Wo m e n ’s I m a g i n g • O r i g i n a l R e s e a r c h Park et al. Neuroendocrine Carcinoma of the Breast
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Women’s Imaging Original Research
Primary Neuroendocrine Carcinoma of the Breast: Clinical, Imaging, and Histologic Features Young Mi Park1,2 Yun Wu 3 Wei Wei 4 Wei Tse Yang1 Park YM, Wu Y, Wei W, Yang WT
Keywords: breast, mammography, MRI, neuroendocrine carcinoma, sonography
OBJECTIVE. The purpose of this study was to evaluate the clinical, imaging, and histopathologic findings of primary neuroendocrine carcinoma of the breast. MATERIALS AND METHODS. A pathology database was searched for the records of patients with a histopathologic diagnosis of primary neuroendocrine carcinoma of the breast who had undergone mammography, sonography, or MRI between 1984 and 2011. The imaging studies of eligible patients were retrospectively reviewed according to the BI-RADS lexicon, and clinical presentation and histopathologic characteristics were documented. Imaging characteristics were compared with historical controls of invasive mammary carcinoma. RESULTS. Eighty-seven patients (84 women, three men; mean age, 62.9 years; range, 28– 89 years) were included in the study. The mean tumor size was 3.1 cm (range, 0.6–11 cm). Sixtyfive of 84 (77.4%) cancers were estrogen and progesterone receptor positive and ERBB2 negative. A palpable mass (55.8%) was a common clinical manifestation. A high-density, round or oval, or lobular mass with nonspiculated margins on mammograms and an irregular (65.4%), hypoechoic (78.4%) mass, with indistinct margins (43.5%), no or enhanced posterior acoustic features (77.9%) on sonograms were common findings. MRI revealed an irregular mass (83.3%), irregular margins (63.6%), and washout kinetics (85.7%). Neuroendocrine carcinoma presented more frequently as masses on mammograms. Calcifications were infrequent compared with their occurrence in invasive mammary cancer. CONCLUSION. Primary neuroendocrine carcinoma of the breast has mammographic features that differ from those of invasive mammary carcinoma. A round, oval, or lobular mass with nonspiculated margins, positive estrogen and progesterone receptor results, and negative ERBB2 results should raise suspicion of primary neuroendocrine carcinoma.
DOI:10.2214/AJR.13.10749 Received February 13, 2013; accepted after revision December 5, 2013. 1 Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Unit 1350, 1515 Holcombe Blvd, Houston, TX 77030. Address correspondence to W. T. Yang ([email protected]). 2
Department of Radiology, Busan Paik Hospital, Inje University, Busan, Korea.
3 Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX. 4 Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
WEB This is a web exclusive article. AJR 2014; 203:W221–W230 0361–803X/14/2032–W221 © American Roentgen Ray Society
P
rimary neuroendocrine carcinoma (NEC) of the breast, an uncommon type of breast carcinoma that exhibits histopathologic and immunohistochemical evidence of neuroendocrine differentiation, accounts for 2–5% of breast carcinomas, according to the World Health Organization (WHO) [1]. NEC derives from neuroendocrine cells that are present throughout the body and arises most commonly in the bronchopulmonary system and gastrointestinal tract. Immunohistochemical staining for specific neuroendocrine markers, including synaptophysin and chromogranin, is the current standard for confirming neuroendocrine differentiation. In 2003, the WHO histologic classification of tumors of the breast and female genital organs recognized primary NEC of the breast as a distinct entity and added it to the catego-
ry of neuroendocrine tumors [1]. The WHO classification defines mammary NEC as the expression of one or more neuroendocrine markers in more than 50% of tumor cells. Neuroendocrine tumors include solid NEC, atypical carcinoid tumors, small cell or oat cell carcinoma, and large cell NEC. The biologic behavior and most effective treatment of primary NEC of the breast have not been well established. There have been several studies on the new WHO criteria of NEC [2–7]. Several publications have described the histologic features and prognostic factors of primary NECs of the breast that met WHO classification criteria [8–10]. Those studies showed that primary NEC of the breast is a unique clinicopathologic entity and has a poor clinical outcome compared with invasive ductal carcinoma (IDC) not otherwise specified with similar
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Park et al. pathologic stage [8]. Other investigators [11] have reported that NEC of the breast has a molecular profile distinct from that of IDC not otherwise specified. Histologically, NEC of the breast is underrecognized in routine practice. In a previous study [10], the correct diagnosis was initially rendered in fewer than one third of cases. Because staining of neuroendocrine markers is not routinely performed on invasive breast carcinomas, morphologic clues suggestive of NEC must be recognized to prompt immunohistochemical confirmation for appropriate classification. Therefore, knowledge of the imaging features of this entity will be helpful in ensuring the correct diagnosis. We conducted this retrospective review to identify mammographic, sonographic, and MRI characteristics and clinical and histologic features in patients with primary NEC of the breast. Materials and Methods Patient Selection and Data Collection A search was performed of the breast medical oncology and pathology databases of our comprehensive cancer center for the records of patients with the diagnosis of primary NEC of the breast between January 1984 and June 2011. Our institution is a tertiary referral center for patients undergoing screening mammography, diagnostic mammographic workup, and surgical, medical, and radiation therapy for breast cancer. Only patients who had available images from mammographic, sonographic, or MRI examinations at the time of diagnosis that had been acquired at our institution or an outside institution were included in our study. Our institutional review board approved this retrospective data collection and analysis and provided a waiver of the requirement for informed consent. The following data were obtained from medical charts: age, sex, laterality, initial presenting signs, and family or personal history of breast cancer. All images and accompanying radiology reports were retrospectively reviewed by two breast radiologists (9 and 16 years of experience) using BIRADS [12–14].
Mammography Standard two-view mammography (craniocaudal and mediolateral oblique) had been performed with additional views as necessary with a Lorad M3 (Hologic) mammography unit, DMR series unit (GE Healthcare), or Lorad Selenia digital technique (Hologic). Mammograms were retrospectively reviewed for breast density, mass, calcification, architectural distortion, and
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focal asymmetry. Breast density was graded as mainly fatty, scattered fibroglandular, and heterogeneously or extremely dense. Masses were reviewed for shape, margin, and density. The morphologic features and distribution of calcifications were recorded. The location and maximum size of the lesion were also recorded. Multifocality was defined as the presence of two or more foci of disease in the same quadrant of the breast. Multicentricity was defined as the presence of disease in multiple quadrants of the breast. In cases of multifocality or multicentricity, the largest lesion was analyzed.
Sonography Breast ultrasound at our institution was performed by technologists using a 13–7-MHz or 10–5-MHz linear-array transducer (Elegra, Siemens Healthcare; Acuson Antares, Siemens Healthcare; or ATL Ultramark 9, Philips Healthcare) with review by one of 13 breast imaging radiologists (all with 5–20 years of experience in breast ultrasound). Sonograms were reviewed for lesion characteristics such as shape, margins, echogenicity, orientation, posterior acoustic features, lesion boundaries, and vascularity. Multifocality, multicentricity, and size were determined as for mammography.
