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Invasive Micropapillary Carcinoma of the Breast: Mammographic, Sonographic, and MRI Features

¹ Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1350, Houston, TX 77030.
² Department of Surgical Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.

Received July 14, 2008; accepted after revision January 9, 2009.

 
Presented at the 2008 annual meeting of the American Roentgen Ray Society, Washington, DC.

Address correspondence to W. T. Yang (wyang{at}mdanderson.org).

WEB This is a Web exclusive article.

Abstract

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OBJECTIVE. The purpose of this study was to describe the clinical, imaging, and histopathologic findings of invasive micropapillary carcinoma of the breast.

CONCLUSION. The imaging characteristics of invasive micropapillary carcinoma are highly suggestive of malignancy. The lesion is a high-density irregular mass with indistinct margins associated with microcalcifications on mammograms; a solid irregular hypoechoic mass with indistinct margins and frequent axillary nodal involvement on sonograms; and a multifocal mass on MR images. This tumor may necessitate aggressive management.

Keywords: breast • carcinoma • mammography • micropapillary • MRI • neoplasm • pathology • prognosis • sonography

Introduction

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Invasive micropapillary carcinoma is a rare, clinically aggressive variant of invasive ductal cancer that accounts for 0.7-3% of all cases of breast cancer [1-3]. It has only recently been recognized as a morphologically distinct entity. This tumor is a unique entity characterized by tubuloalveolar or pseudopapillary structures lacking a fibrovascular core and surrounded by clear, empty spaces [1-6] that mimic lymphovascular invasion but are a result of retraction artifact. Nevertheless, invasive micropapillary carcinoma expresses marked lymphotropism, extensive axillary lymph node involvement, and frequent local recurrence [3, 7-9]. Knowledge of the radiologic features of this entity would be useful in alerting breast imagers to this possible diagnosis; however, there is scant information in the medical literature describing this topic [9-11]. We therefore retrospectively evaluated the imaging, clinical, and histopathologic findings of invasive micropapillary carcinoma in patients who underwent mammography, sonography, and MRI of the breast.

Materials and Methods

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Study Population
A surgical pathology database at a single institution was searched to identify the cases of patients who received a diagnosis of invasive micropapillary carcinoma from January 1999 to December 2007 and who had undergone preoperative imaging with mammography, sonography, or MRI. Of 80 patients with invasive micropapillary carcinoma referred to this institution, 28 had images available for review, and a total of 29 tumors were identified. A waiver of informed consent was obtained, and the institutional review board approved this HIPAA-compliant study.

Mammography
Standard two-view mammography was performed with one of two units (Lorad M3, Hologic; DMR, GE Healthcare). Additional views were acquired as deemed necessary. The mammographically detected lesions were reviewed according to the American College of Radiology BI-RADS mammography lexicon [12], which describes the presence and location of masses; the presence, morphologic characteristics, and distribution of calcifications; the shape, margin, and density of masses; and associated findings, such as skin, nipple, or pectoralis muscle involvement and associated axillary adenopathy.

Sonography
Real-time gray-scale and color Doppler sonography was performed with an Elegra unit (Siemens Healthcare) with a 13- to 5-MHz linear array transducer or an ATL Ultramark 9 unit (Philips Healthcare) with a 10- to 5-MHz linear array transducer. The gray-scale parameters assessed included presence and type of lesion (solid, complex cystic, or architectural distortion) and the shape, margin features, posterior acoustic phenomena, echogenicity, vascularity, and surrounding tissue features of the lesion (e.g., skin, nipple, or pectoralis muscle involvement and ductal extension). Lesions were classified according to the BI-RADS ultrasound lexicon [13]. In addition, the sonographic status of regional nodal basins, including the axillary, internal mammary, and supraclavicular regions, was included, according to previously published criteria [14, 15].

View larger version (172K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A —34-year-old woman with swelling of left breast. Final pathologic result was invasive micropapillary carcinoma and associated ductal carcinoma in situ, micropapillary and cribriform types associated with calcifications. Lateromedial magnification mammogram of left breast shows heterogeneous calcifications (arrows). White circle is nipple marker.

View larger version (58K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B —34-year-old woman with swelling of left breast. Final pathologic result was invasive micropapillary carcinoma and associated ductal carcinoma in situ, micropapillary and cribriform types associated with calcifications. Extended-field-of-view sonogram shows multiple solid hypoechoic masses (arrowheads) in superior aspect of left breast.

