Diagnosis and Clinical Management of Neuroendocrine Tumor of the Breast: Report of Six Cases and Systematic Review of Existing Literature

Alberto Bottini; Alessandro De Luca; Andrea Sagona; Corrado Tinterri; Emilia Marrazzo; Erika Barbieri; Federico Frusone; Giulia Puliani; Giuseppe Canavese; Wolfgang Gatzemeier

doi:10.31487/j.ACO.2020.01.02

Article
Article Info
Author Info
Figures & Tables
References

Diagnosis and Clinical Management of Neuroendocrine Tumor of the Breast: Report of Six Cases and Systematic Review of Existing Literature

A B S T R A C T

Introduction: Neuroendocrine neoplasm of the breast (bNENs) are considered a rare disease, even if in WHO data they represent about 2-5 % of all breast cancer. The last WHO classification includes: well-differentiated neuroendocrine tumor (bNET), neuroendocrine carcinoma (NEC) and invasive carcinoma with neuroendocrine differentiation. The current knowledge on clinical management of bNENs is poor and patients are usually treated according to non-endocrine tumor components guidelines.
Materials and Methods: We presented our experience of six cases of bNENs. Moreover, we conducted a systematic review of published data on diagnosis, treatment and outcome of this kind of tumors.
Results: bNENS usually presented as palpable breast masses, classically appearing as irregular hypoechoic lesions at US examination and as hyperdense masses at mammography. Usually pre-operative tumor biopsy is not able to recognize the neuroendocrine components and the final diagnosis is performed only on definitive histopathological assessment. The most frequent subtype seems to be neuroendocrine carcinoma and synaptophysin is positive in most specimens. Treatment strategies, including surgical treatment, radiotherapy and medical treatment are nowadays based on current non-endocrine breast cancer guidelines, independently from neuroendocrine components, even if some studies have proposed the use of somatostatin analogues for bNET and cisplatin-etoposide for NEC. Prognosis of all bNENs, especially of poorly differentiated neoplasia, seems worse compared to non-neuroendocrine breast cancer and stage and morphology seem the best predictor of tumor outcome.
Conclusions: We provide an algorithm for clinical management of bNETs, basing on available data. More studies are necessary for confirming the best treatment strategy for these patients, in order to improve clinical outcome.

Keywords

Neuroendocrine tumor (NET), breast, neuroendocrine carcinoma, carcinoid, neuroendocrine neoplasia

Introduction

The first description of a neuroendocrine tumor (NET) of the breast dates back to 1963: an invasive breast cancer morphologically similar to intestinal carcinoids [1]. World Health Organization (WHO) recognized neuroendocrine tumors of the breast as a separate entity of breast cancer only in 2003, defining them as primary neuroendocrine carcinomas exhibiting morphological features of gastrointestinal and pulmonary NETs in which more than 50% of the cells expresses neuroendocrine markers (chromogranin A and synaptophysin) [2]. In 2012 the cut-off of 50% of the cells expressing neuroendocrine markers was eliminated and bNENs were divided in groups according to morphology: well-differentiated (carcinoid-like) neuroendocrine tumor (bNET), poorly differentiated neuroendocrine carcinoma (NEC) small-cell neuroendocrine carcinoma (SCNC) and invasive carcinoma with neuroendocrine differentiation (ICNE) [3]. According to WHO data, bNENs represent about 2-5 % of all breast cancer [4]. In data from SEER database bNENs represent less than 0.1% of total invasive carcinomas of the breast [5]. Probably these frequencies may underestimate the real incidence of bNENs: retrospective studies on breast tumor specimens showed high incidence of neuroendocrine cells with positive neuroendocrine markers [6, 7]. Nowadays, the impact of neuroendocrine differentiation of breast cancer on diagnosis, treatment and outcome is still unclear. Because of the low incidence of this kind of neoplasia, no clinical trials or guidelines are available on this topic. The aim of this systematic review is to summarize clinical presentation, diagnosis, treatment and outcomes of all available cases in Literature, adding our personal experience of six cases.

Materials and Methods

I Article Identification

We searched PubMed, Embase, Google Scholar and Cochrane databases for English language studies on neudoendocrine tumor of the breast. Search terms used were: “neuroendocrine tumor” AND breast, “neuroendocrine tumour” AND breast; “neuroendocrine cancer” AND breast; “neuroendocrine carcinoma” AND breast.

II Eligibility Criteria

We included English-language studies on humans with any of the following design: randomized clinical trials, prospective non-randomized trials, retrospective studies, case reports and case series. We selected cases classified by the pathologist as neuroendocrine breast tumor, according to WHO classification used at time of publication (2003 or 2012). For article published before 2003, we included cases defined as breast neuroendocrine tumors or carcinoids by the Authors. We included in the systematic reviews only articles with data on at least one of the following topics: clinical presentation, treatments and outcomes of neuroendocrine tumors of the breast. Last search date was February 2019.

III Article Selection

Each study was screened by abstract and title and potentially eligible studies were further assessed in detail by retrieving full-length articles. Each full-length article was independently reviewed by two separate Authors following inclusion criteria. Two authors independently extracted data from the articles that met the inclusion criteria. A standardized form was used to extract the following information: year of publication, type of study, number of patients included, age at diagnosis, sex, familiarity for breast tumors, other known risk factors for breast cancer, clinical presentation, palpability, diagnostic procedures (ultrasound, mammography, MRI, CT, PET, fine needle aspiration and biopsy), treatment strategy (surgery, medical treatment, radiotherapy), histopathological examination including immunohistochemistry, stadiation and outcomes.

Results

I Case Series

We present six cases of bNENs diagnosed in Humanitas Research Hospital of Milan from 2012 to 2018. All patients provided written informed consent to case publication. All cases were females, mean age 64.2 ± 13.7. All patients presented with breast lumps (in one case painful). When performed, breast ultrasound (US) always showed a mass (in three cases hypoechoic mass) and mammography showed 4 spiculated and 1 regular margin hyperdense lesion of 0.8-2.7 cm of maximum diameter. Breast magnetic resonance imaging (MRI) was not performed in all cases due to lack of indication. Biopsy showed in all cases infiltrating breast carcinoma but only in one case succeeded in identifying neuroendocrine differentiation. All patients underwent surgical intervention. Surgery on tumor mass was in 4 cases breast conservative surgery (BCS) and in 2 cases total mastectomy; axillary surgery consisted of 3 lymphadenectomies and 3 sentinel lymph node biopsies. Radiotherapy was performed in the 4 cases of BCS. Definitive histopathological evaluation confirmed in all cases the neuroendocrine differentiation: 2 bNET, 2 breast NEC and 2 ICNE. In our case series synaptophysin has been the most important neuroendocrine marker, been positive in 6/6 cases. Chromogranin was positive in 1/3 cases while NSE was never evaluated. 5/6 (83,3%) cases showed positivity for both oestrogen and progesterone receptors. Ki67 ranged from 10 to 90%.

