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 Table of Contents  
CASE REPORT
Year : 2019  |  Volume : 52  |  Issue : 1  |  Page : 28-32

Metastatic lung neuroendocrine carcinoma presenting as a breast lump


1 Department of General Surgery, Kuo General Hospital, Tainan, Taiwan
2 Department of Pathology, Kuo General Hospital, Tainan, Taiwan
3 Department of Internal Medicine, Kuo General Hospital, Tainan, Taiwan

Date of Submission22-May-2018
Date of Decision09-Jul-2018
Date of Acceptance20-Nov-2018
Date of Web Publication18-Feb-2019

Correspondence Address:
Dr. Yu-Lin Chang
Department of Internal Medicine, Tainan Kuo General Hospital, No. 22, Sec. 2, Minsheng Rd., West Central Dist., Tainan City 700
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/fjs.fjs_55_18

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  Abstract 

This case is a 78-year-old woman with hypertension, diabetes mellitus, cardiovascular disease, valvular heart failure and hepatitis C. She presented to outpatient department for her right breast lump. The pathology of the core biopsy under breast sonography showed carcinoma with neuroendocrine features. Its immunohistochemical study showed negative for estrogen receptor (ER), progesterone Receptor (PR), HER2/neu and GATA-3, and positive for chromogranin A, synaptophysin, and TTF-1. A staging workup was then performed. The computed tomography (CT) of chest and abdomen revealed another mass in the left lung. CT-guided biopsy was done for the lung mass. According to the results of immunostains, a primary lung large cell neuroendocrine carcinoma (LCNEC) with breast metastasis was diagnosed. The patient received chemotherapy with etoposide and carboplatin for 6 cycles. The CT performed 3 and 5 months later showed that the response of the tumors was stable.

Keywords: Breast neuroendocrine carcinoma, immunohistochemistry, lung large cell neuroendocrine carcinoma, lung neuroendocrine carcinoma


How to cite this article:
Huang TC, Kang WY, Tsao SY, Chang YL. Metastatic lung neuroendocrine carcinoma presenting as a breast lump. Formos J Surg 2019;52:28-32

How to cite this URL:
Huang TC, Kang WY, Tsao SY, Chang YL. Metastatic lung neuroendocrine carcinoma presenting as a breast lump. Formos J Surg [serial online] 2019 [cited 2019 May 25];52:28-32. Available from: http://www.e-fjs.org/text.asp?2019/52/1/28/250870


  Introduction Top


Neuroendocrine carcinoma is a rare cancer. However, neuroendocrine tumors have increased in overall incidence over the past 30 years. Improvements in diagnostic technology and increased awareness of neuroendocrine tumors may play a significant role.[1] After the gastrointestinal tract, the lung is the second most common site for neuroendocrine tumors. The lung neuroendocrine tumors account for 25% of all neuroendocrine tumors and 1%–2% of all lung cancers.[2]

Primary neuroendocrine tumors of the breast are rare. The first case was described by Cubilla and Woodruff in 1977. The incidence is <0.1% of all breast cancers and <1% of all neuroendocrine tumors. Metastatic tumors to the breast are also uncommon. They account for approximately 1% to 2% of all breast tumors.[3]

Metastatic neuroendocrine tumors to the breast are extremely rare. In 2017, Papa et al. reported that the first documented case of breast metastasis from large cell neuroendocrine carcinoma (LCNEC) of the lung. The breast nodule and lung lesions were biopsied, and their histology and molecular diagnosis were LCNEC of the lung. The patient received chemotherapy with cisplatin-etoposide and then with topotecan. Unluckily, a computed tomography (CT) scan evaluation after months of treatment showed a progressive disease. The death occurred later.[4] We present a rare case of lung neuroendocrine carcinoma initially presenting as a breast lump in her right breast.