MRI Breast MRI had been performed for 15 patients. MRI examinations at our institution were performed with patients lying prone in a 1.5-T system (Signa Excite, GE Healthcare) with a dedicated seven-channel breast coil (BBC-127, Invivo). Image sequences included unenhanced bilateral axial T1-weighted spin-echo imaging (TR/TE, 500/12); sagittal fat-suppressed T2-weighted fast spin-echo imaging (TR/TE, 6000/85) followed by 3D fat-suppressed fastspoiled gradient-echo imaging (TR/TE, 18/4; flip angle, 15°; bandwidth, 50 kHz) once before and three times after patients were given an IV bolus injection of gadopentetate dimeglumine (0.2 mmol/kg body weight; Magnevist, Bayer Schering Pharma) at 3 mL/s with a Spectris injector (Medrad); and delayed contrast-enhanced axial T1-weighted 3D fat-suppressed fastspoiled gradient-echo imaging. The FOV was 160–220 mm, and the matrix size was 256 × 256 pixels. Subtraction images were also reviewed. Commercially available MRI computer-assisted diagnosis software with color-coded time-intensity mapping (DynaCAD, Invivo) was used for time-intensity analysis. Images were reviewed for lesion type, that is, mass versus nonmass enhancement. Masses were reviewed for shape, margin, and enhancement pat-
tern. Nonmass enhancement was analyzed for lesion distribution and internal enhancement pattern. Lesion kinetics were also evaluated. The presence of skin, nipple, or pectoralis muscle involvement was also noted. Multifocality, multicentricity, and size were determined as for mammography.
Histopathologic Analysis The study population was not consecutively registered, because NEC is a rare disease that requires confirmation by immunohistochemical staining of neuroendocrine markers. Approximately two thirds of the NECs in this study were retrospectively diagnosed during case review as having the pathologic features suggestive of neuroendocrine tumors. The findings were further confirmed by immunohistochemical staining for neuroendocrine markers based on 2003 WHO diagnostic criteria [1]. Of the tumors subjected to immunohistochemical staining of neuroendocrine markers, approximately one third to one half did not have a positive stain result at immunohistochemical analysis and were not included in the study. The histopathologic features in each case were reviewed by a breast pathologist. All NEC cases were confirmed with positive results of immunohistochemical staining for synaptophysin (syn88, BioGenex Laboratories) and/or chromogranin A (PHE5, Chemicon International) in more than 50% of the invasive tumor cells. Our cases included solid NEC, atypical carcinoid tumors, and large cell NEC and excluded small cell carcinoma and low-grade solid papillary carcinoma with a predominant in situ component. The following pathologic parameters were recorded: estrogen receptor (ER), progesterone receptor (PR), and ERBB2 (formerly HER2 or HER2/neu) status; modified Black nuclear grade; histologic type; and axillary node status.
Statistical Analysis Summary statistics of lesion characteristics were tabulated by frequency and percentage. Comparisons of ultrasound and mammographic features between primary NEC and historical controls of invasive mammary carcinoma and molecular subtype (when available) were performed by Fisher exact test. No adjustment was made for multiple testing because of the exploratory nature of this study. All tests were two-sided, and p 0.99
> 0.99
0.53
0.77
Unknown
2
p Lesion boundary Abrupt interface
52 (70.3)
86 (72)
63
50 (64)
40 (91)
153 (78)
Echogenic halo
22 (29.7)
34 (28)
12
28 (36)
4 (9)
44 (22)
0.87
0.053
0.49
0.01
0.21
Unknown p
19
Note—Numbers in parentheses are percentages. ER = estrogen receptor, PR = progesterone receptor.
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Neuroendocrine Carcinoma of the Breast
A
B
C
D
Fig. 1—78-year-old woman with palpable left breast mass. A, Left mediolateral magnification mammogram shows hyperdense lobular mass (arrow) with indistinct margins in lower center. B, Transverse ultrasound image shows 3-cm irregular hypoechoic mass (arrows) with indistinct margins in lower central left breast. C, Power Doppler sonogram shows penetrating and peripheral increased vascular signal in mass. Ultrasound-guided biopsy and histologic analysis confirmed primary neuroendocrine carcinoma. D, Histopathologic appearance of invasive neuroendocrine carcinoma of breast. Photomicrographs show nodular appearance and focal mucinous differentiation (arrow) (H and E, ×20, top left), nested growth pattern (H and E, ×40, top right), tumor cells diffusely positive for neuroendocrine marker synaptophysin (> 90%) (×40, bottom left), and tumor cells focally positive for chromogranin (~25%) (×40, bottom right).
had pain, nipple discharge, nipple retraction, skin change, palpable axillary mass, breast discomfort, or arm swelling. Twenty-six of the 86 patients (30.2%) had no symptoms. In 24 of these cases, the diagnosis was made at routine screening mammography; in one case at follow-up MRI after surgery for ipsilateral ductal carcinoma in situ (DCIS); and in one at CT of the abdomen for evaluation of metastatic liver disease. Fifteen of 85 (17.6%) patients had a first-degree family history (mother or sister) of breast cancer.
Mammography All 87 patients had undergone mammography. NEC was visible on 82 of the 87 (94.3%) mammograms and occult on five (5.7%). All mammographically occult cancers were visible at sonography. The mean size of the 82 cancers was 3.1 cm (range, 0.6–11 cm; median, 2.5 cm). On mammograms the cancers most commonly appeared as a mass (68/82 [82.9%]). Calcifications were found on 23 of 87 (26.4%) mammograms; were associated with 14 masses, three focal asymmetries, and two architectural distortions; and were the only finding in
four cases. Of the 68 masses, two had an unknown shape. Of the other 66, 46 (69.7%) were round, oval, or lobular (Fig. 1), and 20 (30.3%) were irregular. Fifty-three of the 68 (77.9%) masses had circumscribed, obscured, indistinct, or m icrolobulated margins; 15 (22.1%) had spiculated margins (Table 1). Sonography Of the 80 patients whose sonograms were available, 79 (98.8%) had tumors that were visible at sonography. The other patient had a tumor that could not be discriminated
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Park et al. from numerous cystic and hypoechoic nodules throughout the breast. The mean size of the 79 lesions at sonography was 2.5 cm (range, 0.6–8.6 cm; median, 1.9 cm). The lesions were most commonly irregular masses (51/78 [65.4%]), hypoechoic (62/79 [78.4%]), or indistinctly marginated (34/78 [43.6%]) and had no or enhanced posterior acoustic features (60/77 [77.9%]). In 68 patients with NEC who underwent color or power Doppler sonography, 59 (86.8%) masses had increased vascularity (Table 2). MRI All 15 patients with NEC who underwent breast MRI had an abnormality. Seven of the 15 (46.7%) cancers had multiple regions of enhancement. The mean size of the 15 lesions on MR images was 4.3 cm (range, 0.8–11 cm; median, 3.3 cm). Twelve of the 15 (80%) cancers exhibited mass enhancement, and three (20%), nonmass enhancement. The lesions with mass enhancement at MRI were most commonly irregular in shape (10/12 [83.3%]), had irregular margins (7/11 [63.6%], and had a rim or heterogeneous internal enhancement pattern (7/12 [58.3%]). NEC was most commonly associated with a washout pattern in time-intensity kinetics analysis (12/14, 85.7%) (Table 3). In three of seven cancers with multiple lesions at MRI, multifocality or multicentricity was identified only with MRI. One patient had a DCIS component between the NEC and the nipple that was identified only with MRI (Fig. 2). Another had a synchronous contralateral IDC that was seen only on MR images (Fig. 3). Two patients with nipple and skin invasion had findings visualized only at MRI. In one patient, the cancer was histologically confirmed after MRI-guided needle biopsy because it could not be diagnosed with confidence at mammography owing to its presentation as a subtle focal asymmetry. Six cancers were seen with all three modalities, but MRI more clearly showed the index tumor and entire disease extent than did mammography or sonography. Histopathologic Results and Treatment Diagnosis was established by results of imaging-guided core needle biopsy in 76 patients. Seventy-one of the 87 (81.6%) patients underwent biopsy with ultrasound, four (4.6%) with stereotactic, and one (1.1%) with MRI guidance. Ultrasound-guided fine-needle aspiration biopsy was performed for three (3.4%) patients and surgical biopsy for eight (9.2%).