After definitive diagnosis, all patients performed a total body scans (18FDG PET/CT and contrast-enhanced total body CT scans) for excluding neuroendocrine neoplasm of other origin. After surgical removal, patients underwent chemotherapy or hormonal therapy according to associated non-endocrine breast tumor histotype guidelines (2 only hormone therapy, 1 chemotherapy, 3 hormone therapy associated to chemotherapy). One patient with NEC developed liver and bone metastasis after 6 months and is now alive with metastatic disease after one year of follow-up. Medium follow-up of other cases was 65 (35-120) months: 3 patients are today alive and disease free, two are alive with local recurrence. All data are summarized in Table 1A.

Figure 1: Flowchart of literature eligibility assessment process.

Enlarge Image

II Systematic Review

From the initial search we retrieved 445 articles. After screening for title and abstract we identified 140 potentially eligible articles. After full text examination a total of 117 articles were included in this systematic review (Figure 1). 102 articles were case reports on a total of 113 bNENs. Available data are summarized in Table 1B. 15 articles were retrospective studies or case series on a total number of 731 patients: data are summarized in Table 2.

Table 1A: Case series.

Preoperative diagnosis

Treatment

Tumor biology

Follow-up

Case

Age

Clin pres

US

MX

CT

PET

Bio / Cit

Nadj

treat

Surgery

Adj treat

Adj RT

pTNM

Tum size

LNs

Histo-type

CrA

Syn

ER

PR

Her2

Ki67

FUP

(mo)

Alive status

1

66

BL

NA

Neg

Bio

NO

BCS + ALND

ADR/CPA + DTX + Ana

Yes

T2N3aM0

2,3

12/14

ICNE

NA

+

70%

60%

0

10%

120

AWD

2

54

BL

HyBM

SBM

Neg

Bio

NO

Mast + SLNB

ADR/CPA + DTX + Ana

No

T2N0M0

2,7

0/1

NET

-

+

95%

29%

0

70%

60

NED

3

43

PBM

HyBM, N+

SBM

Neg

BoMet, LMet

Bio

Yes

Mast + ALND

CDDP + VP-16

Yes

T4bN3aM1

12

9/14

NEC

+

0

90%

12

AWD

4

66

BL

BM

HypBM

Neg

Bio

NO

BCS + ALND

ADR/CPA + DTX + Ana

Yes

T1N3aM0

0,8

13/15

ICNE

NA

+

80%

70%

0

12%

53

AWD

5

78

BL

HyBM

SBM

Neg

Bio

NO

BCS + SLNB

Ana

No

T1cN0M0

1,9

0/16

NET

-

+

95%

1+

25%

76

NED

6

78

BL

BM

SBM

Neg

Bio

NO

BCS + SLNB

Ana

Yes

T1cN0M0

2

0/2

NEC

NA

+

95%

0

20%

70

NED

HeadingS: NA = Not available data; Clin Pres = Clinical presentation; US = breast Ultrasound; MX = mammography; Bio = biopsy; Cit = citology; Ad treat = adjuvant treatment (chemotherapy and/or hormone therapy); Adj RT = adjuvant radiotherapy; Tum size = tumor size (centimeters); LNs = lymph nodes removed; CrA = Chromogranin A; Syn = Synaptophisin; ER = Estrogen receptor; PR = Progesterone receptor; Her2 = her2-neu receptor; FUP = follow-up (months).

Clinical and radiological findings: Pos = positive for malignancy; Neg = negative for malignancy; BM = Breast Mass; CM = carcinomatous mastitis; N+ = axillary adenopathy, PBM = Painful breast mass; BL = breast lump; SR = Skin retraction, NR = nipple retraction, PLM = Paget-like Mass; BND = Bloody nipple discharge; UBM = Ulcerated Breast Mass; MBM = Multilobulated breast mass; HyBM = Hypoechoic (US) / Hypodense (MX) breast mass; Hyp = Hyperechoic (US) / Hyperdense breast mass = HeBM = Heterogeneous breast mass, SBM = Spiculated breast mass, Mic = microcalcifications, BoMet = Bone Metastases; LMet = Lung metastasis; PAMet = Perianal metastases, PiMet = Pituitary metastases; PaMet = Pancreatic metastases; PE = Pleural effusion; MMet = Multiple metastases; IBM = Isoechoic breast mass
Neg = Negative; Sus = suspicious; LMet = lung metastasis.
Mast = Mastectomy; BCS = Breast Conservative Surgery; SLNB = Sentinel Lymph Node Biopsy; ALND = Axillary Lymph Node Dissection.

Chemotherapy: ChT = chemotherapy (not defined); HoT = hormone therapy (not defined); CDDP = Cisplatin, CBL = Carboplatin, VP-16 = Etoposide, CPT-11 = Irinotecan, 5-FU = Fluorouracil, EPI = Epirubicin, CAP = Capecitabine, DTX = Docetaxel, 5’-DFUR = 50 deoxy-5-fluorouridine, Tor = Toremifene, CPA = Cyclophosphamide, EPI = Epirubicin, Tam = Tamoxifen, Tor = Torenifene, Let = Letrozole, S = Streptozotocin, MTX = Methotrexate, Ana = Anastrazole, AI = Aromatase inhibitor, LHRH = Leutinising hormone releasing hormone analogue, UFT = Uracil & Tegafur, PTX = Paclitaxel, ADR = Adriamycin (Doxorubicin), Sando = Sandostatin, Som = Somatostatin; Ever = Everolimus, Bev = Bevacizumab, Erl = Erlotinib; Palb = Palbociclib; Oct = Octreotide.

Histology: SCNC = Small Cell Neuroendocrine Carcinoma, ICNE = Invasive carcinoma with neuroendocrine differentiation; NET = well-differentiated neuroendocrine tumor; NEC = poorly differentiated neuroendocrine carcinoma.

Follow-up: NED = No evidence of disease; AWD = Alive with disease; DOD = Died of disease; DUC = Died of Uncertain cause †Median follow-up.

Table 1B: Case reports available in literature.

