Primary Neuroendocrine Carcinoma of the Breast: Radiologic and Pathologic Correlation Yu Sung Yoon, Shin Young Kim, Ji-Hye Lee, Sung Yong Kim, Sun Wook Han PII: DOI: Reference:
S0899-7071(14)00144-2 doi: 10.1016/j.clinimag.2014.05.009 JCT 7631
To appear in:
Journal of Clinical Imaging
Received date: Revised date: Accepted date:
25 December 2013 9 May 2014 19 May 2014
Please cite this article as: Yoon Yu Sung, Kim Shin Young, Lee Ji-Hye, Kim Sung Yong, Han Sun Wook, Primary Neuroendocrine Carcinoma of the Breast: Radiologic and Pathologic Correlation, Journal of Clinical Imaging (2014), doi: 10.1016/j.clinimag.2014.05.009
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Primary Neuroendocrine Carcinoma of the Breast:
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Radiologic and Pathologic Correlation
Yu Sung Yoon1, Shin Young Kim1, Ji-Hye Lee2, Sung Yong Kim3, Sun Wook Han3
Department of Pathology2, Department of Surgery3 Address correspondence to:
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Shin Young Kim, M.D.
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Soonchunhyang University Cheonan Hospital, Department of Radiology1,
Department of Radiology
Soonchunhyang University Cheonan Hospital, 23-20 Bongmyung-dong, Dongnam-gu, Cheonan, Chungchungnam-do, Korea, 330-721, E-mail)
[email protected]
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Tel) +82-41-570-3515
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Fax) +82-41-579-9026
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Abstract
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Primary neuroendocrine carcinoma of the breast (PNCB) is a rare type of breast cancer.
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There have been few reports on PNCB and radiologic-pathologic correlation in PNCB has not been described thoroughly. We present a rare case of pathologically confirmed poorly
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differentiated PNCB removed via lumpectomy. Image findings on mammography, ultrasonography (USG), computed tomography (CT), magnetic resonance image (MRI) and
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positron emission tomography-computed tomography (PET-CT) are also presented.
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Keywords: Neuroendocrine, Poorly differentiated, Breast, US, MRI
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Introduction
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Neuroendocrine tumors can occur in a variety of extrapulmonary sites such as the breast,
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larynx, gastrointestinal tract, prostate, bladder, ovary, and cervix. Neuroendocrine tumors affecting the breast are very rare and were first reported in 1983 [1-2]. Despite their rarity, it
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is important to differentiate them from other poorly differentiated breast cancers or metastatic small cell carcinoma of the lung because of the therapeutic or prognostic implications for
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these patients [2]. There are few studies sufficiently describing imaging and pathologic findings of primary neuroendocrine carcinoma of the breast (PNCB). Our case showed good
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correlation between radiologic and pathologic findings.
Case Report
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A 44-year-old woman visited our hospital for a palpable left breast mass first noticed three months ago. Physical examination revealed a 5cm sized fixed soft mass in the lower outer
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quadrant of the left breast. Mammography revealed a 1.8 cm sized indistinct round
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hyperdense mass in the lower outer quadrant of the left breast. There was no combined abnormal calcification (Fig. 1). On USG, a 1.7 cm sized partly angulated round hypoechoic mass with mild posterior acoustic enhancement was noted. Color doppler image showed slightly increased vascularity. There were no significantly enlarged lymph nodes in the ipsilateral axilla. The lesion was diagnosed as Breast Imaging-Reporting and Data System(BI-RADS) category 5, and a USG-guided core needle biopsy was performed (Fig.2). The histopathology result was invasive carcinoma with neuroendocrine features. MRI was performed using the 3.0T system as part of a surgical plan and to look for additional lesions. The mass had homogeneous low signal intensity on T1 weighted image (WI) and iso signal intensity on T2 WI. An early contrast enhanced T1 WI showed heterogeneous rapid initial
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enhancement. The dynamic enhancement curve showed a plateau (Fig.3). Contrast-enhanced
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chest CT was performed to confirm the PNCB diagnosis. There were no mass-like lesions in
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either lung fields, but a relatively well-defined heterogeneous enhancing mass was noted in the left breast parenchyma (Fig.4). PET-CT was performed as part of the metastatic work-up.
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Trans-axial fusion PET-CT image showed intense fluorodeoxyglucose (FDG) uptake (SUV = 7.94) in the left breast mass (Fig. 5). No additional lesion with increased FDG uptake was
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detected in the whole body or left axillary area. A lumpectomy was performed under general anesthesia.