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Sixty-five of 84 (77.4%) cancers examined for ER, PR, and ERBB2 status were ER- and PRpositive and ERBB2-negative. Most of the tumors (67/85 [78.8%]) were intermediate nuclear grade (modified Black) (Table 4). Axillary lymph node metastasis was frequently found at the time of diagnosis (39/83 [47.0%]). Pathologic stages at presentation according to the American Joint Committee on Cancer staging system, 7th edition [15], were as follows: stage I in 37 (42.5%) patients, stage II in 26 (29.9%), stage III in 13 (14.9%), and stage IV in 11 (12.6%). The most comTABLE 3: MRI Findings of 15 Patients With Primary Neuroendocrine Carcinoma of the Breast MRI Finding
No. of Patients (%)
Breast Mass enhancement
12 (80.0)
Nonmass enhancement
3 (20.0)
Mass characteristics (n = 12) Shape Irregular
10 (83.3)
Oval
1 (8.3)
Round
1 (8.3)
Margin Irregular
7 (63.6)
Spiculated
4(36.4)
Unknown
1
Internal enhancement pattern Homogeneous
5 (41.7)
Rim enhancement
4 (33.3)
Heterogeneous
3 (25.0)
Nonmass characteristics (n = 3)
TABLE 4: Histopathologic Findings Among 87 Patients with Primary Neuroendocrine Carcinoma of the Breast at Diagnosis No. of Patients
Feature Histologic subtype IDC + DCIS
35 (40.2)
IDC
25 (28.7)
IDC + mucinous differentiation
17 (19.5)
IDC + ILC
8 (9.2)
Unknown
2
TMN stage IA
37 (42.5)
IIA
13 (14.9)
IIB
13 (14.9)
IIIA
5 (5.7)
IIIB
6 (6.9)
IIIC
2 (2.3)
IV
11 (12.6)
Estrogen receptor status Positive
86 (98.9)
Negative
1 (1.1)
Progesterone receptor status Positive
67 (77.0)
Negative
19 (21.8)
Unknown
1
ERBB2 overexpression
Internal enhancement pattern Clumped
2 (66.7)
Reticular-dendritic
1 (33.3)
Distribution Segmental
1 (33.3)
Regional
1 (33.3)
Diffuse
1 (33.3)
Time-intensity kinetics Washout
12 (85.7)
Plateau
2 (14.3)
Unknown
mon distant metastatic sites in patients with stage IV disease at diagnosis were bone (n = 9) and liver (n = 5); other sites included the lungs and mediastinal lymph nodes (n = 2), brain (n = 1), adrenal gland (n = 1), and omentum (n = 1). Of the 78 patients who underwent
1
Note—Statistical analysis excluded unknown cases. Percentages in parentheses do not add up to 100 owing to rounding.
Positive
2 (2.4)
Negative
82 (97.6)
Unknown
3
Modified Black nuclear grade Well differentiated
8 (9.4)
Intermediate differentiation
67 (78.8)
Poorly differentiated
10 (11.7)
Unknown
2
Note—Statistical analysis excluded unknown cases. Numbers in parentheses are percentages and do not add to 100 in some instances owing to rounding. IDC = invasive ductal carcinoma, DCIS = ductal carcinoma in situ, ILC = invasive lobular carcinoma, ER = estrogen receptor, PR = progesterone receptor.
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Neuroendocrine Carcinoma of the Breast
A
B Fig. 2—53-year-old woman with palpable lump in left breast. A, Left mediolateral oblique mammograms shows oval isodense mass (single arrow) with obscured margins in upper outer quadrant and axillary lymphadenopathy (double arrows). B, Transverse sonogram of left breast shows circumscribed oval hypoechoic mass (arrow). Histopathologic analysis at ultrasound-guided biopsy revealed primary neuroendocrine carcinoma. A and B represent caliper-based measurements obtained of this mass. C, Sagittal dynamic contrast-enhanced MR image in early subtraction phase shows 1.5-cm rim-enhancing mass with associated postbiopsy clip (long straight arrow). Enlarged enhancing lymph nodes (curved arrow) also are evident. Approximately 2 cm anterior and inferior to index mass, nonmass ductal enhancement extends to base of nipple (short straight arrows). This was occult on mammograms and ultrasound images. Histopathologic result after MRI-guided biopsy was ductal carcinoma in situ.
C surgery for treatment, 52 underwent segmental mastectomy and 26 underwent modified radical mastectomy. Seven patients underwent conservative medical treatment only, and two patients were lost to follow-up. Comparison of the Imaging Features of Neuroendocrine Carcinoma With Historical Reports of Invasive Mammary Cancer Comparison of the imaging (ultrasound and mammography) features between primary NEC and historical controls of invasive mammary carcinoma [16–19] are detailed in Tables 1 and 2. NECs present more frequently as masses on mammograms (62%) than do invasive mammary cancers (29%, 38%, and 53% in the historical reports) [16–18]. Calcifications are an infre-
quent finding in NEC (21%) compared with invasive mammary cancers (54%, 47%, and 47%) [16–18]. The mammographic features of NEC include an oval, round, or lobular mass (70%), which is similar to findings for triple-negative breast cancer in two previously reported series (75% and 51%) [16, 18]. The margins of NEC on mammograms are infrequently spiculated (18%), a finding also similar to triple-negative breast cancer (18% and 21%) [16, 18]. At sonography, NECs are frequently masses with indistinct margins (44%), compared with invasive mammary cancers (11% and 19%) [17, 19]. The lack of posterior phenomena is a notable sonographic feature of NEC (55%) compared with invasive mammary cancer (46%, 43%, and 19%) [17–19].
Discussion Primary NEC of the breast is an uncommon neoplasm, and the biologic behavior, treatment, and prognosis are not well recognized. In our study, NEC had a high incidence of ER positivity (98.9%), PR positivity (77.0%), and ERBB2 negativity (97.6%), and tumors frequently had intermediate modified Black nuclear grade differentiation (78.8%). Hormone receptor positivity is typically associated with well-differentiated tumors, which have a better prognosis than undifferentiated tumors. A 2010 study [8] showed that NEC of the breast is an aggressive tumor with a higher tendency toward local and distant recurrence and poorer overall survival compared with a ge-, sex-, race-, tumor stage–, and ERBB2 sta-
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Park et al.
A
B
C
D
Fig. 3—68-year-old woman with right nipple discharge and nipple retraction. Histopathologic analysis at ultrasound-guided biopsy revealed primary neuroendocrine carcinoma in right breast. A, Bilateral craniocaudal mammograms show irregular high-density mass (short arrow) with spiculated margins in center of right breast. Postbiopsy clip (long arrow) in left breast represents site of previous biopsy with benign finding. B, Extended-FOV ultrasound image of right breast shows irregular hypoechoic mass (arrow) with microlobulated margins. C, Sagittal early phase dynamic contrast-enhanced subtraction MR image of right breast shows irregular mass (arrow) with irregular margins and rim enhancement. D, Sagittal early phase dynamic contrast-enhanced subtraction MR image of left breast shows nonmasslike contrast enhancement with linear distribution (arrows). Area had washout time-intensity kinetic pattern (not shown) and was occult on mammograms and sonograms. Histopathologic result after MRI-guided core biopsy was invasive ductal carcinoma.