Histopathologic Assessment
A text search for "invasive micropapillary" was performed on the institution's surgical pathology database. All pathology reports retrieved were re viewed by a breast pathologist with 9 years' experience. The pathologic specimens reviewed included total mastectomy, segmental mastectomy, and core biopsy specimens. Cases with only invasive micropapillary features or only component of invasive micropapillary carcinoma were excluded. In all cases in the database, at least representative histologic sections of tumor were reviewed at our institution, where breast pathologists have reviewed all cases of breast cancer since 1999. Information retrieved from the pathology reports, medical records, or both included the presence of associated ductal carcinoma in situ (DCIS), lymphovascular invasion, axillary lymph node status, and hormone receptor and HER2 status.

Results

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Clinical Findings
The study sample included 28 patients: 27 women and one man. One woman had bilateral invasive micropapillary carcinoma, so a total of 29 tumors were evaluated. The median patient age was 56 years (range, 28-76 years). The initial manifestation was a palpable mass in 17 of the 28 patients (61%) and a screening mammographic abnormality in the other 11 (39%). Associated skin retraction was found in one of the 17 patients with palpable masses (6%), nipple retraction in one (6%), and erythema in three (18%). The left breast was involved in 20 of the 28 patients (71%), the right breast in seven (25%), and both breasts in one (3%).

Imaging Findings
Mammography—All patients underwent mammography. A mass with microcalcifications was visible in the cases of 13 of the 29 tumors (45%) (Figs. 1A, and 1B), a mass only in seven (24%) (Figs. 2A, 2B, and 2C), microcalcifications only in five (17%) (Figs. 3A, 3B, and 3C), focal asymmetry with microcalcifications in one case (3%), density in one (3%), and architectural distortion in one (3%). The tumor was mammographically occult in one patient (3%). These findings are presented in Table 1. Table 2 shows the tumor size measurements obtained with mammography, sonography, and MRI. Of the 20 masses detected with mammography, 13 (65%) were localized in the outer upper quadrant. The predominant features were irregular shape of 16 of 20 tumors (80%), spiculated margins of 11 (55%), and high density of 17 (85%).

View larger version (182K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2A —71-year-old woman with asymptomatic screening-detected abnormality. Final pathologic result was invasive micropapillary carcinoma. Craniocaudal spot compression mammogram of left breast shows regular high-density mass with spiculated margins (arrow).

View larger version (183K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2B —71-year-old woman with asymptomatic screening-detected abnormality. Final pathologic result was invasive micropapillary carcinoma. Gray-scale longitudinal sonogram of left breast shows irregular solid hypoechoic mass with angular margins (arrows).

View larger version (199K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2C —71-year-old woman with asymptomatic screening-detected abnormality. Final pathologic result was invasive micropapillary carcinoma. Photomicrograph shows typical histomorphologic findings of invasive micropapillary carcinoma. Micropapillary clusters of tumor cells surrounded by spaces represent retraction artifact (arrow).

View larger version (131K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3A —38-year-old woman with palpable mass in left breast. Final pathologic result was invasive micropapillary carcinoma with associated ductal carcinoma in situ. Lateromedial magnification mammogram of left breast shows segmental fine linear branching (white arrow) and grouped coarse heterogeneous calcifications (black arrows).

View larger version (155K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3B —38-year-old woman with palpable mass in left breast. Final pathologic result was invasive micropapillary carcinoma with associated ductal carcinoma in situ. Transverse gray-scale sonogram shows multiple solid irregular hypoechoic masses (arrows) with indistinct margins.

View larger version (147K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3C —38-year-old woman with palpable mass in left breast. Final pathologic result was invasive micropapillary carcinoma with associated ductal carcinoma in situ. Longitudinal gray-scale sonogram of left axilla shows solid oval hypoechoic lymph node (arrows) without echogenic hilus. Result of ultrasound-guided fine-needle aspiration biopsy was metastatic carcinoma.

Microcalcifications were present in a total of 19 tumors. The most common morphologic feature was pleomorphism (11 of 19 tumors, 57%), and the most common distribution was clustered or grouped (12 of 19 tumors, 63%). Of the five patients in whom microcalcifications were the only finding, sonography showed no evidence of invasive micropapillary carcinoma in three patients and multiple masses in one patient. The fifth patient did not undergo sonography.