Author

Preoperative diagnosis

Treatment

Tumor biology

Follow-up

Author

(year)

Year

Age

Clin pres

US

MX

CT

PET

Bio / Cit

Nadj

treat

Surgery

Adj treat

Adj RT

pTNM

Tum size

LNs

Histo-type

CrA

Syn

ER

PR

Her2

Ki67

FUP

(mo)

Alive status

Wade[23]

1983

52

UBM N+

MBM

Neg

NO

Bio

NO

Mast + ALND

VP-16

NO

T4N1M0

10

25/25

SCNC

NA

Jundt[24]

1984

52

NA

TXN1M1

NA

+/?

NA

14

DOD

Francois[25]

1995

68

BM

HeBM

HBM

Neg

NO

Cit

NO

Mast + ALND

CPA/ADR/VP-16

Yes

T2N0M0

4

0/12

SCNC

NA

-

NA

21

DUC

Chua[26]

1997

45

BM

NA

Bio

NO

BCS

NA

NO

T2N0MX

4,5

NA

SCNC

-

+

-

NA

<1

NED

Yalcin[27]

1997

63

BM

Neg

NA

Bio

NO

Mast + ALND

NO

T2N0M0

5

0/?

NET

+

NA

18

NED

Fukunaga[28]

1998

51

BM

Neg

BM

Neg

NO

NA

Mast + ALND

NA

T2N0M0

2,5

0/29

NET

+

-

+

-

NA

16

NED

Fukunaga[29]

1998

38

BM

Neg

NO

NA

NO

Mast + ALND

NO

T2N1M0

2,5

1/7

NEC

+

-

12%

72

NED

Sebenik[30]

1998

67

NA

Yes

Mast + ALND

NA

T2NXM0

4

NA

33

NED

Samli[31]

2000

60

PBM

BM

Neg

NO

Bio

Yes

Mast + ALND

CDDP/VP-16+

5-FU/CPA/EPI

Yes

T4N1M0

4,5

10/11

SCNC

+

NA

6

AWD

Yamasaki[32]

2000

41

BM

Neg

SBM

Neg

Sus

Cit

NO

Mast + ALND

CPA/MTX/5-FU

NO

T2N0M0

3,5

0/5

SCNC

+

-

NA

16

NED

Hoang[33]

2001

41

NA

T3NXMX

14,5

NA

51

NA

T3NXMX

8

NA

Salmo[34]

2001

46

NA

NO

BCS

ChT

YES

T2N0M0

4

NA

9

NED

Berruti[35]

2004

59

LMet

Neg

LMet

NO

NA

Yes

LMet resection

Tam

NO

TXNXM1

NA

NEC

+

-

12

144

NED

Bigotti[36]

2004

56

CM

BM

NA

Neg

Bio

Yes

NO

ChT + Som

NO

T3N1M0

18

2/9

SCNC

-

+

-

NA

15

DOD

Bergman[37]

2004

61

BL

BM

Neg

Bio

NO

Mast + ALND

NO

T2N1M0

2,5

2/5

SCNC

-

NA

Jochems[38]

2004

71

BM

NA

BM

Neg

Bio

NO

Mast + ALND

Tam

NO

T2N0M0

3

0/10

NEC

+

-

NA

12

NED

Mariscal[39]

2004

53

BM, SR, N+

HyBM

BM, N+

Neg

Bio

Yes

BCS + ALND

HoT

NO

T3N1M0

5,5

1/?

SCNC

NA

+

NA

6

NED

Sridhar[40]

2004

58

NA

NO

BCS

ChT

YES

T2N1M0

2

NA

18

NED

Yamamoto [41]

2004

53

NA

Neg

NA

NO

NA

NO

T3N2M0

6,5

NA

-

NA

34

NED

75

NA

Neg

NA

NO

NA

CPA/MTX/5-FU + HoT

NO

T2N1M0

2,5

NA

+

NA

43

NED

Adegbola[42]

2005

46

BL

NA

Neg

NO

BCS

CDDP/VP-16+

Yes

T1NXM0

1

0

SCNC

+

-

NA

-

NA

48

NED

60

BM

NA

Neg

NO

BCS

CDDP/VP-16+

Yes

T1NxM0

1,7

0

SCNC

+

-

NA

-

NA

20

DOD

61

BM, N+

NA

Neg

NO

BCS

CDDP/VP-16+

Yes

T1NxM1

1,7

0

SCNC

+

-

NA

-

NA

6

AWD

Stein[43]

2005

54

BM, N+

NA

Bio

Yes

Mast + ALND

NO

Yes

T1N1M0

1,5

5/15

SCNC

+

NA

-

NA

24

NED

Tsai[44]

2005

42

BM

NA

Neg

NA

Bio

NA

Mast

NA

NEC

+

NA

Fujimoto[45]

2007

40

BL, BND

HyBM

Neg

NO

Bio

NO

Mast + SLNB

Ana

NO

T2(m)N0

M0

2

0/1

NEC

+

NA

+

NA

Hennessy[46]

2007

63

PAMet

Neg

BMet

PAMet

NO

Bio

NO

Mast + SLNB

ChT/Tam

NO

TXNXM1

NA

NEC

+

NA

AWD

Kitakata[47]

2007

44

BL

HyBM

BM

Neg

NO

Mast + ALND

CPA/Epi + DTX

NO

T2N1M0

4,5

2/15

SCNC

-

+

-

+

-

NA

22

NED

La Rosa[48]

2007

49

BL

Pos

NO

Cit

NO

Mast

ChT

NO

T2NXMX

2,5

NA

NEC

+

-

NA

Vidulich[49]

2007

76

BM, N+, PE

BM, N+

NA

LMet

MMet

Cit, Bio

NO

Oct/Ever, Bev/Erl

NO

T4N1M1

5

NA

NEC

+

-

NA

AWD

Yaren[50]

2007

76

NA

Neg

NA

NO

Mast + ALND

HoT

NO

T2N0M0

5

0/13

NA

+

NA

12

NED

Jeong[51]

2008

39

BL

IBM

HypBM

NO

Mast + ALND

ChT / Hot

Yes

T2N1M1

2,2

2/14

NEC

+

NA

32

NED

Kim[52]

2008

27

BM

HeBM

BM

Neg

Bio

NO

BCS + ALND

ChT

Yes

T2NXM0

3,2

NA

NEC

+

-

NA

18

NED

Kinoshita[53]

2008

31

BL

HyBM

Neg

MMet

NO

Bio

Yes

Mast + ALND

CDDP/CPT-11

NO

T2N1M1

3,7

7/30

SCNC

+

-

+

-

NA

1

AWD

Lopez Garcia[54]

2008

31

NA

Neg

NA

NO

Mast + ALND

NO

YES

T3N1MX

10

2/15

NA

-

NA

15

DOD

Mecca[55]

2008

70

PLM

NA

NO

NA

NO

BCS + SLNB

NO

T4N1M0

1,9

2/2

NEC

NA

+

NA

12

NED

Ogawa[11]

2008

34

BM

HeBM

HypBM

Neg

NA

Bio

NA

BCS

NA

T2NXM0

2,7

NA

NET

+

-

+

NA

7

NED

Pagani[56]

2008

62

NA

BCS + ALND

NA

T1N2MX

1,5

19/20

NA

+

NA

41

NA

Mast + ALND

NA

T2N1MX

4,1

1/18

NA

Sadanaga[57]

2008

33

NA

Yes

Mast ALND

ChT

YES

T2N0M0

4

0/?

