna MP: Pathologic findings in DCIS of the breast: Morphologic features, angiogenesis, HER-2/neu and hormone receptors. Exp Mol Pathol 70:303-316, 2001. 7) Quinn CM, Ostrowski JL, Parkin GJS, Horgan K, Benson EA: Ductal carcinoma in situ of the breast: the clinical significance of histological classification. Histopathology 30:113-119, 1997. 144