Sonography—Sonography was performed on 27 tumors. A mass was visible in 23 (85%) cases (Figs. 1A, 1B, 2A, 2B, 2C, 3A, 3B, 3C, 4A, and 4B) and architectural distortion in one (4%) case. Sonography did not depict invasive micropapillary carcinoma in three cases (11%). The sonographic features of masses are presented in Table 1. Sonography also helped to determine the extent of disease. Of the 23 masses, eight (35%) were multifocal, and one (4%) was multicentric.

View larger version (52K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4A —61-year-old woman with palpable left breast mass. Final pathologic result was invasive micropapillary carcinoma. Mammogram (not shown) depicted heterogeneously dense breast without suspicious findings. Sagittal dynamic contrast-enhanced T1-weighted subtraction MR image of left breast shows multiple areas of clumped ductal enhancement (arrows) with multicentric involvement.

View larger version (19K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4B —61-year-old woman with palpable left breast mass. Final pathologic result was invasive micropapillary carcinoma. Mammogram (not shown) depicted heterogeneously dense breast without suspicious findings. Kinetic analysis of A shows rapid initial enhancement and plateau curve.

MRI—MRI was performed on four patients (five tumors, one patient having bilateral breast cancer) who had equivocal findings at mammography and sonography. Four enhancing masses were present in three patients, and nonmasslike enhancement was found in two patients (Figs. 4A, and 4B). The most common features of masses were irregular shape and spiculated margins (Figs. 5A, 5B, and 5C). One of the tumors with nonmasslike enhancement had diffuse clumped enhancement (Figs. 4A, and 4B) and the other had diffuse stippled enhancement. The kinetics of all lesions suggested the presence of malignancy with a rapid initial increase and washout or plateau on dynamic contrast-enhanced studies (Figs. 4A, 4B, 5A, 5B, and 5C).

View larger version (78K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5A —58-year-old woman with palpable mass in lower inner quadrant of left breast. Final pathologic result was invasive micropapillary carcinoma. Mammogram (not shown) depicted heterogeneously dense breast without suspicious findings. Axial contrast-enhanced T1-weighted fat-suppressed MR image of left breast shows palpable irregular enhancing mass (short arrow) with spiculated margins in posterior aspect of breast and second enhancing mass (long arrow) in subareolar position.

View larger version (100K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5B —58-year-old woman with palpable mass in lower inner quadrant of left breast. Final pathologic result was invasive micropapillary carcinoma. Mammogram (not shown) depicted heterogeneously dense breast without suspicious findings. Sagittal dynamic contrast-enhanced T1-weighted subtraction MR image of right breast shows small enhancing mass (arrow, B) with rapid initial enhancement and washout kinetics (C).

View larger version (13K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 5C —58-year-old woman with palpable mass in lower inner quadrant of left breast. Final pathologic result was invasive micropapillary carcinoma. Mammogram (not shown) depicted heterogeneously dense breast without suspicious findings. Sagittal dynamic contrast-enhanced T1-weighted subtraction MR image of right breast shows small enhancing mass (arrow, B) with rapid initial enhancement and washout kinetics (C).

Treatment and Histologic Findings
All 28 patients underwent surgery. Modified radical mastectomy was performed on 20 patients (one patient underwent bilateral mastectomy for bilateral cancer), and eight patients underwent breast conservation surgery. Of the 29 tumor specimens, 15 were obtained at total mastectomy, seven at segmental mastectomy, and seven at core needle biopsy. Lymphovascular invasion was found in 16 of 29 (55%) tumors, and 11 of the 16 (69%) had lymph node metastasis. Ten tumors were subjected to sentinel lymph node biopsy, 14 to axillary nodal dissection, and five to both sentinel lymph node biopsy and axillary nodal dissection. Axillary nodal metastasis was identified in the cases of 18 of 29 (62%) tumors.

An intraductal component was found in 26 of the 28 patients (93%). These tumors were usually of mixed histologic type with cribriform, solid, and micropapillary patterns. Immunohistochemical studies showed estrogen receptor expression in 23 patients (82%), progesterone receptor in 17 (61%), and HER2 overexpression in 12 patients (43%).

Discussion

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Invasive micropapillary carcinoma is an uncommon tumor that has more aggressive clinical behavior than invasive ductal carcinoma, not otherwise specified, with a high degree of lymph node involvement [1-7]. This entity has only recently been characterized as distinct from carcinomas with micropapillary features [1-7]. The most common clinical manifestation of invasive micropapillary carcinoma in our study was a palpable mass (17 of 28 patients, 61%); however, in a large number of patients (11 of 28, 39%) the masses were detected at screening mammography. The most common clinical finding in a study by Günhan-Bilgen et al. [11] was a palpable mass (94% of tumors). The left breast was affected more frequently in our study (19 of 28 patients, 68%) than was the right breast. This finding is similar to results presented by Kim et al. [8], who found the left breast affected in 60% of patients (23 of 38).

