Invasive Ductal Carcinoma with Fibrotic Focus: Mammographic and Sonographic Findings with Histopathologic Correlation

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1 Mammograp hy and Sonography of Invasive Ductal arcinoma reast Imaging linical Observations Shara Millman Oken 1 ecilia L. Mercado 2 Lorenzo Memeo 3 Hanina Hibshoosh 3 Oken SM, Mercado L, Memeo L, Hibshoosh H Received July 30, 2004; accepted after revision October 15, Department of Radiology, reast Imaging, olumbia University Medical enter New York Presbyterian Hospital, Herbert Irving Pavilion, 161 Fort Washington ve., 10th Fl., Ste. 1051, New York, NY ddress correspondence to S. M. Oken (sm800@columbia.edu). 2 Department of Radiology, New York University ancer enter, New York, NY Department of Pathology, olumbia University Medical enter New York Presbyterian Hospital, New York, NY JR 2005; 185: X/05/ merican Roentgen Ray Society Invasive Ductal arcinoma with Fibrotic Focus: Mammographic and Sonographic Findings with Histopathologic orrelation OJETIVE. We sought to define the imaging findings of invasive ductal carcinoma with fibrotic focus and its associated histopathologic correlation. ONLUSION. Radiologists should be aware of the imaging characteristics of this newly described entity because of the significant prognostic implications and perhaps to prompt the pathologist to assess for the presence of a fibrotic focus at excision. nvasive ductal carcinoma of the I breast with fibrotic focus has been described in the recent pathology literature in association with significantly poorer survival than invasive ductal carcinoma without a fibrotic focus [1 9]. These lesions have a predilection for lung and brain metastases and have been shown to be a useful parameter for predicting tumor recurrence, early metastasis to a distant organ, and early tumor death [1 9]. Histologically, the fibrotic focus is a scarlike area composed of fibroblasts and collagen fibers that occupies varying percentages of the volume of an invasive ductal breast cancer. To our knowledge, the imaging characteristics of this entity have not yet been described. Our study objective was to describe the mammographic and sonographic findings of invasive ductal carcinoma with fibrotic focus and correlate those imaging findings with its histopathologic features. Materials and Methods We retrospectively reviewed mammograms and sonograms of 30 excision-proven cases of invasive ductal carcinoma with fibrotic focus collected over a period of 5 years, 5 months (December 1997 to pril 2003). The medical history and physical and imaging findings were analyzed in all patients. Mammographic and sonographic images were retrospectively reviewed by two independent radiologists, both fellowship-trained in breast imaging. Evaluation was then performed as a consensus interpretation. Each mammographic lesion was assessed in terms of size, margins, and presence or absence of associated calcifications. When possible, sonographic lesions were assessed in terms of echogenicity, size, the presence or absence of posterior shadowing or posterior acoustic enhancement, and margin characteristics. ll lesions were categorized according to I-RDS [10]. linical parameters including the palpable nature of the lesion and patient age were ascertained from medical records. Imaging characteristics were then correlated with histopathologic findings. Results Our study set consisted of 30 lesions in 30 patients. Patients ranged in age from 34 to 83 years, with a mean of 62 years. Twenty-one of the 30 lesions were palpable on physical examination. Lesion size was based on the largest imaging dimension on sonography if available or on mammography if sonography was not available. Lesion size ranged from 1.0 to 3.4 cm (mean, 1.9 cm). ll lesions (100%) were classified as I-RDS category 5, both on prospective review and on retrospective review. The mammographic appearance of the lesions studied included 20 spiculated masses, seven partially circumscribed masses, one mass with macrolobulated margins, one mass with microlobulated margins, and three ill-defined areas of increased density (Fig. 1). Eleven (37%) of 30 lesions had associated pleomorphic calcifications. Histopathology of all lesions (100%) revealed moderate to poorly differentiated invasive ductal carcinoma. Sonography examinations were available for review in 24 of the 30 cases. ll 24 lesions (100%) were solid hypoechoic masses with irregular or microlobulated margins. Lobulation seen sonographically did not necessarily correlate with micro- or macrolobulation seen mammographically. Ten (42%) of 24 lesions 490 JR:185, ugust 2005