NA

60

NED

Ulamec[58]

2008

60

Hematuria

BM

NA

Yes

Mast + ALND

HoT

Yes

T4N2M1

4,5

9/9

NEC

-

+

5%

18

NED

Akhtar[59]

2009

40

BL, N+

NA

Cit, Bio

NA

Mast + ALND

NA

T3NXMX

8,5

NA

NEC

NA

+

NA

Burckhardt[60]

2009

84

NA

Yes

Mast + ALND

HoT

NO

T2N1M0

3

+/?

NA

+

NA

NED

El Hassani[61]

2009

40

BM

NA

BM

Neg

NO

Bio

Yes

NO

VP16-CDDP

NA

T4NXMX

NA

NEC

+

NA

1

DOD

Ersahin[62]

2009

50

NA

BCS

NA

T3NXM0

2,5

NA

12

NED

Haji[63]

2009

68

NA

YES

Mast + ALND

NO

T3N1M0

5,8

NA

6

DOD

Hojo[64]

2009

60

NA

NO

Mast + ALND

NO

T3N0M1

3

0/?

NA

26

AWD

Lee[65]

2009

65

BM

HyBM

HypBM

NO

Neg

NO

BCS + SLNB

HoT

NO

T1N0M0

1,6

0/1

NEC

NA

+

-

NA

NED

Okoshi[66]

2009

63

BM

HyBM

HypBM

Neg

No

Cit

NO

BCS + ALND

ChT

Yes

T2N0M0

2

0/?

NET

-

+

-

+

NA

44

NED

Rivero[67]

2009

41

NA

YES

BCS

NO

Yes

T3N0M0

6

0/?

NA

20

NED

Rineer[68]

2009

81

NA

YES

BCS

NO

Yes

T3N1M0

5

NA

26

AWD

Salama[69]

2009

48

BoMet

NA

YES

NO

T4NXMX

2,5

NA

+

NA

<1

AWD

Sartori[70]

2009

70

NA

Neg

NA

NO

BCS + ALND

Som

Yes

T1N3M0

1,8

34/?

NA

+

NA

12

NED

Stita[71]

2009

64

BM

Neg

NO

NA

NO

Mast + ALND

ChT

NO

T2N0M0

3

0/?

NET

+

NA

8

NED

Yamaguchi[72]

2009

51

BM

NA

Neg

Bio

NO

Mast + ALND

PTX

NO

T2N0M0

2,5

NA

SCNC

+

-

85%

12

AWD

Christie[73]

2010

61

NA

NO

BCS

NO

T3N2M0

3

NA

3

DOD

Goucha[74]

2010

40

NA

NO

BCS + ALND

NO

Yes

T1N0MX

1,8

0/15

NA

+

NA

12

NED

Honami[75]

2010

54

BND

HyBM

Neg

NO

No

Bio

NO

BCS

HoT

Yes

T1NXMX

1,5

NA

ICNE

+

NA

-

NA

18

NED

Huettemann [76]

2010

65

NA

Neg

NA

NO

Mast + ALND

DTX/Bev

NO

T3N1M1

9

NA

Latif[77]

2010

53

BM

Neg

BM

NO

Neg

Cit, Bio

Yes

BCS + SLNB

Tam/Som

Yes

T3N0M0

1 cm

0/1

SCNC

+

-

NA

-

NA

Saglam[78]

2010

60

NA

Neg

NA

NO

T4N1M1

0,6

1/1

NA

+

NA

26

DOD

Salman[79]

2010

72

NA

Neg

NA

NO

Mast + ALND

Letr

NO

TXNXM1

NA

+

NA

12

NED

Buttar[80]

2011

63

Jaundice

NA

Pos

NO

Bio

NO

Tam/Ana

NO

T2N0M1

NA

0/1

NEC

-

+

NA

-

NA

12

NED

Cesaretti[81]

2011

68

BM, N+

BL

HypBM

NA

Cit, Bio

NO

BCS + ALND

ADR/CPA + Ana

Yes

T1cN0Mx

1,1

0/19

NEC

+

-

7%

34

NED

Ghanem[82]

2011

64

BM, N+

BN

Neg

NA

Bio

Yes

Mast + ALND

ADR/CPA + Ana

YES

T3N2M0

8

16/23

NA

+

NA

+

-

10%

32

AWD

Jach[83]

2011

28

BL

BN

NA

Bio

NO

BCS + ALND

ADR + Tam

YES

T1N0M0

1,1

0/4

ICNE

+

NA

+

NA

40%

NA

Kavasaki[84]

2011

43

BND

BM

NA

NO

BCS

NA

T1N0M0

1,2

0/4

NEC

+

NA

+

NA

Kawanishi [85]

2011

67

UBM

HyBM

BM

NA

Cit, Bio

NO

BCS + SLNB

Ana

NO

T1N0M0

0,8

0/1

NEC

+

NA

-

NA

12

NED

Navrozoglou[86]

2011

73

NO

BN

NA

Neg

Bio

NO

Mast + ALND

NO

T1N0M0

1,1

0/17

NET

+

NA

48

NED

Nicoletti[87]

2011

40

BM

BN

Neg

NO

Bio

NO

Mast + ALND

ADR/CPA + CBL/VP-16 + Tam/LHRH

NO

T2N1M0

3

1/16

SCNC

+

-

+

96

NED

Nozoe[88]

2011

57

BL

HyBM

BM

NA

NO

Mast + ALND

CMF + AI

NA

3

0/?

NEC

NA

+

-

NA

Zhang[89]

2011

29

BND

BM

NO

Cit

NO

BCS + SLNB

CPA/EPI/5-FU + DTX + Tor

NA

T2N0M0

2

0/2

NET

+

-

1%

20

NED

Alkaied[90]

2012

83

Anorexia

Neg

NO

Pos

Bio

Yes

NO

Letr - Ana

NA

TXNXM1

NA

SCNC

-

+

NA

12

NED

Flessas[91]

2012

59

NO

NA

Mic

NO

Bio

NO

BCS +ALND

NA

T2N1M0

2,8

1/?