Invasive micropapillary carcinoma is characterized on H and E-stained slides by small clusters of tumor cells with inverse polarity, surrounding clear spaces resembling lymphovascular channels, and a high nuclear grade. The aggressiveness of invasive micropapillary carcinoma is presumed to be related to lymphotropism and the inverse polarity of the tumor cell clusters [2]. In most cases, massive axillary lymph node metastasis is present at diagnosis [7-9]. Sonography depicted 72% of lesions of metastatic axillary lymphadenopathy in our study and can therefore play an important role in identification and confirmation of the presence of metastatic lymph node disease. Lymphatic vessel invasion is an independent adverse prognostic factor and a marker of lymph node metastasis [7-9]. Zekioglu et al. [9] found lymphatic vessel invasion in 75% of cases, in 82% of which lymph node metastasis was present. In our series, lymphatic vessel invasion was found in 55% of the tumors. Of these, 69% also had lymph node metastasis. Axillary lymph node dissection was performed for 66% (19/29) of the tumors. Nodal positivity was present in 62%. This finding is concordant with those of Zekioglu et al., who reported a 69% incidence of positive lymph nodes.

Invasive micropapillary carcinoma has some pathologic features different from those of typical invasive carcinoma. It has a poor prognosis, such as a high incidence of estrogen (82%) and progesterone (60%) receptor positivity in our study. This finding is similar to the results of Walsh and Bleiweiss [7], who found high rates of positivity for estrogen and progesterone receptors (90% and 70%, respectively). Hormone receptor positivity is typically found in better-differentiated tumors, which have a better prognosis. We also found a high percentage of ERRB2 (formerly HER2 or HER2/neu) overexpression (43%), which is similar to the finding by Walsh and Bleiweiss, who reported ERRB2 positivity in 60% of cases. We found that most cases of associated DCIS had a mixture of cribriform, solid, and micropapillary patterns. In the study by Walsh and Bleiweiss, the most frequent intraductal component was micropapillary.

The imaging characteristics of invasive micropapillary carcinoma are highly suggestive of malignancy. These tumors typically appear as a high-density irregular mass with spiculated margins that is often associated with microcalcifications. These findings are comparable with those of Günhan-Bilgen et al. [11]. Microcalcifications with and without an associated mass or focal asymmetry were found in 66% of the tumors in our study, in contrast to 43% in the study by Günhan-Bilgen et al. These microcalcifications were likely representative of an associated DCIS component. The most common sonographic feature in our study was an irregularly shaped solid hypoechoic mass with indistinct margins, concordant with the findings reported by Günhan-Bilgen et al. Posterior acoustic shadowing or enhancement and hypervascularity were not distinctive findings of this tumor.

To our knowledge, only one case report [10] has described the MRI findings of invasive micropapillary carcinoma as a homogeneously hypointense mass on T1-weighted images and a heterogeneously hyperintense mass on T2-weighted images. The margins were irregular and enhancement was patchy. Those authors did not describe the enhancement kinetics. Although our number of cases was small, we consider MRI an important diagnostic tool for this variant of breast cancer, specifically for defining disease extent and multifocality in all four patients. In one case, MRI depicted a tumor in the contralateral breast that was mammographically occult. This finding supported a change in staging and subsequent management.

A limitation of this study was the small sample size, which reflects the rarity of this uncommon but aggressive tumor. A second limitation was the retrospective nature of the study, in which not all patients underwent imaging of the tumors with all three techniques. Many of the tumors, however, were diagnosed during a period in which MRI was not a widely used preoperative imaging tool.

The imaging characteristics of invasive micropapillary carcinoma are highly suggestive of malignancy. Mammography typically shows a high-density irregular mass with spiculated margins that is often associated with microcalcifications. The sonographic appearance is frequently a solid hypoechoic mass that is irregular in shape with indistinct margins without posterior acoustic enhancement or shadowing. Invasive micropapillary carcinoma has a high incidence of regional lymph node involvement. Therefore, a meticulous sonographic study should aid in assessment for nodal involvement, which necessitates aggressive management. MRI is a useful preoperative tool for defining tumor extent and excluding multifocality, the presence of which influences surgical planning.

References

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