2 Mammography and Sonography of Invasive Ductal arcinoma showed posterior acoustic shadowing, and four (17%) showed partial through-transmission. The imaging characteristic common to 18 (75%) of the 24 lesions for which sonography examinations were available was focal increased echogenicity within the hypoechoic lesion itself. This internal increased echogenicity either was seen focally in a centric (Fig. 2) or eccentric location (Fig. 2) or was seen in an infiltrative pattern within the lesion (Fig. 2). The sonographic findings of focal increased echogenicity were seen to directly correlate with the fibrotic focus in the lesions seen histologically (Fig. 3). We liken this appearance to an island in a lake, with the island represented by the focal increased echogenicity sonographically and by the fibrotic focus histologically. The lake is represented by a hypoechoic tumor rim sonographically and the surrounding tumor rim histologically. Discussion Invasive ductal carcinoma of the breast with fibrotic focus was first described in the pathology literature in 1996 by Hasebe et al. [1]. This feature has been shown to be an indicator of tumor aggressiveness, associated with a significantly poorer survival than that seen in invasive ductal carcinoma without a fibrotic focus, with a predilection for brain and lung metastases [1 8]. Moreover, the presence of a fibrotic focus in invasive ductal carcinoma is associated with a significantly poorer short-term [2] and long-term [3] survival. Overall survival curves for patients with invasive ductal carcinoma with fibrotic focus and those without a fibrotic focus have been shown to differ significantly [5]. Fig. 1 Mammographic findings of invasive ductal carcinoma with fibrotic focus., Mammogram in 55-year-old woman with invasive ductal carcinoma with fibrotic focus shows spiculated mass with associated pleomorphic calcifications. Skin lesion is marked in lower left-hand corner., Spot compression tangential view in 56-year-old woman with invasive ductal carcinoma with fibrotic focus shows partially circumscribed mass without associated calcifications., Spot compression tangential view over palpable lesion in 51-year-old woman with invasive ductal carcinoma with fibrotic focus shows ill-defined area of high density (arrows). These lesions exhibit clinicopathologically and phenotypically significantly higher tumor aggressiveness and proliferative activity than invasive ductal carcinoma without a fibrotic focus, with overexpression of c-erb-2 protein, nuclear accumulation of p53, high proliferative cell nuclear antigen index, aneuploidy, and high tumor angiogenesis [1 8, 11, 12]. The fibrotic focus has been shown to be a useful parameter for predicting tumor recurrence, early tumor death, and initial metastasis to distant organs the lung and brain, in particular [2, 3, 5, 7 9]. In addition, the presence of fibrotic focus, in combination with strand growth pattern of invasive ductal carcinoma, has been shown to be a significant histopathologic factor associated with initial bony metastases [13]. In fact, Hasebe et al. [12] proposed a new histologic prognostic JR:185, ugust

3 classification scheme for invasive ductal carcinoma that incorporates the presence of fibrotic focus for a more sensitive and specific prediction of patient outcome. olpaert et al. [14] also described the presence of fibrotic focus in the primary tumor to be an independent prognostic factor for early distant relapse in lymph node negative breast cancers. However, in addition to invasive ductal carcinoma, olpaert and colleagues also included invasive lobular carcinoma and special types of invasive ductal carcinoma. They subsequently showed fibrotic focus to be a marker of intratumoral hypoxia that promotes angiogenesis, thereby rendering fibrotic focus a marker for increased angiogenesis. This may, in turn, allow tumors to reach their full metastatic potential [15, 16]. Histologically, a fibrotic focus is a mixture of fibroblasts and collagen fibers that can occupy varying amounts of the volume of an invasive ductal carcinoma [3]. The fibrous bands expand radially into the surrounding tumor and resemble the appearance of a scar. The fibrotic focus is always surrounded by a highly cellular zone of infiltrating ductal carcinoma cells that occupy varying percentages of the tumor area (Fig. 4). Eighteen (75%) of the 24 lesions studied sonographically showed focal internal increased echogenicity on sonography. However, six (25%) of 24 did not. We hypothesize that any condition that lessens the histologic Fig. 2 Sonographic findings of invasive ductal carcinoma with fibrotic focus., Image in 82-year-old woman with invasive ductal carcinoma shows that echogenic fibrotic focus (arrows) is seen focally and centrally. Fibrotic focus is surrounded by the hypoechoic tumor rim., Image in 69-year-old woman with invasive ductal carcinoma shows that echogenic fibrotic focus (arrow) is seen focally and eccentrically., Image in 63-year-old woman with invasive ductal carcinoma shows echogenic fibrotic focus (arrow) in infiltrative pattern. distinction of two separate regions within the lesion specifically, the invasive tumor and the fibrotic focus will render the fibrotic focus less evident on sonography. Four possible explanations for the lack of visualization of a fibrotic focus in 25% of the cases include edema within the fibrotic focus, the presence of tumor necrosis within the fibrotic focus, evolving or small fibrotic focus with residual tumor cells present, or the size relationship between the fibrotic focus and the invasive tumor. For example, we found that only the echogenic fibrotic focus was well visualized on sonography in a lesion that showed a large fibrotic focus with a small surrounding tumor rim, whereas the hypoechoic tumor rim was not visualized on sonography. 492 JR:185, ugust 2005