tus–matched cases of IDC not otherwise specified. That study also showed that neuroendocrine differentiation is an adverse prognostic factor independent of ER and PR status and nuclear grade. The imaging characteristics of NEC have been described in several case reports [20– 26]. The results of those studies suggest that the mammographic findings of primary NEC of the breast differ from findings typical of invasive mammary carcinoma, which tends to have an irregular shape, spiculated margins, and associated microcalcifications. To our knowledge, ours is the largest series describing the imaging findings of primary
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NEC of the breast. In our study, NEC most commonly appeared mammographically as a high-density round, oval, or lobular noncalcified mass with nonspiculated margins (e.g., circumscribed, obscured, microlobulated, or indistinct margins). Shin et al. [27] found that mammographic findings of lesions with nonspiculated margins or hyperdense masses were associated with ER-negative breast cancer. In another study, Yang et al. [16] found that triple-receptor-negative cancers that appeared as masses were most frequently round, oval, or lobular and had indistinct margins, whereas ER-positive cancers were more frequently irregular in shape
and spiculated in margin than were triplenegative cancers. The most common sonographic feature of NEC in our study was a solid irregular hypoechoic mass with indistinct margins and no change in posterior features or posterior enhancement in 78% of tumors. Our study is interesting in that although primary NEC of the breast is most commonly ER positive (98.9%) and ERBB2 negative (97.6%), the imaging features are similar to those of ER-negative and triple-negative cancers. Primary NEC of the breast tends not to have imaging features related to hormone receptor status (ER pos-
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Neuroendocrine Carcinoma of the Breast itivity). We suspect that neuroendocrine differentiation itself may influence the radiologic presentation. The lack of spiculated margins on mammograms and the lack of posterior shadowing on ultrasound images may reflect the neuroendocrine morphologic features of these tumors, which are similar to neuroendocrine tumors in the gastrointestinal tract and the lung [10]. It is thus not surprising that the mammographic and sonographic findings of NEC resemble the findings of metastasis from extramammary malignancies to the breast [28]. Three case reports have described the MRI findings associated with NEC of the breast [22, 24, 26]. In contrast to the mammographic findings associated with NEC, the MRI findings frequently suggested characteristics associated with malignancy. The most frequent MRI finding in our study was an irregular mass with irregular margins and washout time-intensity kinetics, features highly suspicious for malignancy. In 6 of the 15 (40.0%) cancers for which MRI findings were available, synchronous contralateral cancer, multifocality, multicentricity, DCIS component, and skin invasion were revealed only at MRI. In seven cancers (46.7%), MRI better showed the index tumor and disease extent than did mammography or sonography. Our findings suggest that MRI is an important tool in the diagnosis of NEC, specifically for defining disease extent and multifocal and multicentric disease. The possibility of metastasis to the breast should always be considered when NEC is identified in the breast. Upalakalin et al. [29] found that 36% of cases of NEC in the breast reported in the published literature were metastasis. Some authors insist that the presence of in situ carcinoma with areas of ductal, lobular, or papillary differentiation within the breast is highly suggestive of a primary NEC rather than a metastatic tumor [30–32]. It is difficult, however, to differentiate metastatic and primary NEC of the breast histologically. Clinical and radiologic findings and immunohistochemical stains are helpful in this regard [33, 34]. A limitation of our study was its retrospective design, in which not all patients underwent all three imaging modalities, so not all variables were available for the entire set of patients. Second, there was potential for sample bias because we included only patients who had available mammograms, sonograms, and MR images at the time of diagnosis. Third, the radiologic reviewers were not blinded to the pathologic results, and so-
nograms and MR images were reviewed in conjunction with the mammographic results. Conclusion The mammographic characteristics of primary NEC of the breast differ from those of typical invasive mammary cancer. Mammography frequently shows a high-density round, oval, or lobular mass with nonspiculated margins. Sonography commonly reveals a solid, irregular, hypoechoic, hypervascular mass with indistinct margins and posterior enhancement or with no posterior acoustic features and with associated hypervascularity. MRI shows features of an irregular mass with irregular margins and washout time-intensity kinetics. Histologically, primary NEC of the breast has a high incidence of ER and PR positivity and ERBB2 negativity. Combined with these histologic findings, the imaging features reported in this study should raise suspicion of a primary NEC of the breast and aid in prompt immunohistochemical confirmation for appropriate classification. References 1. Tavassoli FA, Devilee P. Pathology and genetics. In: Tumors of the breast and female genital organs. WHO Classification of Tumors Series. Lyon, France: IARC Press, 2003:32–34 2. Sapino A, Righi L, Cassoni P, et al. Expression of apocrine differentiation markers in neuroendocrine breast carcinomas of aged women. Mod Pathol 2001; 14:768–776 3. Makretsov N, Gilks CB, Coldman AJ, et al. Tissue microarray analysis of neuroendocrine differentiation and its prognostic significance in breast cancer. Hum Pathol 2003; 34:1001–1008 4. López-Bonet E, Alonso-Ruano M, Barraza G, Vazquez-Martin A, Bernadó L, Menendez JA. Solid neuroendocrine breast carcinomas: incidence, clinico-pathological features and immunohistochemical profiling. Oncol Rep 2008; 20:1369–1374 5. Zekioglu O, Erhan Y, Ciris M, et al. Neuroendocrine differentiated carcinomas of the breast: a distinct entity. Breast 2003; 12:251–257 6. Rovera F, Masciocchi P, Coglitore A, et al. Neuroendocrine carcinomas of the breast. Int J Surg 2008; 6(suppl 1):S113–S115 7. Righi L, Sapino A, Marchio C, et al. Neuroendocrine differentiation in breast cancer: established facts and unsolved problems. Semin Diagn Pathol 2010; 27:69–76 8. Wei B, Ding T, Xing Y, et al. Invasive neuroendocrine carcinoma of the breast: a distinctive subtype of aggressive mammary carcinoma. Cancer 2010; 116:4463–4473 9. Tang F, Wei B, Tian Z, et al. Invasive mammary
carcinoma with neuroendocrine differentiation: histological features and diagnostic challenges. Histopathology 2011; 59:106–115 10. Tian Z, Wei B, Tang F, et al. Prognostic significance of tumor grading and staging in mammary carcinomas with neuroendocrine differentiation. Hum Pathol 2011; 42:1169–1177 11. Weigelt B, Geyer FC, Horlings HM, et al. Mucinous and neuroendocrine breast carcinomas are transcriptionally distinct from invasive ductal carcinomas of no special type. Mod Pathol 2009; 22:1401–1414 12. Sickles EA, D’Orsi CJ, Bassett LW, et al. Mammography. In: ACR BI-RADS atlas: breast imaging reporting and data system. Reston, VA: American College of Radiology, 2013 13. Mendelson EB, Böhm-Vélez M, Berg WA, et al. Ultrasound. In: ACR BI-RADS atlas: breast imaging reporting and data system. Reston, VA: American College of Radiology, 2013 14. Morris EA, Comstock CE, Lee CH, et al. Magnetic Resonance Imaging. In: ACR BI-RADS atlas: breast imaging reporting and data system. Reston, VA: American College of Radiology, 2013 15. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. American Joint Committee on Cancer staging manual, 7th ed. New York: Springer, 2009 16. Yang WT, Dryden M, Broglio K, et al. Mammographic features of triple receptor-negative primary breast cancers in young premenopausal women. Breast Cancer Res Treat 2008; 111:405–410 17. Ko ES, Lee BH, Noh WC, Kim MS, Lee SA. Triple-negative breast cancer: correlation between imaging and pathological findings. Eur Radiol 2010; 20:1111–1117 18. Krizmanich-Conniff KM, Paramagul C, et al. Triple receptor-negative breast cancer: imaging and clinical characteristics. AJR 2012; 199:458–464 19. Irshad A, Leddy R, Pisano E, et al. Assessing the role of ultrasound in predicting the biological behavior of breast cancer. AJR 2013; 200:284–290 20. Wade PM Jr, Mills SE, Read M, Cloud W, Lambert MJ 3rd, Smith RE. Small cell neuroendocrine (oat cell) carcinoma of the breast. Cancer 1983; 52:121–125 21. Rubini G, D’Eredita G. Tc-99m sestamibi and In111 DTPA octreotide uptake in breast carcinoma with neuroendocrine differentiation. Clin Nucl Med 2000; 25:482–483 22. Günhan-Bilgen I, Zekioglu O, Ustün EE, Memis A, Erhan Y. Neuroendocrine differentiated breast carcinoma: imaging features correlated with clinical and histopathological findings. Eur Radiol 2003; 13:788–793 23. Mariscal A, Balliu E, Diaz R, Casas JD, Gallart AM. Primary oat cell carcinoma of the breast: imaging features. AJR 2004; 183:1169–1171
