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1 Department of Radiology, Division of Abdominal Imaging and Intervention,
Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston,
MA 02115.
2 Institute for Radiology, Rorschacherstrasse 95, Kantonsspital St. Gallen, St.
Gallen 9007, Switzerland.
Received June 9, 2003;
accepted after revision September 25, 2003.
Address correspondence to K. J. Mortele
(kmortele{at}partners.org).
Abstract
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MATERIALS AND METHODS. Abdominal CT scans of 200 consecutive women with breast carcinoma (mean age, 57 years; range, 33–81 years), obtained over a 7-month period, were retrospectively reviewed. Fifty-eight women had hepatic metastases. Two hundred seventy-two CT scans, including present and prior examinations (mean [± SD], 4.6 ± 2 per patient), were evaluated. The number and diameter of liver metastases at all examinations, chemotherapeutic agents used, histopathologic diagnosis of breast tumor, and tumor-receptor status were compared in patients with and without capsular retraction. Descriptive analyses of the variables and comparisons of means and proportions as well as correlations were conducted.
RESULTS. Hepatic capsular retraction was observed in 29 patients with hepatic metastases (50%). Retraction ranged from 1 to 10 mm in depth. Patients with capsular retraction had significantly larger metastases than those without retraction (p < 0.05). The associations between retraction and increase in size of the subjacent metastasis and between retraction and decrease in size were statistically significant (p < 0.05). Capsular retraction was independent of the number of hepatic metastases, histopathologic diagnosis, tumor-receptor status, and chemotherapeutic regimen.
CONCLUSION. Hepatic capsular retraction is common in patients with hepatic metastases from breast cancer and is associated with larger metastases and both increase and decrease in subjacent lesion size. It is unrelated to lesion number, histopathology, receptor status, or chemotherapeutic regimen.
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Although hepatic capsular retraction in the setting of breast carcinoma is common, to our knowledge, its prevalence is unknown. Also, we do not know whether capsular retraction is more likely to be associated with larger or smaller subjacent metastases. Finally, it is unclear whether a change in size of subjacent metastases is necessary for retraction to occur or if only a decrease in size is necessary to evoke this phenomenon. Therefore, this study was conducted to evaluate the prevalence and significance of capsular retraction in patients with breast cancer undergoing routine screening for metastases. It also investigates the associations between the presence of this morphologic pattern with size, number of lesions, change in size over time, histopathology, tumor-receptor status, and chemotherapeutic regimen.
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CT Technique
In all patients, MDCT of the abdomen (Volume Zoom, Siemens, Forchheim,
Germany) was performed 70 sec after administration of 100 mL of IV contrast
material ([iopromide] Ultravist-300, Berlex Laboratories, Madison, NJ) and 900
mL of oral barium sulfate suspension (Ready Cat, E-Z-EM, Westbury, NY),
administered 120 min before scanning. Images were obtained at 4 x 2.5 mm
collimation with a 3-mm effective slice thickness and reconstructed at 5-mm
intervals. IV contrast material was administered using a mechanical power
injector at a rate of 3 mL/sec.
Analysis of CT Images
CT images were evaluated retrospectively using PACS (picture archiving and
communication system, Impax Alliance DS3000, Agfa, Ridgefield Park, NJ), with
the radiologist unaware of clinical and pathologic information. In addition to
the number of metastases, the size of the largest and smallest individual
metastases was recorded. The number of metastases was divided into three
separate groups: a single lesion, two to 10 metastases, and greater than 10
metastases. In patients with capsular retraction, the size of the largest
subjacent metastasis was obtained. The subjacent metastasis was considered the
lesion closest to the retraction. Subsequently, the number and size were
compared before CT to evaluate the change. Measurements of the size of an
individual metastasis were obtained by measuring the largest diameter in the
anteroposterior and transverse axes with electronic calipers. Measurements of
the depth of the retraction, if present, were obtained by measuring the
greatest distance from the hepatic capsule to its expected course and
perpendicular to a line through the hepatic capsule.
Pathology and Treatment Analysis
Tumor histopathology of the primary breast cancer and the tumor-receptor
status (estrogen, progesterone, and human epithelial growth factor [type 2]
receptor) were recorded. The pathologic diagnosis of breast cancer specimens
showed intraductal carcinoma in 50 patients, intralobular carcinoma in two
patients, and metaplastic carcinoma in one patient. The histopathologic
diagnosis for five patients with metastases was not available.