Grossly, the tumor was pale grayish-white with a relatively smooth border and measured 2.2 x 2 cm (Fig.6). Microscopically, the tumor was densely cellular with tumor cells arranged in
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solid nests and trabeculae without tubule formation showing foci of rosette-like structures
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invading a collagenous stroma (Fig.7). The tumor cells were round to ovoid and exhibited mildly pleomorphic nuclei with a coarse chromatin pattern and moderate amount of granular
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eosinophilic cytoplasm (Fig.8). Mitosis was frequent. Immunohistochemically, tumor cells
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revealed diffuse cytoplasmic positivity for synaptophysin (Fig.9) and focal positivity for chromogranin. Progesterone and estrogen receptors were also positive. The final diagnosis was poorly differentiated neuroendocrine carcinoma. She had been treated 5 times with postoperative chemotherapy (cyclophosphamide + adriamycin). No evidence of local or distant metastasis or symptomatic discomfort was noted. Follow-up breast USG and mammography performed 2 months later revealed no evidence of recurrence.
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Discussion
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Neuroendocrine tumors can occur in various sites of the body: the lung being the most
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common site, while the breast is one of the rarest sites for an extrapulmonary primary neuroendocrine tumor [1-2]. PNCB is extremely rare, accounting for approximately less than
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0.1% of all variants of breast cancer and less than 1% of all neuroendocrine tumors of the body [9]. PNCB and neuroendocrine tumor of the lung have similar morphologic features.
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PNCB shows a broad spectrum of severity from relatively non-aggressive carcinoid tumor to highly aggressive small cell carcinoma [3, 4]. PNCB usually occurs in the 6th or 7th decade of life [5]. The new classification of PNCB by the World Health Organization Classification of Tumors of the Breast, 4th edition (2013), includes well-differentiated neuroendocrine tumor,
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poorly differentiated neuroendocrine carcinoma (small cell carcinoma), and carcinoma with
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neuroendocrine differentiation. A poorly differentiated neuroendocrine carcinoma is the rarest type [4].
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Imaging findings of PNCB have been described in only a few reported cases. Günhan-
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Bilgen et al. [6] reported that most examples of this tumor type showed hyperdense round masses with predominantly spiculated or lobulated margins on mammography. Mariscal et al. [3]reported PNCB as a partially obscured round hyperdense mass, similar to our case. They reported sonographic findings of PNCB as having mostly homogeneous echogenicity with some posterior acoustic enhancement. None of the cases showed posterior acoustic shadowing or had a cystic portion [6]. Another study[3] also reported combined posterior acoustic enhancement and a homogeneous hypoechoic solid mass. The PNBC in our case had homogeneous hypoechoic echo texture with posterior acoustic enhancement without cystic portion, which correlated with previously reported cases. MR images in our case were similar with those from other reports[1-6] with regard to the relatively homogeneous early
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enhancement pattern. There were some differing descriptions of the mass on mammography,
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US, and MRI, wherein some reports noted microlobulated margins. CT showed a well-
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defined heterogeneous enhancing mass without lung parenchymal lesion. Radiologic findings of PNCB were described as a relatively defined homogeneous solid mass with heterogeneous
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enhancement and no internal degenerative or necrotic portion. In Latif et al’s study[2], PETCT showed hypermetabolic activity in the breast mass and axillary lymph nodes. Our case
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also showed intense FDG uptake (SUV = 7.94) in the left breast mass without axillary lymph node involvement.
PNCB histogenesis is still unclear because the presence of neuroendocrine cells in the normal breast has not been conclusively shown[7]. Poorly differentiated PNCB contains
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sheets of small round cells that have dark nuclei, scant cytoplasm, fine granular nuclear
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chromatin, and indistinct nucleoli. Histologically, the differential diagnosis for PNCB should include Merkel cell neoplasm, malignant lymphoma, malignant melanoma, undifferentiated
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carcinoma, and metastatic small cell carcinoma of the lung. There is no distinct clinical
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feature that would reliably differentiate PNCB from other types of breast cancer [5]. It is difficult to distinguish a metastatic tumor from PNCB based on histology alone because of similarities in morphology and immunohistochemical patterns [8]. There were some histopathologic characteristics that have been previously reported. Immunohistochemical staining of the tumor cells for chromogranin, neuron-specific enolase, and synaptophysin are usually positive in PNCB. Microscopic evidence of neuroendocrine differentiation is found in more than 50% of the cell population. Presence of an in situ component of a common variant of breast cancer in histological sections have been found, as well as nuclear positivity for estrogen and progesterone receptors with absolute negativity for HER2/neu receptors [5, 9]. E-cadherin and Chromogranin A stains were positive in our case, while a Pan-CK stain done
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on the sentinel lymph node was negative.
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Because of the extreme rarity and consequent paucity of long-term statistical data, it is
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nearly impossible to draw a conclusive prognosis. Low-grade poorly differentiated PNCB responds well to conventional treatment [5]. However, large-sized tumor, small cellularity,
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high nuclear grade, no estrogen and progesterone receptors, lymphovascular invasion, lymph node involvement, and distant metastases are adverse prognostic factors associated with poor
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outcome [9].PNCB is rare andshows a broad spectrum of severity. As a result, no standard treatment for this disease exists. The most effective treatment includes surgical removal such as modified radical mastectomy with axillary lymph node dissection and additional adjuvant chemotherapy. There was a discrepancy between surgical treatment of our patient and
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recommended surgical treatment because of the patient’s demand for minimal surgery.