ICNE

+

NA

Graça[92]

2012

83

BM

BN

BM

Neg

Cit

NO

BCS + SLNB

HoT

NO

T2N0M0

2,4

0/1

NEC

NA

+

NA

NED

Menéndez [93]

2012

44

NO

NA

BM

NA

NO

BCS + ALND

5-FU/EPI/CPA

Yes

T2N0M0

2

1/?

NEC

NA

+

-

NA

48

NED

68

NO

NA

BM

NA

NO

BCS + SLNB

5-FU/EPI/CPA + DTX + Ana

Yes

3,6

NA

NEC

+

NA

24

NED

58

NO

NA

BM

NO

Bio

NO

BCS + SLNB

5-FU/EPI/CPA

Yes

T1N0M0

1

0/1

NEC

NA

+

-

NA

8

AWD

69

NO

HyBM

BM

NA

BCS + SLNB

NA

T1N0M0

1,4

0/1

ICNE

+

-

10%

2

NED

Miura[94]

2012

72

NO

NA

Neg

NA

Cit, Bio

NO

BCS + SLNB

NA

1,5

0/1

NEC

+

-

1%

NA

Psoma[95]

2012

46

BM

HyBM

HypBM

Neg

NO

NA

NO

Mast + ALND

CDDP/EPI/VP-16

Yes

T3N0M0

6,5

NA

NET

+

NA

6

NED

Su[96]

2012

75

PBM

HyBM

HypBM

Neg

NA

Bio

NO

Mast + ALND

Let

NO

T2N0M0

4

0/?

ICNE

+

-

NA

20

NED

Watrowski [97]

2012

56

BM

HyBM

NA

NO

Bio

NO

BCS + SLNB

CPA/EPI/5-FU + HoT

Yes

T1N0M0

1,7

0/1

NET

NA

+

-

46%

15

NED

Yavas[98]

2012

77

BM, N+

BM

HypBM

Neg

NO

NA

NO

Mast + ALND

NO

T2N1M0

3

5/16

ICNE

NA

+

NA

15

NED

Abbasi[99]

2013

37

BL, N+

NA

BoMet

NA

Bio

NO

Mast + ALND

5-FU/ADR/CPA + CDDP + VP-16

NO

T3N2M1

7,5

9/19

ICNE

+

NA

6

NED

Angarita[100]

2013

51

BL

Neg

SBM

Neg

NO

Bio

Yes

BCS + ALND

CDDP/VP-16 + PTX

NA

T2N0M0

3,2

0/?

ICNE

+

-

NA

-

>20%

13

AWD

Chang[101]

2013

42

BL

MBM

HypBM

NO

Neg

Cit

No

NO

NA

T2N1M0

NA

+/?

NEC

+

NA

-

NA

Hanna[102]

2013

60

PBM

Neg

NO

Bio

NO

BCS

CBL/VP-16

NO

T1N2M0

1,4

4/11

NEC

-

+

NA

-

NA

Senetta[103]

2013

82

Asthenia

BM

NA

PiMet

NO

Bio

NO

BCS + SLNB

HoT

NO

T1NXM1

2,3

NA

NEC

+

-

10

NA

Yoon[8]

2013

44

BM

HyBM

Neg

Bio

NA

Mast + ALND

CPA/ADR

NA

T2NXM0

2

NA

NEC

+

NA

2

NED

Cinkir[104]

2014

75

BM

NA

Bio

NO

Mast + ALND

CDDP/VP-16

Yes

T0N0M0

0

0/?

SCNC

+

-

5%

30%

NED

2014

77

PBM

SBM

NA

Bio

NO

Mast + ALND

AI

NO

T2NXM0

2,3

NA

NEC

+

-

10%

9%

NED

Pagano[105]

2014

51

BL, NR

NA

BM

Neg

NA

Bio

NO

Mast + ALND

CPA/MTX/5-FU + Tam

NA

T2N2M0

3,5

5/28

NET

+

-

30

126

AWD

Suhani[106]

2014

66

BL

NA

Neg

NA

Bio

NO

Mast + ALND

CPA/ADR/5-FU + AI

Yes

T3N1M0

6,5

1/15

NET

+

-

+

-

NA

48

NED

55

BL

NA

Neg

NA

Bio

NO

Mast + ALND

CPA/ADR/5-FU + AI

Yes

T2N1M0

4,5

2/16

NET

+

-

+

-

NA

36

NED

50

BL

NA

Neg

NA

Bio

NO

Mast + ALND

CPA/ADR/5-FU + AI

Yes

T2N0M0

4

0/18

NET

+

-

NA

18

NED

60

BL, BND

NA

Neg

NA

Bio

NO

Mast + ALND

CPA/ADR/5-FU + AI

Yes

T3N1M0

5,5

1/16

NET

-

+

-

NA

9

NED

Janosky[107]

2015

34

BL

Neg

HypBM

NA

Neg

Bio

Yes

BCS + ALND

CBL/PTX

Yes

T2N0M0

3,5

0/?

NEC

+

-

NA

-

100%

2

AWD

Kawasaki[108]

2015

60

SR

HyBM

NA

Neg

NO

Bio

NO

BCS + ALND

Ana

NO

T1N0M0

1,2

0/4

NEC

+

-

+

NA

0

6.3%

48

AWD

Rana[109]

2015

65

BL

NA

Neg

NO

Bio

NA

Mast + ALND

NA

T3N2M0

6

4/20

NEC

+

-

NA

Santos-Juanez[110]

2015

80

BM

Neg

Pos

NO

Bio

Yes

NO

Yes

T4NXM1

17

NA

NET

+

-

10%

5

NED

Sherwell-Cabello[111]

2015

60

BL, N+

NA

Neg

NA

NO

Mast + ALND

CBL/VP-16

Yes

T3N3M0

6

11/15

NET

-

+

-

70%

6

NED

Wei[112]

2015

43

BM

HyBM

MBM

NO

Bio

Yes

Mast + ALND

NA

T2N1M0

3

1/?

NET

+

-

+

10%

NA

Alva[113]

2016

53

BL

Neg

SBM

Neg

NO

Cit

NO

Mast + ALND

NA

T2N0M0

5

0/10

NEC

+

-

NA

-

NA

Christensen [114]

2016

73

SR

BM

PaMet

NA

BCS + ALND

NA

T2N3M1

3,8

18/21

ICNE

-

+

NA

4,5

AWD

D'antonio [115]

2016

50

BL

Neg

Bio

NO

BCS + ALND

NO

T1N0M0

1,5

0/?