The different chemotherapeutic regimens used in these patients were also recorded. The chemotherapeutic drugs used in this study included cyclophosphamide (n = 24); doxorubicin (n = 27); paclitaxel (n = 22); cyclophosphamide, methotrexate, and 5-fluorouracil (n = 9); trastuzumab (n = 19); mitomycins (n = 1); docetaxel (n = 3); liposomal doxorubicin (n = 5); vinorelbine tartrate (n = 18); gemcitabine hydrochloride (n = 2); and capecitabine (n = 10). The chemotherapeutic agents reviewed were used as both single agents and in multiple therapeutic combinations over an accumulated period of 216 months.
Correlation Analysis
Data were analyzed for associations between the presence of capsular
retraction and the size of metastases, change in size of metastases over time,
number of metastases, histopathologic type of breast carcinoma specimen,
tumor-receptor status, and chemotherapeutic regimes, using Pearson's
chi-square test.
For associations found to be statistically significant (defined as p < 0.05), we tested correlations using Spearman's nonparametric tests. Differences in tumor size by category were tested using the Mann-Whitney nonparametric test. All statistical analyses were performed using commercially available software (SPSS version 11.0, Statistical Package for the Social Sciences, Chicago, IL) for Windows (Microsoft, Redmond, WA).
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Of 58 patients who had metastases, 34 (59%) had more than 10 metastases; 17 (29%) had two to 10 metastases; and seven (12%) had a single metastasis. We did not observe a correlation between the presence of hepatic capsular retraction and lesion number (p > 0.05).
The mean size in the axial plane of the single largest and the single smallest metastases associated with capsular retraction was compared with the single largest and single smallest metastases in those patients without capsular retraction. The mean size of the largest and smallest metastases associated with capsular retraction was 2,559 cm2 (standard error [SE] = 590) and 50 cm2 (SE = 10), respectively. The mean size of individual largest and smallest metastases associated with no capsular retraction was 1,333 cm2 (SE = 297) and 41 cm2 (SE = 7), respectively. The size of the largest metastasis in patients with capsular retraction was significantly larger than the size of the largest metastasis in patients without capsular retraction (p < 0.05). There was no significant (p > 0.05) difference in the size of the smallest metastasis between the patients with and without retraction.
In 29 patients with capsular retraction, change in size of subjacent
metastasis was noted in 18 patients when compared with prior CT findings
(Fig. 1). Of these, eight were
associated with reduction in size of the subjacent metastasis (Fig.
2A,
2B). In 10 patients with
capsular retraction, retraction was associated with an increase in the size of
the subjacent metastasis (Fig.
3A,
3B). When testing the
significant associations for correlation, we observed a moderately strong
correlation between capsular retraction and decrease in size (
= 0.46,
p < 0.05). The correlation between retraction and increase in size
of the subjacent metastasis was weaker ( = 0.32), but statistically
significant (p < 0.05).
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In the 29 patients without capsular retraction, 23 did not have a change in the size of their metastases; one patient showed a decrease in size, whereas five patients had an increase in size.
Histopathologic and Treatment Evaluation
No statistically significant correlation was found between the type of
breast cancer and the presence of capsular retraction (p > 0.05).
Table 1 shows tumor-receptor
expression in breast cancer patients with and without hepatic capsular
retraction. No significant correlation between tumor-receptor expression and
capsular retraction was found. Similarly, no significant correlation between
type of chemotherapy and capsular retraction was found.
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Identifying metastases as the cause of hepatic capsular retraction is usually based on a combination of clinical history and radiologic findings. CT allows recognition and evaluation of capsular retraction, a morphologic pattern characterized by focal flattening or concavity of the normal convex hepatic contour that occurs at the site of a subjacent metastasis. Hepatic metastases from breast carcinoma are usually multiple, variable in size, hypovascular, and most commonly hypoattenuating to normal hepatic parenchyma on both unenhanced and contrast-enhanced CT [1, 15, 16].