  Case Report Top


A 78-year-old woman with past history of hypertension, diabetes mellitus, cardiovascular disease, valvular heart failure, and hepatitis C presented to our outpatient department for her right breast lump in September 2017. She did not have pulmonary symptom such as coughs or dyspnea. She has no family history of breast cancer, hormone replacement, or herb use. The physical examination revealed one 3 cm tumor at right lower outer breast, without skin change or nipple discharge. Her breast sonography showed a 3.3 cm irregular homogenous hypoechoic mass [Figure 1], without duct or skin change. Under echo-guided, tissue from core needle biopsy was obtained for pathology.
Figure 1: The breast ultrasound demonstrates a 33mm irregular homogenous hypoechoic mass

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The pathology revealed a carcinoma with neuroendocrine features, including trabecular pattern and organoid nesting [Figure 2]. There was no evidence of intraductal carcinoma, lymphatic and venous invasion, or microcalcification. Its immunohistochemic study showed negative for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2)/neu and GATA-3 [Figure 3], and positive for chromogranin A, synaptophysin [Figure 4], and thyroid transcription factor (TTF-1) [Figure 3]. Due to primary breast neuroendocrine carcinomas are extremely rare, a staging workup was performed.
Figure 2: Low-power and high-power images of H and E-stained sections showed carcinoma with neuroendocrine features including trabecular pattern, the presence of solid nests or clusters of atypical cells with abundant cytoplasm and hyperchromatic nuclei. Negative for intraductal carcinoma. The morphological features of the lung tumor are identical to those of the breast tumor. NEC: Neuroendocrine carcinoma

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Figure 3: The immunohistochemic staining of the breast tumor showed negative for estrogen receptor, progesterone receptor, and GATA-3, positive for thyroid transcription factor (×200). NEC: Neuroendocrine carcinoma

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Figure 4: The immunohistochemic staining of the breast tumor and lung tumor showed positive for chromogranin A and synaptophysin (×200). NEC: Neuroendocrine carcinoma

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The mammogram of the bilateral breasts revealed a mass at lower outer quadrant of right breast, about 4.1 cm in size and 5 cm away from nipple, with circumscribed margin. No cluster of microcalcifications was noted [Figure 5].
Figure 5: The mammogram with right craniocaudal view reveals a lobular high-density mass at lower outer quadrant of right breast, about 4.1 cm in size and 5 cm from nipple, with circumscribed margin (arrow)

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The CT of the chest and abdomen revealed a lobular soft-tissue mass at 7:00 region of right breast about 3.4 cm in size with homogeneous enhancement and a 3.9 cm mass in the left lingular lung with mild homogeneous enhancement [Figure 6]. There was an enlarged mediastinum lymph node about 2.7 cm in size and suspected as a metastasis. The magnetic resonance imaging (MRI) of the brain revealed no definite brain metastasis.
Figure 6: The computed tomography of chest and abdomen showed: (a) A lobular soft-tissue mass at 7:00 region of right breast, about 3.4cm in size and 3.5cm from nipple, with homogeneous enhancement (white arrow) (b) A lobular lesion at lingular segment of the left upper lung lobe, about 3.9cm in the greatest dimension, with mild homogeneous enhancement (black arrow)

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The CT-guided biopsy was performed for the lung mass. The pathology revealed the presence of solid nests or clusters of atypical cells with abundant cytoplasm and hyperchromatic nuclei [Figure 2]. In immunohistochemical stains, the atypical cells are positive for synaptophysin and chromogranin A [Figure 4] and negative for GATA-3. The morphological features and immunohistochemical stains of the tumor are identical to those of the breast tumor. A primary pulmonary neuroendocrine carcinoma LCNEC with breast metastasis is more likely.

The final diagnosis was a lung LCNEC, Stage IV, cT2N2M1, with breast metastasis.

The patient received chemotherapy with EP regimen (etoposide and carboplatin) for 6 cycles. The chest and abdominal CT in January 2018, revealed partial regression of lung tumor (3.5 cm) and metastatic lymph node but progressive change of the right breast tumor (3.8 cm). The follow-up CT in March 2018, revealed partial regression of the left lung cancer (3.25 cm) and no significant interval change of the right breast metastatic mass (3.84 cm) as compared with the CT scan in January 2018. The follow-up brain MRI in March 2018, revealed no definite brain metastasis.