ICNE

+

-

+

-

<5%

12

NED

Mečiarová[116]

2016

42

BL

HyBM

HypBM, Mic

Neg

NA

NO

BCS + SLNB

VP-16/CDDP

Yes

T2N1M0

3,2

1/1

NEC

+

-

50%

36

NED

Nakai[117]

2016

46

PBM

HyBM, N+

NA

Neg

NA

Bio

NO

Mast + ALND

CPA/EPI/5-FU

NA

T2N2M0

2,3

9/17

NET

+

61%

4

NED

Takanami [118]

2016

57

Neuralgia

NA

Pos

NA

Bio

NA

Mast + ALND

NA

T2N0M0

NA

NET

NA

180

AWD

Abou Dalle[119]

2017

47

NO

NA

BM

NO

Neg

Bio

NO

Mast + SLNB

CDDP/VP-16 + 5-FU/EPI/CPA + Tam

NO

T2N0M0

3

0/4

SCNC

+

NA

-

50%

10

NED

Maqsood [120]

2017

67

Neuralgia

HyBM

BM

MMet

Bio

Yes

NO

Let + Palb

NO

T1NXM1

1

NEC

-

+

NA

-

NA

3

AWD

Soe[121]

2017

57

BL

HyBM

HypBM

NA

BoMet

NA

NO

BCS

CDDP/VP-16 + Oct

NO

T2NXM1

4

NA

NET

+

NA

15%

18

NED

Headings: NA = Not available data; Clin Pres = Clinical presentation; US = breast Ultrasound; MX = mammography; Bio = biopsy; Cit = citology; Ad treat = adjuvant treatment (chemotherapy and/or hormone therapy); Adj RT = adjuvant radiotherapy; Tum size = tumor size (centimeters); LNs = lymph nodes removed; CrA = Chromogranin A; Syn = Synaptophisin; ER = Estrogen receptor; PR = Progesterone receptor; Her2 = her2-neu receptor; FUP = follow-up (months)

Clinical and radiological findings: Pos = positive for malignancy; Neg = negative for malignancy; BM = Breast Mass; CM = carcinomatous mastitis; N+ = axillary adenopathy, PBM = Painful breast mass; BL = breast lump; SR = Skin retraction, NR = nipple retraction, PLM = Paget-like Mass; BND = Bloody nipple discharge; UBM = Ulcerated Breast Mass; MBM = Multilobulated breast mass; HyBM = Hypoechoic (US) / Hypodense (MX) breast mass; Hyp = Hyperechoic (US) / Hyperdense breast mass = HeBM = Heterogeneous breast mass, SBM = Spiculated breast mass, Mic = microcalcifications, BoMet = Bone Metastases; LMet = Lung metastasis; PAMet = Perianal metastases, PiMet = Pituitary metastases; PaMet = Pancreatic metastases; PE = Pleural effusion; MMet = Multiple metastases; IBM = Isoechoic breast mass
Neg = Negative; Sus = suspicious; LMet = lung metastasis
Mast = Mastectomy; BCS = Breast Conservative Surgery; SLNB = Sentinel Lymph Node Biopsy; ALND = Axillary Lymph Node Dissection

Chemotherapy: ChT = chemotherapy (not defined); HoT = hormone therapy (not defined); CDDP = Cisplatin, CBL = Carboplatin, VP-16 = Etoposide, CPT-11 = Irinotecan, 5-FU = Fluorouracil, EPI = Epirubicin, CAP = Capecitabine, DTX = Docetaxel, 5’-DFUR = 50 deoxy-5-fluorouridine, Tor = Toremifene, CPA = Cyclophosphamide, EPI = Epirubicin, Tam = Tamoxifen, Tor = Torenifene, Let = Letrozole, S = Streptozotocin, MTX = Methotrexate, Ana = Anastrazole, AI = Aromatase inhibitor, LHRH = Leutinising hormone releasing hormone analogue, UFT = Uracil & Tegafur, PTX = Paclitaxel, ADR = Adriamycin (Doxorubicin), Sando = Sandostatin, Som = Somatostatin; Ever = Everolimus, Bev = Bevacizumab, Erl = Erlotinib; Palb = Palbociclib; Oct = Octreotide

Histology: SCNC = Small Cell Neuroendocrine Carcinoma, ICNE = Invasive carcinoma with neuroendocrine differentiation; NET = well-differentiated neuroendocrine tumor; NEC = poorly differentiated neuroendocrine carcinoma

Follow-Up: NED = No evidence of disease; AWD = Alive with disease; DOD = Died of disease; DUC = Died of Uncertain cause
†Median follow-up

Table 2: Case series and retrospective studies reported in literature.