Although capsular retraction associated with hepatic metastases has been shown in patients with breast carcinoma treated with systemic chemotherapy [3], the importance of the actual size or change in size of the subjacent metastatic lesion has been given little attention in the literature. Furthermore, to the best of our knowledge, capsular retraction associated with an increase in lesion size has not been shown to date. Lack of direct histologic correlation of capsular retraction with both increase and decrease in subjacent lesion size is a limitation of this study and warrants further evaluation. However, potential explanations are proposed.
In patients in whom metastases are shrinking, capsular retraction may be explained by scarring of treated tumor tissue. In some patients with metastases associated with treated breast carcinoma, the imaging characteristics are similar to those of cirrhosis (i.e., pseudocirrhosis) [3, 17]. Pathologic findings suggest nodular regenerative hyperplasia as a possible cause [3], with areas of retracted tumor tissue and scarring delineating areas of regeneration, similar to those in macronodular cirrhosis. This mechanism, however, does not explain why, as shown in our study, larger metastases are more likely to be associated with hepatic capsular retraction than smaller metastases and how an increase in the size of a subjacent metastasis can also result in capsular retraction. There are reports in the literature of a cirrhotic-appearing liver in the setting of untreated diffuse metastases from breast carcinoma [6, 18]. It is differentiated from a pseudocirrhotic-appearing liver due to metastases associated with treated breast carcinoma in that the intervening liver tissue between fibrous bands is associated with substantial disruption of the normal hepatic architecture. The cirrhotic appearance is caused by dense areas of fibrosis and tumor infiltration, with little recognizable normal liver parenchyma [17, 18]. It would therefore seem possible that growth of a lesion could likewise result in a localized distortion of the normal lobular pattern and focal replacement by fibrous tissue, thereby resulting in capsular retraction.
Chemotherapeutic agents induce hepatotoxic effects [19] because hepatocytes biotransform chemotherapeutic agents into free radicals through biochemical oxidation-reduction reactions in the cytochrome P-450 system. The free radicals that result are thought to impair cell membrane function. One of the agents most closely associated with this chemical behavior is methotrexate [19–21]. However, no difference in prevalence of hepatic capsular retraction was shown in our study between patients who received this drug and those who received other drugs.
There has been much interest in the evaluation of tumor-receptor expression of the breast primary tumor and that of metastases and survival after recurrence. The estrogen-receptor status of the primary tumor appears to be more important for prognosis than the estrogen-receptor status of bone and hepatic metastases [22]. It has also been shown that patients with estrogen-receptor-positive primary tumors have significantly more recurrences in bone, whereas estrogen-receptor-negative tumors recur more often in the liver [22]. In our study, the number of patients with hepatic metastases whose initial breast tumor had estrogen-receptor-positive status was similar to that of patients with a negative-receptor status. In addition, no significant difference in capsular retraction was found between those whose initial tumor showed estrogen-receptor-positive status and those whose tumors did not. The hypothesis that tumor cell clones with different estrogen-receptor content are selected and adapted to grow in various anatomic sites [22] is not supported by this study because tumors with different receptor content manifested similar radiographic features.
Although it is possible that certain pathologic types of hepatic metastases from breast cancer contain a considerable amount of fibrous tissue, a review of the literature does not show a clear association between certain breast metastases and amount of fibrous tissue and stroma. However, an association between some metastatic breast cancer–derived cell lines and tumor fibrosis may be present at a more biochemical level. For example, an extracellular matrix-modulating enzyme, lysyl oxidase–related protein-1, highly expressed in breast cancer–derived cell lines, has been shown to induce a high concentration of dense collagen fibers and fibrotic foci [23]. It is not yet clear if an association between certain breast cancer metastases and extracellular matrix-modulating enzymes exists.
In conclusion, hepatic capsular retraction in patients with breast carcinoma with hepatic metastases is a morphologic pattern that is predominantly associated with larger metastases and with a change in size (both an increase and a decrease) of the subjacent metastasis over time. This study, therefore, proposes that capsular retraction induced by subjacent lesion change is not simply a reflection of posttreatment reduction in size. It raises the hypothesis that localized distortion of the normal lobular hepatic pattern, either due to tumor growth or fibrosis, may be a possible explanation. Capsular retraction is independent of the number of hepatic metastases, histopathologic diagnosis, tumor-receptor status, and chemotherapeutic regimen.
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