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Park et al. 24. Fujimoto Y, Yagyu R, Murase K, et al. A case of solid neuroendocrine carcinoma of the breast in a 40-yearold woman. Breast Cancer 2007; 14:250–253 25. Kim JW, Woo OH, Cho KR, et al. Primary large cell neuroendocrine carcinoma of the breast: radiologic and pathologic findings. J Korean Med Sci 2008; 23:1118–1120 26. Ogawa H, Nishio A, Satake H, et al. Neuroendocrine tumor in the breast. Radiat Med 2008; 26:28–32 27. Shin HJ, Kim HH, Huh MO, et al. Correlation between mammographic and sonographic findings and prognostic factors in patients with node-negative invasive breast cancer. Br J Radiol 2011;
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84:19–30 28. Yang WT, Muttarak M, Ho LW. Nonmammary malignancies of the breast: ultrasound, CT, and MRI. Semin Ultrasound CT MR 2000; 21:375–394 29. Upalakalin JN, Collins LC, Tawa N, Parangi S. Carcinoid tumors in the breast. Am J Surg 2006; 191:799–805 30. Sapino A, Righi L, Cassoni P, Papotti M, Pietribiasi F, Bussolati G. Expression of the neuroendocrine phenotype in carcinomas of the breast. Semin Diagn Pathol 2000; 17:127–137 31. Dardick L, O’Neill EJ, Saxena NC, Corner TP, Bormanis P, Weinstein EC. Metastatic neoplasm
presenting as primary cancer of the breast. Mil Med 1984; 149:411–414 32. Papotti M, Gherardi G, Eusebi V, Pagani A, Bussolati G. Primary oat cell (neuroendocrine) carcinoma of the breast. Virchows Arch A Pathol Anat Histopathol 1992; 420:103–108 33. Latif N, Rosa M, Samian L, Rana F. An unusual case of primary small cell neuroendocrine carcinoma of the breast. Breast J 2010; 16:647–651 34. Perry KD, Reynolds C, Rosen DG, et al. Metastatic neuroendocrine tumors in the breast: a potential mimic of in situ and invasive mammary carcinoma. Histopathology 2011; 59:619–630
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Women’s Imaging Original Research
Primary Neuroendocrine Carcinoma of the Breast: Clinical, Imaging, and Histologic Features Young Mi Park1,2 Yun Wu 3 Wei Wei 4 Wei Tse Yang1 Park YM, Wu Y, Wei W, Yang WT
Keywords: breast, mammography, MRI, neuroendocrine carcinoma, sonography
OBJECTIVE. The purpose of this study was to evaluate the clinical, imaging, and histopathologic findings of primary neuroendocrine carcinoma of the breast. MATERIALS AND METHODS. A pathology database was searched for the records of patients with a histopathologic diagnosis of primary neuroendocrine carcinoma of the breast who had undergone mammography, sonography, or MRI between 1984 and 2011. The imaging studies of eligible patients were retrospectively reviewed according to the BI-RADS lexicon, and clinical presentation and histopathologic characteristics were documented. Imaging characteristics were compared with historical controls of invasive mammary carcinoma. RESULTS. Eighty-seven patients (84 women, three men; mean age, 62.9 years; range, 28– 89 years) were included in the study. The mean tumor size was 3.1 cm (range, 0.6–11 cm). Sixtyfive of 84 (77.4%) cancers were estrogen and progesterone receptor positive and ERBB2 negative. A palpable mass (55.8%) was a common clinical manifestation. A high-density, round or oval, or lobular mass with nonspiculated margins on mammograms and an irregular (65.4%), hypoechoic (78.4%) mass, with indistinct margins (43.5%), no or enhanced posterior acoustic features (77.9%) on sonograms were common findings. MRI revealed an irregular mass (83.3%), irregular margins (63.6%), and washout kinetics (85.7%). Neuroendocrine carcinoma presented more frequently as masses on mammograms. Calcifications were infrequent compared with their occurrence in invasive mammary cancer. CONCLUSION. Primary neuroendocrine carcinoma of the breast has mammographic features that differ from those of invasive mammary carcinoma. A round, oval, or lobular mass with nonspiculated margins, positive estrogen and progesterone receptor results, and negative ERBB2 results should raise suspicion of primary neuroendocrine carcinoma.
DOI:10.2214/AJR.13.10749 Received February 13, 2013; accepted after revision December 5, 2013. 1 Department of Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Unit 1350, 1515 Holcombe Blvd, Houston, TX 77030. Address correspondence to W. T. Yang ([email protected]). 2
Department of Radiology, Busan Paik Hospital, Inje University, Busan, Korea.
3 Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX. 4 Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
WEB This is a web exclusive article. AJR 2014; 203:W221–W230 0361–803X/14/2032–W221 © American Roentgen Ray Society
P
rimary neuroendocrine carcinoma (NEC) of the breast, an uncommon type of breast carcinoma that exhibits histopathologic and immunohistochemical evidence of neuroendocrine differentiation, accounts for 2–5% of breast carcinomas, according to the World Health Organization (WHO) [1]. NEC derives from neuroendocrine cells that are present throughout the body and arises most commonly in the bronchopulmonary system and gastrointestinal tract. Immunohistochemical staining for specific neuroendocrine markers, including synaptophysin and chromogranin, is the current standard for confirming neuroendocrine differentiation. In 2003, the WHO histologic classification of tumors of the breast and female genital organs recognized primary NEC of the breast as a distinct entity and added it to the catego-
ry of neuroendocrine tumors [1]. The WHO classification defines mammary NEC as the expression of one or more neuroendocrine markers in more than 50% of tumor cells. Neuroendocrine tumors include solid NEC, atypical carcinoid tumors, small cell or oat cell carcinoma, and large cell NEC. The biologic behavior and most effective treatment of primary NEC of the breast have not been well established. There have been several studies on the new WHO criteria of NEC [2–7]. Several publications have described the histologic features and prognostic factors of primary NECs of the breast that met WHO classification criteria [8–10]. Those studies showed that primary NEC of the breast is a unique clinicopathologic entity and has a poor clinical outcome compared with invasive ductal carcinoma (IDC) not otherwise specified with similar
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Park et al. pathologic stage [8]. Other investigators [11] have reported that NEC of the breast has a molecular profile distinct from that of IDC not otherwise specified. Histologically, NEC of the breast is underrecognized in routine practice. In a previous study [10], the correct diagnosis was initially rendered in fewer than one third of cases. Because staining of neuroendocrine markers is not routinely performed on invasive breast carcinomas, morphologic clues suggestive of NEC must be recognized to prompt immunohistochemical confirmation for appropriate classification. Therefore, knowledge of the imaging features of this entity will be helpful in ensuring the correct diagnosis. We conducted this retrospective review to identify mammographic, sonographic, and MRI characteristics and clinical and histologic features in patients with primary NEC of the breast. Materials and Methods Patient Selection and Data Collection A search was performed of the breast medical oncology and pathology databases of our comprehensive cancer center for the records of patients with the diagnosis of primary NEC of the breast between January 1984 and June 2011. Our institution is a tertiary referral center for patients undergoing screening mammography, diagnostic mammographic workup, and surgical, medical, and radiation therapy for breast cancer. Only patients who had available images from mammographic, sonographic, or MRI examinations at the time of diagnosis that had been acquired at our institution or an outside institution were included in our study. Our institutional review board approved this retrospective data collection and analysis and provided a waiver of the requirement for informed consent. The following data were obtained from medical charts: age, sex, laterality, initial presenting signs, and family or personal history of breast cancer. All images and accompanying radiology reports were retrospectively reviewed by two breast radiologists (9 and 16 years of experience) using BIRADS [12–14].