4 Mammography and Sonography of Invasive Ductal arcinoma onversely, two of the six cases with fibrotic focus not visualized on sonography had a very small fibrotic focus in relation to a large invasive tumor rim. Often a combination of factors lessened the distinction between the two components. In four cases, a large amount of edema was identified within the fibrotic focus, and in three cases, two of which Fig. 3 Sonographic findings of fibrotic focus with direct correlation to fibrotic focus seen histologically. and, Sonogram () and photograph of histology specimen () in 55-year-old woman with invasive ductal carcinoma show central echogenic fibrotic focus (arrow) that is surrounded by hypoechoic tumor rim. orresponding mammographic image is shown in Figure 1. and D, Sonogram () and photograph of histology specimen (D) in 56-year-old woman with invasive ductal carcinoma show eccentric fibrotic focus. orresponding mammographic image is seen in Figure 1. also had edema, there was tumor necrosis within the fibrotic focus itself. In summary, 100% of the cases studied had imaging findings highly suspicious for malignancy. In particular, the imaging characteristic common to 75% of these lesions on sonography was the presence of focal internal increased echogenicity, that directly correlated with the fibrotic focus seen histologically. In conclusion, radiologists should be aware of the imaging characteristics of this newly described entity because of its prognostic significance. The finding of increased focal internal echogenicity on sonography preoperatively may prompt the pathologist to assess D JR:185, ugust

5 Fig. 4 Photomicrograph of histology specimen of an invasive ductal carcinoma with fibrotic focus showing the fibrotic focus composed of collagen fibers (black arrow) and fibroblasts (white arrows). for the presence or absence of a fibrotic focus at excision. References 1. Hasebe T, Tsuda H, Hirohashi S, et al. Fibrotic focus in invasive ductal carcinoma: an indicator of high tumor aggressiveness. Jpn J ancer Res 1996; 87: Hasebe T, Tsuda H, Tsubono Y, Imoto S, Mukai K. Fibrotic focus in invasive ductal carcinoma of the breast: a histopathological prognostic parameter for tumor recurrence and tumor death within three years after the initial operation. Jpn J ancer Res 1997; 88: Hasebe T, Tsuda H, Hirohashi S, et al. Fibrotic focus in infiltrating ductal carcinoma of the breast: a significant histopathological prognostic parameter for predicting the long-term survival of the patients. reast ancer Res Treat 1998; 49: Tsuda H, Takarabe T, Hasegawa T, Murata T, Hirohashi S. Myoepithelial differentiation in high-grade invasive ductal carcinomas with large central acellular zones. Hum Pathol 1999; 30: Tsuda H, Takarabe T, Hasegawa F, Fukutomi T, Hirohashi S. Large, central acellular zones indicating myoepithelial tumor differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain metastases. m J Surg Pathol 2000; 24: Jimenez RE, Wallis T, Visscher DW. entrally necrotizing carcinomas of the breast: a distinct histologic subtype with aggressive clinical behavior. m J Surg Pathol 2001; 25: Hasebe T, Sasaki S, Imoto S, Ochiai. Highly proliferative fibroblasts forming fibrotic focus govern metastasis of invasive ductal carcinoma of the breast. Mod Pathol 2001; 14: Hasebe T, Sasaki S, Imoto S, Mukai K, Yokose T, Ochiai. Prognostic significance of fibrotic focus in invasive ductal carcinoma of the breast: a prospective observational study. Mod Pathol 2002; 15: Hasebe T, Sasaki S, Imoto S, Ochiai. Proliferative activity of intratumoral fibroblasts is closely correlated with lymph node and distant organ metastases of invasive ductal carcinoma of the breast. m J Pathol 2000; 156: merican ollege of Radiology. Illustrated breast imaging and reporting data system (I-RDS), 3rd ed. Reston, V: merican ollege of Radiology, Hasebe T, Imoto S, Ogura T, Mukai K. Significance of basic fibroblast growth factor and fibroblast receptor protein expression in the formation of fibrotic focus in invasive ductal carcinoma of the breast. Jpn J ancer Res 1997; 88: Hasebe T, Mukai K, Tsuda H, Ochiai. New prognostic histological parameter of invasive ductal carcinoma of the breast: clinicopathological significance of fibrotic focus. Pathol Int 2000; 50: Koyama T, Hasebe T, Tsuda H, et al. Histological factors associated with initial bone metastasis of invasive ductal carcinoma of the breast. Jpn J ancer Res 1999; 90: olpaert, Vermeulen P, Jeuris W, et al. Early distant relapse in node-negative breast cancer patients is not predicted by occult axillary lymph node metastases, but by the features of the primary tumor. J Pathol 2001; 193: olpaert G, Vermeulen P, van eest P, et al. Intratumoral hypoxia resulting in the presence of a fibrotic focus is an independent predictor of early distant relapse in lymph node-negative breast cancer patients. Histopathology 2001; 39: olpaert G, Vermeulen P, Fox S, Harris L, Dirix LY, Van Marck E. The presence of a fibrotic focus in invasive breast carcinoma correlates with the expression of carbonic anhydrase IX and is a marker of hypoxia and poor prognosis. reast ancer Res Treat 2003; 81: JR:185, ugust 2005