To evaluate the response of the treatment with revised Response Evaluation Criteria in Solid Tumors Guideline, the carcinomas were stable disease with the chemotherapy. The treatment for the metastatic carcinoma continues, and the alternative treatment will be planed.


  Discussion Top


A primary neuroendocrine tumor in breast is extremely rare. When a neuroendocrine tumor in the breast is identified, it is important to differentiate a primary breast neuroendocrine tumor from a metastatic disease to the breast because of the differences in treatment.[5]

Carcinoids appear to have increased in overall incidence over the past 30 years. Imaging study for the whole body including brain should be performed to trace other possible neuroendocrine tumor. When neuroendocrine carcinomas were noted in different organs, besides examination for the connection of clinical history and imaging findings, immunohistochemistry was helpful in identifying the primary site. The discussion below is the process to identify the primary site from the two neuroendocrine carcinomas found in our case.

  1. Tracing the clinical history, this patient did not have carcinoid syndrome such as diarrhea and cutaneous flushing. She did not have a history of neuroendocrine tumor or any other cancer
  2. Reviewing the literatures, the imaging characteristics of primary neuroendocrine carcinomas of the breast include (1). Irregular and ill-defined, hypoechoic, oval, or round lesion on breast ultrasound (2) round or oval high-density mass with ill-defined margin on mammogram (3) irregular mass with irregular margin, washout kinetics on the breast MRI [Table 1][6]

  3. The imaging characteristics of metastatic carcinoid tumors of the breasts include (1) most masses are irregular, hypoechoic on breast ultrasound (2) tend to be circumscribed masses on mammogram (3) may present as a rapidly enhancing mass with the most suspicious kinetic enhancement pattern on breast MRI [Table 1].[7] Our case had an irregular homogenous hypoechoic mass on breast ultrasound and a mass with circumscribed margin on mammogram that compatible with features of metastatic neuroendocrine carcinoma. However, these features could not definitely differentiate her breast neuroendocrine carcinoma to be primary or metastatic
  4. Immunohistochemistry plays a critical role on identifying for primary site of the neuroendocrine carcinomas. Most breast carcinomas with neuroendocrine differentiation are positive for ER and GATA3. Metastatic neuroendocrine carcinomas are usually negative for ER and GATA3. Metastatic neuroendocrine tumors often showed immunoreactivity for site-specific stains.[8]
Table 1: The imaging characteristics of primary and metastatic carcinoid tumors of the breasts

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The examples are TTF-1 for pulmonary origin, CDX2 for intestinal tract origin, ER/PR, mammaglobin, and GATA3 for mammary origin.[8] These immunohistochemical stains aid in distinguishing true primary tumors from metastatic tumors.

The immunohistochemical study of the breast tumor of our case showed (1) negative for ER, PR, and GATA-3 (2) positive for chromogranin and synaptophysin A (3) positive for TTF-1. The morphological features and immunostains of the lung tumor are identical to those of the breast tumor. Therefore, a primary lung neuroendocrine carcinoma with breast metastasis was favored.

The World Health Organization classification of lung tumors in 2015 uses immunohistochemistry throughout the classification. Neuroendocrine tumors are grouped together in one category. According to this classification, neuroendocrine tumors are classified into several subtypes: small cell carcinoma, LCNEC, carcinoid tumors (typical and atypical carcinoid tumor), adenosquamous carcinoma, sarcomatoid carcinomas, and some other types.[9]

LCNEC and small cell carcinoma are recognized as histologically high-grade carcinomas.[10] Histologically, LCNEC is defined as a nonsmall cell carcinoma with neuroendocrine morphology such as organoid or trabecular patterns, rosette-like structures and confirmation of neuroendocrine differentiation with immunohistochemistry.[10] The morphologic features in our case are compatible with the presentation of LCNEC. In operable patients, surgically resected tumors provide exact diagnosis. Our case had metastatic carcinoma, meaning in advanced disease, thus surgery was not adequate for her. We prescribed chemotherapy with proper regimen for treating LCNEC.