Mammography Standard two-view mammography (craniocaudal and mediolateral oblique) had been performed with additional views as necessary with a Lorad M3 (Hologic) mammography unit, DMR series unit (GE Healthcare), or Lorad Selenia digital technique (Hologic). Mammograms were retrospectively reviewed for breast density, mass, calcification, architectural distortion, and
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focal asymmetry. Breast density was graded as mainly fatty, scattered fibroglandular, and heterogeneously or extremely dense. Masses were reviewed for shape, margin, and density. The morphologic features and distribution of calcifications were recorded. The location and maximum size of the lesion were also recorded. Multifocality was defined as the presence of two or more foci of disease in the same quadrant of the breast. Multicentricity was defined as the presence of disease in multiple quadrants of the breast. In cases of multifocality or multicentricity, the largest lesion was analyzed.
Sonography Breast ultrasound at our institution was performed by technologists using a 13–7-MHz or 10–5-MHz linear-array transducer (Elegra, Siemens Healthcare; Acuson Antares, Siemens Healthcare; or ATL Ultramark 9, Philips Healthcare) with review by one of 13 breast imaging radiologists (all with 5–20 years of experience in breast ultrasound). Sonograms were reviewed for lesion characteristics such as shape, margins, echogenicity, orientation, posterior acoustic features, lesion boundaries, and vascularity. Multifocality, multicentricity, and size were determined as for mammography.
MRI Breast MRI had been performed for 15 patients. MRI examinations at our institution were performed with patients lying prone in a 1.5-T system (Signa Excite, GE Healthcare) with a dedicated seven-channel breast coil (BBC-127, Invivo). Image sequences included unenhanced bilateral axial T1-weighted spin-echo imaging (TR/TE, 500/12); sagittal fat-suppressed T2-weighted fast spin-echo imaging (TR/TE, 6000/85) followed by 3D fat-suppressed fastspoiled gradient-echo imaging (TR/TE, 18/4; flip angle, 15°; bandwidth, 50 kHz) once before and three times after patients were given an IV bolus injection of gadopentetate dimeglumine (0.2 mmol/kg body weight; Magnevist, Bayer Schering Pharma) at 3 mL/s with a Spectris injector (Medrad); and delayed contrast-enhanced axial T1-weighted 3D fat-suppressed fastspoiled gradient-echo imaging. The FOV was 160–220 mm, and the matrix size was 256 × 256 pixels. Subtraction images were also reviewed. Commercially available MRI computer-assisted diagnosis software with color-coded time-intensity mapping (DynaCAD, Invivo) was used for time-intensity analysis. Images were reviewed for lesion type, that is, mass versus nonmass enhancement. Masses were reviewed for shape, margin, and enhancement pat-
tern. Nonmass enhancement was analyzed for lesion distribution and internal enhancement pattern. Lesion kinetics were also evaluated. The presence of skin, nipple, or pectoralis muscle involvement was also noted. Multifocality, multicentricity, and size were determined as for mammography.
Histopathologic Analysis The study population was not consecutively registered, because NEC is a rare disease that requires confirmation by immunohistochemical staining of neuroendocrine markers. Approximately two thirds of the NECs in this study were retrospectively diagnosed during case review as having the pathologic features suggestive of neuroendocrine tumors. The findings were further confirmed by immunohistochemical staining for neuroendocrine markers based on 2003 WHO diagnostic criteria [1]. Of the tumors subjected to immunohistochemical staining of neuroendocrine markers, approximately one third to one half did not have a positive stain result at immunohistochemical analysis and were not included in the study. The histopathologic features in each case were reviewed by a breast pathologist. All NEC cases were confirmed with positive results of immunohistochemical staining for synaptophysin (syn88, BioGenex Laboratories) and/or chromogranin A (PHE5, Chemicon International) in more than 50% of the invasive tumor cells. Our cases included solid NEC, atypical carcinoid tumors, and large cell NEC and excluded small cell carcinoma and low-grade solid papillary carcinoma with a predominant in situ component. The following pathologic parameters were recorded: estrogen receptor (ER), progesterone receptor (PR), and ERBB2 (formerly HER2 or HER2/neu) status; modified Black nuclear grade; histologic type; and axillary node status.
Statistical Analysis Summary statistics of lesion characteristics were tabulated by frequency and percentage. Comparisons of ultrasound and mammographic features between primary NEC and historical controls of invasive mammary carcinoma and molecular subtype (when available) were performed by Fisher exact test. No adjustment was made for multiple testing because of the exploratory nature of this study. All tests were two-sided, and p 0.99
> 0.99
0.53
0.77
Unknown
2
p Lesion boundary Abrupt interface
52 (70.3)
86 (72)
63
50 (64)
40 (91)
153 (78)
Echogenic halo
22 (29.7)
34 (28)
12
28 (36)
4 (9)
44 (22)
0.87
0.053
0.49
0.01
0.21
Unknown p
19
Note—Numbers in parentheses are percentages. ER = estrogen receptor, PR = progesterone receptor.
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Neuroendocrine Carcinoma of the Breast
A
B
C
D
Fig. 1—78-year-old woman with palpable left breast mass. A, Left mediolateral magnification mammogram shows hyperdense lobular mass (arrow) with indistinct margins in lower center. B, Transverse ultrasound image shows 3-cm irregular hypoechoic mass (arrows) with indistinct margins in lower central left breast. C, Power Doppler sonogram shows penetrating and peripheral increased vascular signal in mass. Ultrasound-guided biopsy and histologic analysis confirmed primary neuroendocrine carcinoma. D, Histopathologic appearance of invasive neuroendocrine carcinoma of breast. Photomicrographs show nodular appearance and focal mucinous differentiation (arrow) (H and E, ×20, top left), nested growth pattern (H and E, ×40, top right), tumor cells diffusely positive for neuroendocrine marker synaptophysin (> 90%) (×40, bottom left), and tumor cells focally positive for chromogranin (~25%) (×40, bottom right).
had pain, nipple discharge, nipple retraction, skin change, palpable axillary mass, breast discomfort, or arm swelling. Twenty-six of the 86 patients (30.2%) had no symptoms. In 24 of these cases, the diagnosis was made at routine screening mammography; in one case at follow-up MRI after surgery for ipsilateral ductal carcinoma in situ (DCIS); and in one at CT of the abdomen for evaluation of metastatic liver disease. Fifteen of 85 (17.6%) patients had a first-degree family history (mother or sister) of breast cancer.