Author	Year	Study type	N. patients	Mean age (range)	Only breast	N+ (%)	M1 (%)	ER+	PR+	Her2+	CrA+	Syn+	Mast	BCS	No surgery	Adj RT	Adj CHT	Adj OT	Mean FUP (range)
Papotti[122]	1992	CS*	4	56 (41-64)	25,00%	75,00%	50,00%	NA	NA	NA	NA	NA	100,00%	0,00%	0,00%	25,00%	25,00%	25,00%	20,5(9-44)
Shin[123]	2000	CS*	9	55,4 (43-70)	44,44%	55,56%	0,00%	66,67%	55,56%	0,00%	44,44%	44,44%	33,33%	66,67%	0,00%	44,44%	77,78%	0,00%	20,3(3-35)
Zekioglu[124]	2003	CS**	12	65,0 (43-49)	91,67%	8,33%	0,00%	91,67%	91,67%	16,67%	41,67%	91,67%	50,00%	50,00%	0,00%	NA	NA	NA	24,1(1-54)
Bonet[125]	2008	CS**	7	61,3 (35-88)	57,14%	42,86%	NA	100,00%	100,00%	14,29%	0%	100%	71,43%	14,29%	14,29%	28,57%	28,57%	100,00%	51,64(2, 7-115,5)
Tian[126]	2011	Ret**	74	61 (29-82)	52,70%	41,89%	8,11%	95,00%	80,00%	9,00%	NA	NA	40,54%	57,81%	17,27%	NA	NA	NA	46,92 (0-260)
Kanat[127]	2011	CS**	7	43,8 (29-56)	14,29%	85,71%	28,57%	28,57%	28,57%	0,00%	57,14%	100%	85,71%	14,29%	0,00%	71,43%	85,71%	28,57%	22,4(9-48)
Kawasaki[128]	2011	Ret**	27	47,8 (28-74)	95,83%	4,17%	0,00%	100,00%	100,00%	54,17%	NA	NA	37,50%	62,50%	0,00%	NA	NA	NA	83,7 (64-101)
Zhang[129]	2013	Ret**	107	65 (25-95)	NA	NA	NA	94,39%	85,05%	2,80%	NA	NA	NA	NA	NA	NA	NA	NA	27† (3-134)
Wu[130]	2012	Ret**	13	55,4 (36-78)	92,31%	7,69%	7,69%	100,00%	100,00%	0,00%	69,23%	30,77%	100,00%	0,00%	0,00%	NA	NA	100,00%	67,5 (41-89)
Rovera[131]	2013	Ret**	96	70,1 (40-94)	NA	NA	NA	90,00%	75,00%	1,04%	NA	NA	30,21%	31,25%	36,46%	48,00%	5,00%	75,00%	88† (4-242)
Zhu[132]	2013	Ret**	22	52,5 (29-77)	NA	NA	NA	90,91%	95,00%	25,00%	95,00%	14,29%	68,18%	31,82%	0,00%	0,00%	63,64%	90,91%	64,5 (4-89)
Charfi[133]	2013	Ret***	15	62,3 (37-78)	73,33%	26,67%	0,00%	80,00%	93,33%	0,00%	73,33%	6,67%	80,00%	20,00%	0,00%	86,67%	46,67%	60,00%	40,14 (3-125)
Cloyd[134]	2014	Ret***	284	NA	43,40%	36,20%	20,40%	46,5%	35,6%	NA	NA	NA	35,20%	36,60%	27,80%	41,50%	NA	NA	NA
Jeon[135]	2014	Ret***	11	54,7 (29-79)	NA	NA	NA	100,00%	100,00%	0,00%	54,55%	0,00%	36,36%	63,64%	0.00%	NA	NA	NA	38,6 (21-76)
Roininen[136]	2017	Ret***	43	66 (NA)	55,8%	39,53%	9,3%	97,70%	86,10%	4,70%	69,80%	0,00%	58,20%	39,60%	2,27%	74,40%	34,09%	75,00%	NA

Headings: Ret = retrospective; CS = Case Series;
*Previous to 2003 criteria, ** According to 2003 criteria, *** According to WHO 2012 criteria
†Median follow-up

Clinical Characteristics

From the analysis of 113 reported cases (Table 1), the most frequent clinical presentation was breast mass, which was present in 37 cases (in 7 cases also associated to axillary adenopathy and in 5 cases painful) followed by breast lump in 22 patients (of which 3 associated to axillary adenopathy, 2 to bloody nipple discharge, 1 to nipple retraction) and symptoms due to metastatic diffusion (1 jaundice, 1 haematuria, 1 bone pain, 1 respiratory symptoms, 1 perianal pain, 2 neuralgia). Less frequent clinical presentations were: isolated bloody nipple discharge (3 cases), only skin retraction (2 cases), anorexia (2 cases), locally advance disease in 3 cases (2 ulcerated breast masses, 1 carcinomatous mastitis, 1 Paget like mass). In 33 cases clinical presentation was not reported. Tumor was palpable in 58/77 cases (75%).

Radiological Findings

Radiological findings of bNENs were often similar to other breast cancer histotype, like ductal or lobular breast tumors. From available data, sonography was performed in 61 cases. In 11 cases US failed to detect breast lesions. In the other cases tumor appeared as irregular hypoechoic lesion. Data on mammographic finding was present in 61 cases and tumor always appeared as hyperdense mass. Notably, tumor was detected in all cases in which US and mammography were both performed. Only in 14 cases reported data on breast MRI: tumors appeared as irregular mass, hyperintense in T2-weighted sequences.

Histopathological Assessment

According to morphology, NEC was the most common histotype (36 cases), followed by bNET (20 cases), SCNC (20 cases), ICNE (10 cases). In 27 cases morphology was not described. Estrogen receptors was positive in 60/85 cases, progesterone receptors were positive in 37/53 cases, HER2 were positive in 8/59. Considering neuroendocrine markers, chromogranin was positive in 62/75 cases (83%), synaptophysin was positive 70/78 cases (90%). Considering data from case series and retrospective study (Table 2) chromogranin was positive in 41.67%- 95% of specimen, synaptophysin in 0%-100%.

Treatment

Most of the patients received surgical treatment (97/108 cases). The most frequent type of surgical intervention was total mastectomy, performed in 54/97 cases, followed by breast conservative surgery, in 43/97 cases. These data are concordant with retrospective studies and large case series available, in which mastectomy was performed in 30.21-100% of patients, breast conservative in 0-66.67% and no surgical treatment in 0-36.46% of patients. Considering case reports, radiotherapy was performed in 37/84 cases (44%), similarly to data from retrospective studies and large case series in which radiotherapy rate range from 25 to 86.67%.

Medical therapy was suggested in 79% of patients (73/92). Hormone therapy was indicated in 18/92 (19%), chemotherapy alone 36/92 (39%) and a combination of these two treatments were indicated in 38/92 cases (41%). Somatostatin analogue, the most used drugs in neuroendocrine tumors of other origin, was used only in three cases.

Outcome

Data on tumor outcome are available only for 91 patients: 18 patients were alive with active disease, 8 were dead of disease, 1 dead of uncertain causes and 63 were alive with no evidence of disease with a mean follow-up of 24.01 ± 29.8 months.

Discussion

bNENs are rare entities and no guidelines are available for the management of this kind of neoplasia. According to our systematic review, the most frequent clinical presentation is palpable breast mass, sometimes associated to axillary adenopathy or bloody nipple discharge. bNENs appears as hypervascular and irregular hypoechoic lesions at US examination and as hyperdense masses at mammography [8]. The detection rate of these two instrumental evaluations is high, even if is not possible to clearly differentiate this kind of tumor from another breast cancer histotype [9]. When performed, breast MRI shows irregular masses, usually hyperintense in T2-weighted sequences [8]. Before establishing treatment strategies, as recommended in all suspicious breast lesions, tumor biopsy should be performed, even if it is not always able to recognize a breast neuroendocrine tumor, which is often detected only by definitive histopathological assessment [10].