For patients with lung LCNEC, prognosis is very poor.[11] For the treatment of LCNEC, surgery is adopted for early stage tumors. Adjuvant chemotherapy consisting of platinum and etoposide likely prevents recurrence in patients with resected LCNEC.[10] In patients with advanced lung LCNEC, the chemotherapy regimens used in small cell lung cancer (SCLC) remain the standard of treatment.[11] According to clinical practice guideline of the American Society of Clinical Oncology updated in 2015, the first-line treatment for patients with LCNEC is platinum plus etoposide or the same treatment as other patients with nonsquamous carcinoma.[12]

Despites the chemotherapy regimens used in SCLC are effect in many studies for lung LCNEC, especially for patients with advanced disease, some studies revealed unsatisfactory result. Therefore, some alternative treatment such as octreotide, amrubicin, nadaplatin and irinotecan combination and target therapy are tried in many studies.[11]


  Conclusions Top


It is important to differentiate between a primary breast neuroendocrine tumor and metastatic disease to the breast because of the differences in treatment. In addition to examination for the clinical history and imaging findings, immunohistochemistry was used for identifying the primary site.

For patients with lung LCNEC, the prognosis is very poor. The chemotherapy regimens used in SCLC are often adopted for treatment for patients with advanced lung LCNEC. Some alternative treatments, such as octreotide and target therapy, are studied.

We present a rare case of lung LCNEC, initially presenting as a breast lump in her right breast. Analysis with immunohistochemistry helped us to identify that the lung was the primary site of these two neuroendocrine carcinomas. Proper treatment for her lung LCNEC with breast metastasis is in progress, initially with chemotherapy then may undertake alternative therapies.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given her consent for her images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003;97:934-59.  Back to cited text no. 1
    
2.
Melosky B. Advanced typical and atypical carcinoid tumours of the lung: Management recommendations. Curr Oncol 2018;25:S86-93.  Back to cited text no. 2
    
3.
Amin AL, Kong AL. Metastatic neuroendocrine tumor found on screening mammogram. WMJ 2011;110:140-3.  Back to cited text no. 3
    
4.
Papa A, Rossi L, Verrico M, Di Cristofano C, Moretti V, Strudel M, et al. Breast metastasis and lung large-cell neuroendocrine carcinoma:First clinical observation. Clin Respir J 2017;11:574-8.  Back to cited text no. 4
    
5.
Upalakalin JN, Collins LC, Tawa N, Parangi S. Carcinoid tumors in the breast. Am J Surg 2006;191:799-805.  Back to cited text no. 5
    
6.
Collado-Mesa F, Net JM, Klevos GA, Yepes MM. Primary neuroendocrine carcinoma of the breast: Report of 2 cases and literature review. Radiol Case Rep 2017;12:1-2.  Back to cited text no. 6
    
7.
Lee S, Levine P, Heller SL, Hernandez O, Mercado CL, Chhor CM, et al. Metastatic carcinoid tumor to the breast: Report of two cases and review of the literature. Clin Imaging 2017;42:88-92.  Back to cited text no. 7
    
8.
Mohanty SK, Kim SA, DeLair DF, Bose S, Laury AR, Chopra S, et al. Comparison of metastatic neuroendocrine neoplasms to the breast and primary invasive mammary carcinomas with neuroendocrine differentiation. Mod Pathol 2016;29:788-98.  Back to cited text no. 8
    
9.
Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JH, Beasley MB, et al. The 2015 World Health Organization classification of lung tumors: Impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 2015;10:1243-60.  Back to cited text no. 9
    
10.
Hiroshima K, Mino-Kenudson M. Update on large cell neuroendocrine carcinoma. Transl Lung Cancer Res 2017;6:530-9.  Back to cited text no. 10
    
11.
Lo Russo G, Pusceddu S, Proto C, Macerelli M, Signorelli D, Vitali M, et al. Treatment of lung large cell neuroendocrine carcinoma. Tumour Biol 2016;37:7047-57.  Back to cited text no. 11
    
12.
Masters GA, Temin S, Azzoli CG, Giaccone G, Baker S Jr., Brahmer JR, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2015;33:3488-515.  Back to cited text no. 12
    


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