Mammography All 87 patients had undergone mammography. NEC was visible on 82 of the 87 (94.3%) mammograms and occult on five (5.7%). All mammographically occult cancers were visible at sonography. The mean size of the 82 cancers was 3.1 cm (range, 0.6–11 cm; median, 2.5 cm). On mammograms the cancers most commonly appeared as a mass (68/82 [82.9%]). Calcifications were found on 23 of 87 (26.4%) mammograms; were associated with 14 masses, three focal asymmetries, and two architectural distortions; and were the only finding in
four cases. Of the 68 masses, two had an unknown shape. Of the other 66, 46 (69.7%) were round, oval, or lobular (Fig. 1), and 20 (30.3%) were irregular. Fifty-three of the 68 (77.9%) masses had circumscribed, obscured, indistinct, or m icrolobulated margins; 15 (22.1%) had spiculated margins (Table 1). Sonography Of the 80 patients whose sonograms were available, 79 (98.8%) had tumors that were visible at sonography. The other patient had a tumor that could not be discriminated
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Park et al. from numerous cystic and hypoechoic nodules throughout the breast. The mean size of the 79 lesions at sonography was 2.5 cm (range, 0.6–8.6 cm; median, 1.9 cm). The lesions were most commonly irregular masses (51/78 [65.4%]), hypoechoic (62/79 [78.4%]), or indistinctly marginated (34/78 [43.6%]) and had no or enhanced posterior acoustic features (60/77 [77.9%]). In 68 patients with NEC who underwent color or power Doppler sonography, 59 (86.8%) masses had increased vascularity (Table 2). MRI All 15 patients with NEC who underwent breast MRI had an abnormality. Seven of the 15 (46.7%) cancers had multiple regions of enhancement. The mean size of the 15 lesions on MR images was 4.3 cm (range, 0.8–11 cm; median, 3.3 cm). Twelve of the 15 (80%) cancers exhibited mass enhancement, and three (20%), nonmass enhancement. The lesions with mass enhancement at MRI were most commonly irregular in shape (10/12 [83.3%]), had irregular margins (7/11 [63.6%], and had a rim or heterogeneous internal enhancement pattern (7/12 [58.3%]). NEC was most commonly associated with a washout pattern in time-intensity kinetics analysis (12/14, 85.7%) (Table 3). In three of seven cancers with multiple lesions at MRI, multifocality or multicentricity was identified only with MRI. One patient had a DCIS component between the NEC and the nipple that was identified only with MRI (Fig. 2). Another had a synchronous contralateral IDC that was seen only on MR images (Fig. 3). Two patients with nipple and skin invasion had findings visualized only at MRI. In one patient, the cancer was histologically confirmed after MRI-guided needle biopsy because it could not be diagnosed with confidence at mammography owing to its presentation as a subtle focal asymmetry. Six cancers were seen with all three modalities, but MRI more clearly showed the index tumor and entire disease extent than did mammography or sonography. Histopathologic Results and Treatment Diagnosis was established by results of imaging-guided core needle biopsy in 76 patients. Seventy-one of the 87 (81.6%) patients underwent biopsy with ultrasound, four (4.6%) with stereotactic, and one (1.1%) with MRI guidance. Ultrasound-guided fine-needle aspiration biopsy was performed for three (3.4%) patients and surgical biopsy for eight (9.2%).
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Sixty-five of 84 (77.4%) cancers examined for ER, PR, and ERBB2 status were ER- and PRpositive and ERBB2-negative. Most of the tumors (67/85 [78.8%]) were intermediate nuclear grade (modified Black) (Table 4). Axillary lymph node metastasis was frequently found at the time of diagnosis (39/83 [47.0%]). Pathologic stages at presentation according to the American Joint Committee on Cancer staging system, 7th edition [15], were as follows: stage I in 37 (42.5%) patients, stage II in 26 (29.9%), stage III in 13 (14.9%), and stage IV in 11 (12.6%). The most comTABLE 3: MRI Findings of 15 Patients With Primary Neuroendocrine Carcinoma of the Breast MRI Finding
No. of Patients (%)
Breast Mass enhancement
12 (80.0)
Nonmass enhancement
3 (20.0)
Mass characteristics (n = 12) Shape Irregular
10 (83.3)
Oval
1 (8.3)
Round
1 (8.3)
Margin Irregular
7 (63.6)
Spiculated
4(36.4)
Unknown
1
Internal enhancement pattern Homogeneous
5 (41.7)
Rim enhancement
4 (33.3)
Heterogeneous
3 (25.0)
Nonmass characteristics (n = 3)
TABLE 4: Histopathologic Findings Among 87 Patients with Primary Neuroendocrine Carcinoma of the Breast at Diagnosis No. of Patients
Feature Histologic subtype IDC + DCIS
35 (40.2)
IDC
25 (28.7)
IDC + mucinous differentiation
17 (19.5)
IDC + ILC
8 (9.2)
Unknown
2
TMN stage IA
37 (42.5)
IIA
13 (14.9)
IIB
13 (14.9)
IIIA
5 (5.7)
IIIB
6 (6.9)
IIIC
2 (2.3)
IV
11 (12.6)
Estrogen receptor status Positive
86 (98.9)
Negative
1 (1.1)
Progesterone receptor status Positive
67 (77.0)
Negative
19 (21.8)
Unknown
1
ERBB2 overexpression
Internal enhancement pattern Clumped
2 (66.7)
Reticular-dendritic
1 (33.3)
Distribution Segmental
1 (33.3)
Regional
1 (33.3)
Diffuse
1 (33.3)
Time-intensity kinetics Washout
12 (85.7)
Plateau
2 (14.3)
Unknown
mon distant metastatic sites in patients with stage IV disease at diagnosis were bone (n = 9) and liver (n = 5); other sites included the lungs and mediastinal lymph nodes (n = 2), brain (n = 1), adrenal gland (n = 1), and omentum (n = 1). Of the 78 patients who underwent
1
Note—Statistical analysis excluded unknown cases. Percentages in parentheses do not add up to 100 owing to rounding.
Positive
2 (2.4)
Negative
82 (97.6)
Unknown
3
Modified Black nuclear grade Well differentiated
8 (9.4)
Intermediate differentiation
67 (78.8)
Poorly differentiated
10 (11.7)
Unknown
2
Note—Statistical analysis excluded unknown cases. Numbers in parentheses are percentages and do not add to 100 in some instances owing to rounding. IDC = invasive ductal carcinoma, DCIS = ductal carcinoma in situ, ILC = invasive lobular carcinoma, ER = estrogen receptor, PR = progesterone receptor.
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Neuroendocrine Carcinoma of the Breast
A
B Fig. 2—53-year-old woman with palpable lump in left breast. A, Left mediolateral oblique mammograms shows oval isodense mass (single arrow) with obscured margins in upper outer quadrant and axillary lymphadenopathy (double arrows). B, Transverse sonogram of left breast shows circumscribed oval hypoechoic mass (arrow). Histopathologic analysis at ultrasound-guided biopsy revealed primary neuroendocrine carcinoma. A and B represent caliper-based measurements obtained of this mass. C, Sagittal dynamic contrast-enhanced MR image in early subtraction phase shows 1.5-cm rim-enhancing mass with associated postbiopsy clip (long straight arrow). Enlarged enhancing lymph nodes (curved arrow) also are evident. Approximately 2 cm anterior and inferior to index mass, nonmass ductal enhancement extends to base of nipple (short straight arrows). This was occult on mammograms and ultrasound images. Histopathologic result after MRI-guided biopsy was ductal carcinoma in situ.
C surgery for treatment, 52 underwent segmental mastectomy and 26 underwent modified radical mastectomy. Seven patients underwent conservative medical treatment only, and two patients were lost to follow-up. Comparison of the Imaging Features of Neuroendocrine Carcinoma With Historical Reports of Invasive Mammary Cancer Comparison of the imaging (ultrasound and mammography) features between primary NEC and historical controls of invasive mammary carcinoma [16–19] are detailed in Tables 1 and 2. NECs present more frequently as masses on mammograms (62%) than do invasive mammary cancers (29%, 38%, and 53% in the historical reports) [16–18]. Calcifications are an infre-
quent finding in NEC (21%) compared with invasive mammary cancers (54%, 47%, and 47%) [16–18]. The mammographic features of NEC include an oval, round, or lobular mass (70%), which is similar to findings for triple-negative breast cancer in two previously reported series (75% and 51%) [16, 18]. The margins of NEC on mammograms are infrequently spiculated (18%), a finding also similar to triple-negative breast cancer (18% and 21%) [16, 18]. At sonography, NECs are frequently masses with indistinct margins (44%), compared with invasive mammary cancers (11% and 19%) [17, 19]. The lack of posterior phenomena is a notable sonographic feature of NEC (55%) compared with invasive mammary cancer (46%, 43%, and 19%) [17–19].