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Considering that the biological characteristics of PNCB are similar to small cell carcinoma of the lung, effective drugs for the latter, such as platinum compounds and etoposide, were
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selected to treat these patients [10].
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Poorly-differentiated PNCB is the rarest type of PNCB; consequently, few studies have introduced imaging and pathologic findings. We present a rare case of breast cancer and its diagnostic imaging findings with clinical and pathologic correlation. This may help to differentiate PNCB from other breast cancers and properly treat future cases.
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References
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1. Kitakata H, Yasumoto K, Sudo Y, et al. A case of primary small cell carcinoma of the
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breast. Breast Cancer 2007;14:414-419
2. Latif N, Rosa M, Samian L, et al. An Unusual Case of Primary Small Cell
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Neuroendocrine Carcinoma of the Breast. Breast J. 2010:16:647-651 3. Mariscal A, Balliu E, Díaz R, et al. Primary Oat Cell Carcinoma of the Breast :
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Imaging Features. 2004;183:1169-1171
4. Sinn HP, Kreipe H. A Brief Overview of the WHO Classification of Breast Tumors, 4th Edition, Focusing on Issues and Updates from the 3rd Edition. Breast Care 2013;8:149-154
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5. Irshad A, Ackerman SJ, Pope TL, et al. Rare Breast Lesions: Correlation of Imag- ing
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and Histologic Features with WHO Classification. Radiographics 2008;28:1399-1414 6. Günhan-Bilgen I, Zekioglu O, Ustün EE, et al. Neuroendocrine differentiated breast
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carcinoma: imaging features correlated with clinical and histopathological findings.
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EurRadiol 2003;13:788-793 7. Adegbola T, Connolly CE, Mortimer G. Small cell neuroendocrine carcinoma of the breast: a report of three cases and review of the literature. J ClinPathol. 2005;58:775778 8. Nicoletti S, Papi M, Drudi F, et al. Small cell neuroendocrine tumor of the breast in a 40 year-old woman: a case report. J Med Case Rep. 2010; 30;4:201 9. Rehman A. Primary Neuroendocrine Carcinoma of the Breast. J Coll Physicians Surg Pak. 2013;23:282-284. 10. Ge QD, Lv N, Cao Y, et al. A case report of primary small cell carcinoma of the breast and review of the literature.Chin J Cancer. 2012;31(7):354-358
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Figure Legends
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Fig. 1. (a) Mediolateral oblique mammogram view and (b) craniocaudal mammogram view shows a 1.8cm sized partially obscured round hyperdense mass in the lower outer quadrant of
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the left breast (black arrow).
Fig.2. (a), (b). Ultrasonography reveals a 1.7 cm sized partly angulated round hypoechoic
is noted in the color doppler image.
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mass with mild posterior acoustic enhancement (white arrow). Slightly increased vascularity
Fig.3. MRI was performed using the 3.0T system. (a) On axial non-fat-saturated T1 weighted images, mass shows round, smooth, homogeneous, low signal intensity (white arrow). (b) On
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axial fat-saturated T2 weighted images, mass shows iso signal intensity. (c) Axial fat-
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saturated pre-contrast-enhanced, (d) early (2 min) contrast enhanced, and (e) delayed (6 min) contrast enhanced axial T1 weighted images after bolus administration of gadolinium based
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contrast agent show heterogeneous enhancement. (f) Axial subtraction image reveals
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heterogeneous rapid initial enhancement. (g) Kinetic curve derived from signal intensity measurements in target lesion show a plateau. On all MRI images, there is a 0.6cm sized circumscribed oval homogeneously enhancing nodule in anteromedial aspect from the dominant mass which shows early enhancement without washout pattern. Because the enhancement pattern of it was similar with main mass, excised together. This lesion confirmed as fibroadenomatous change. Fig.4. (a), (b), (c). CT shows a well-defined round heterogeneous enhancing mass (white arrow) in left breast parenchyma. Fig.5. Trans-axial fusion image of PET-CT shows FDG uptake (SUV = 7.94) in left breast mass (white arrow).
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Fig.6. Tumor measures 2.2 cm and pale grayish-white with a relatively smooth border (black
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arrow).
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Fig. 7. Tumor is densely cellular with cells arranged in solid nests(black arrowhead) and trabeculaeshowing foci of rosette-like structures(white arrowhead).Tumor cells(black arrow)
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invading collagenous stroma (white arrow)(H&E, x 200).
Fig. 8. Tumor cells are round to ovoid with moderately pleomorphic nuclei (black arrow) and
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coarse chromatin pattern. A moderate amount of granular eosinophilic cytoplasm is present. Mitosis was frequent (white arrow) (H&E, x400).
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Fig. 9. Tumor cells show diffuse cytoplasmic positivity for synaptophysin (x 400).
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