Discussion Primary NEC of the breast is an uncommon neoplasm, and the biologic behavior, treatment, and prognosis are not well recognized. In our study, NEC had a high incidence of ER positivity (98.9%), PR positivity (77.0%), and ERBB2 negativity (97.6%), and tumors frequently had intermediate modified Black nuclear grade differentiation (78.8%). Hormone receptor positivity is typically associated with well-differentiated tumors, which have a better prognosis than undifferentiated tumors. A 2010 study [8] showed that NEC of the breast is an aggressive tumor with a higher tendency toward local and distant recurrence and poorer overall survival compared with a ge-, sex-, race-, tumor stage–, and ERBB2 sta-
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Park et al.
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B
C
D
Fig. 3—68-year-old woman with right nipple discharge and nipple retraction. Histopathologic analysis at ultrasound-guided biopsy revealed primary neuroendocrine carcinoma in right breast. A, Bilateral craniocaudal mammograms show irregular high-density mass (short arrow) with spiculated margins in center of right breast. Postbiopsy clip (long arrow) in left breast represents site of previous biopsy with benign finding. B, Extended-FOV ultrasound image of right breast shows irregular hypoechoic mass (arrow) with microlobulated margins. C, Sagittal early phase dynamic contrast-enhanced subtraction MR image of right breast shows irregular mass (arrow) with irregular margins and rim enhancement. D, Sagittal early phase dynamic contrast-enhanced subtraction MR image of left breast shows nonmasslike contrast enhancement with linear distribution (arrows). Area had washout time-intensity kinetic pattern (not shown) and was occult on mammograms and sonograms. Histopathologic result after MRI-guided core biopsy was invasive ductal carcinoma.
tus–matched cases of IDC not otherwise specified. That study also showed that neuroendocrine differentiation is an adverse prognostic factor independent of ER and PR status and nuclear grade. The imaging characteristics of NEC have been described in several case reports [20– 26]. The results of those studies suggest that the mammographic findings of primary NEC of the breast differ from findings typical of invasive mammary carcinoma, which tends to have an irregular shape, spiculated margins, and associated microcalcifications. To our knowledge, ours is the largest series describing the imaging findings of primary
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NEC of the breast. In our study, NEC most commonly appeared mammographically as a high-density round, oval, or lobular noncalcified mass with nonspiculated margins (e.g., circumscribed, obscured, microlobulated, or indistinct margins). Shin et al. [27] found that mammographic findings of lesions with nonspiculated margins or hyperdense masses were associated with ER-negative breast cancer. In another study, Yang et al. [16] found that triple-receptor-negative cancers that appeared as masses were most frequently round, oval, or lobular and had indistinct margins, whereas ER-positive cancers were more frequently irregular in shape
and spiculated in margin than were triplenegative cancers. The most common sonographic feature of NEC in our study was a solid irregular hypoechoic mass with indistinct margins and no change in posterior features or posterior enhancement in 78% of tumors. Our study is interesting in that although primary NEC of the breast is most commonly ER positive (98.9%) and ERBB2 negative (97.6%), the imaging features are similar to those of ER-negative and triple-negative cancers. Primary NEC of the breast tends not to have imaging features related to hormone receptor status (ER pos-
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Neuroendocrine Carcinoma of the Breast itivity). We suspect that neuroendocrine differentiation itself may influence the radiologic presentation. The lack of spiculated margins on mammograms and the lack of posterior shadowing on ultrasound images may reflect the neuroendocrine morphologic features of these tumors, which are similar to neuroendocrine tumors in the gastrointestinal tract and the lung [10]. It is thus not surprising that the mammographic and sonographic findings of NEC resemble the findings of metastasis from extramammary malignancies to the breast [28]. Three case reports have described the MRI findings associated with NEC of the breast [22, 24, 26]. In contrast to the mammographic findings associated with NEC, the MRI findings frequently suggested characteristics associated with malignancy. The most frequent MRI finding in our study was an irregular mass with irregular margins and washout time-intensity kinetics, features highly suspicious for malignancy. In 6 of the 15 (40.0%) cancers for which MRI findings were available, synchronous contralateral cancer, multifocality, multicentricity, DCIS component, and skin invasion were revealed only at MRI. In seven cancers (46.7%), MRI better showed the index tumor and disease extent than did mammography or sonography. Our findings suggest that MRI is an important tool in the diagnosis of NEC, specifically for defining disease extent and multifocal and multicentric disease. The possibility of metastasis to the breast should always be considered when NEC is identified in the breast. Upalakalin et al. [29] found that 36% of cases of NEC in the breast reported in the published literature were metastasis. Some authors insist that the presence of in situ carcinoma with areas of ductal, lobular, or papillary differentiation within the breast is highly suggestive of a primary NEC rather than a metastatic tumor [30–32]. It is difficult, however, to differentiate metastatic and primary NEC of the breast histologically. Clinical and radiologic findings and immunohistochemical stains are helpful in this regard [33, 34]. A limitation of our study was its retrospective design, in which not all patients underwent all three imaging modalities, so not all variables were available for the entire set of patients. Second, there was potential for sample bias because we included only patients who had available mammograms, sonograms, and MR images at the time of diagnosis. Third, the radiologic reviewers were not blinded to the pathologic results, and so-
nograms and MR images were reviewed in conjunction with the mammographic results. Conclusion The mammographic characteristics of primary NEC of the breast differ from those of typical invasive mammary cancer. Mammography frequently shows a high-density round, oval, or lobular mass with nonspiculated margins. Sonography commonly reveals a solid, irregular, hypoechoic, hypervascular mass with indistinct margins and posterior enhancement or with no posterior acoustic features and with associated hypervascularity. MRI shows features of an irregular mass with irregular margins and washout time-intensity kinetics. Histologically, primary NEC of the breast has a high incidence of ER and PR positivity and ERBB2 negativity. Combined with these histologic findings, the imaging features reported in this study should raise suspicion of a primary NEC of the breast and aid in prompt immunohistochemical confirmation for appropriate classification. References 1. Tavassoli FA, Devilee P. Pathology and genetics. In: Tumors of the breast and female genital organs. WHO Classification of Tumors Series. Lyon, France: IARC Press, 2003:32–34 2. Sapino A, Righi L, Cassoni P, et al. Expression of apocrine differentiation markers in neuroendocrine breast carcinomas of aged women. Mod Pathol 2001; 14:768–776 3. Makretsov N, Gilks CB, Coldman AJ, et al. Tissue microarray analysis of neuroendocrine differentiation and its prognostic significance in breast cancer. Hum Pathol 2003; 34:1001–1008 4. López-Bonet E, Alonso-Ruano M, Barraza G, Vazquez-Martin A, Bernadó L, Menendez JA. Solid neuroendocrine breast carcinomas: incidence, clinico-pathological features and immunohistochemical profiling. Oncol Rep 2008; 20:1369–1374 5. Zekioglu O, Erhan Y, Ciris M, et al. Neuroendocrine differentiated carcinomas of the breast: a distinct entity. Breast 2003; 12:251–257 6. Rovera F, Masciocchi P, Coglitore A, et al. Neuroendocrine carcinomas of the breast. Int J Surg 2008; 6(suppl 1):S113–S115 7. Righi L, Sapino A, Marchio C, et al. Neuroendocrine differentiation in breast cancer: established facts and unsolved problems. Semin Diagn Pathol 2010; 27:69–76 8. Wei B, Ding T, Xing Y, et al. Invasive neuroendocrine carcinoma of the breast: a distinctive subtype of aggressive mammary carcinoma. Cancer 2010; 116:4463–4473 9. Tang F, Wei B, Tian Z, et al. Invasive mammary
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