The contemporary presence of neuroendocrine cells with ductal carcinoma is usually considered a sign of the breast origin of the neuroendocrine lesions, even if a total body examination is mandatory for excluding neuroendocrine neoplasm of other origin [11]. Recommended imaging techniques are total body CT or PET/CT scan: 68Gallium PET/CT in case of well-differentiated neuroendocrine tumors or 18FDG PET/CT in case of poorly differentiated NEN (NEC, ICNE, SCNC) as commonly performed in other neuroendocrine neoplasia [12]. Considering available data, the most frequent subtype is NEC. Most all cases were positive for synaptophysin staining, followed by chromogranin; hormone receptors and Her2 expressions were heterogeneous but luminal type (estrogen and progesterone receptors positive and HER2 negative) was the most common, as previously published [13]. This finding is in accordance with the hypothesis that bNENs develop from breast stem cells which divides into neuroendocrine and epithelial cells [14].

Surgical treatment strategies are nowadays based on tumor size and lymph node status basing on current breast cancer guidelines, independently of neuroendocrine component. Likewise, radiotherapy is usually performed after BCS [10, 15]. Medical therapy depends on immunohistochemical analysis: in case of strong hormone receptors positivity, hormonal therapy is usually indicated [10]. In hormone-negative tumors, chemotherapy regimens, based on anthracyclines and or taxanes, is often used [10]. The possibility of using a cisplatin and etoposide regimen in breast NEC, as indicated for small cells carcinomas of other origin, has been evaluated only in small studies [16]. Specific treatment for well-differentiated neuroendocrine component is not routinely used. Only in 3 on 113 cases somatostatin analogues have been used as adjuvant therapy. Even if somatostatin analogues are considered first line therapy in the treatment of neuroendocrine tumors of other origin according to ENETS guidelines, this kind of drug is not approved for bNET, probably because of the paucity of data. Interestingly, somatostatin receptors have been found in non-neuroendocrine breast tumors with high estrogen and progesterone receptor expression and low HER2 [17-20]. Moreover, somatostatin analogues are able to reduce breast cancer cells proliferation especially in case of low estrogen levels, providing the rationale for contemporary administration of hormonal therapy and somatostatin analogue therapy [21, 22]. In Figure 2, we propose a diagnostic and therapeutic algorithm for bNENs.

Figure 2: Proposal of diagnostic and therapeutic algorithm for NEN.

Enlarge Image

Finally, if the prognosis of all bNENs is different compared to non-neuroendocrine breast cancer is still debated. From the published cases, only 8 patients on a total of 91 deceased for the disease. When available, histotype of these neoplasms was NEC/SCNC. In the other 4 cases, tumor histology was not reported but tumor stage was advanced, implying that tumor stage and histology could be the main predictors of poor outcome. Data from the SEER database, comparing 142 breast NEC and non-neuroendocrine breast tumors, demonstrated a shorter overall survival and disease-specific survival of breast NEC and in a multivariate analysis neuroendocrine differentiation was an independent determinant of poorer prognosis [5]. Similarly, Bogina et al. have demonstrated a worse prognosis in 55 breast NEC patients compared to 115 matched non-neuroendocrine breast tumors patients [7].

Conclusions

bNENs are rare tumors, usually identified only during definitive histopathological examinations of surgical specimen. bNENs are nowadays treated similarly to non-neuroendocrine breast cancer, but they are very heterogeneous and not well understood. Similarly, to NEN of other origin, we should probably distinguish between well differentiated tumors, NET, and poorly differentiated tumors, NEC/small cells carcinomas regarding treatment and prognosis. Specific trials on adjuvant therapy, for example with somatostatin analogues for well differentiated form, bNET, or classical chemotherapy with cisplatin and etoposide in NEC and SCNC are necessary for establishing the best treatment strategy for these patients and improving clinical outcome.

Abbreviations

NET: neuroendocrine tumor
bNENs: breast neuroendocrine neoplasia
NEC: neuroendocrine carcinoma
ICNE: invasive breast tumor with endocrine differentiation
WHO: World Health Organization
US: ultrasound
MRI: magnetic resonance imaging
BCS: breast conservative surgery

Consent for Publication

All patients provided written informed consent to case publication.

Conflicts of interest

The Authors have no conflicts of interest for this Paper. All authors disclose any financial and personal relationships with other people or organizations in the writing of this Paper.

Funding

None.

Author Contributions

Dr. Federico Frusone and Dr. Giulia Puliani cowrote this paper. Dr. Federico Frusone collected information of the case series from the database of Humanitas Research Hospital of Milan. Dr. Andrea Sagona, Dr. Emilia Marrazzo and Dr. Erika Barbieri helped analysing the results of the case series. Dr. Giulia Puliani and Dr. Federico Frusone performed literature research and analysed the results. Dr. Alessandro De Luca helped analysing these results. Dr. Wolfgang Gatzemeier, Dr. Alberto Bottini and Dr. Corrado Tinterri reviewed the manuscript. All the authors read and approved the final manuscript.

Acknowledgement

We are grateful to Elena Bissolotti who helped us with cases retrievement and to all those who have contributed through discussion and collaboration to the writing of this paper.

Article Info

Article Type

Research Article

Publication history

Received: Wed 25, Dec 2019
Accepted: Thu 09, Jan 2020
Published: Tue 04, Feb 2020

Copyright

© 2023 Corrado Tinterri. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository.
DOI: 10.31487/j.ACO.2020.01.02

Author Info

Alberto Bottini Alessandro De Luca Andrea Sagona Corrado Tinterri Emilia Marrazzo Erika Barbieri Federico Frusone Giulia Puliani Giuseppe Canavese Wolfgang Gatzemeier

Corresponding Author

Corrado Tinterri
Humanitas Research Hospital and Cancer Center, Breast Surgery Department, Milan, Rozzano, Italy

Figures & Tables

Table 1A: Case series.

Preoperative diagnosis

Treatment

Tumor biology

Follow-up

Case

Age

Clin pres

US

MX

CT

PET

Bio / Cit

Nadj

treat

Surgery

Adj treat

Adj RT

pTNM

Tum size

LNs

Histo-type

CrA

Syn

ER

PR

Her2

Ki67

FUP

(mo)

Alive status

1

66

BL

NA

Neg

Bio

NO

BCS + ALND

ADR/CPA + DTX + Ana

Yes

T2N3aM0

2,3

12/14

ICNE

NA

+

70%

60%

0

10%

120

AWD

2

54

BL

HyBM

SBM

Neg

Bio

NO

Mast + SLNB

ADR/CPA + DTX + Ana

No

T2N0M0

2,7

0/1

NET

-

+

95%

29%

0

70%

60

NED

3

43

PBM

HyBM, N+

SBM

Neg

BoMet, LMet

Bio

Yes

Mast + ALND

CDDP + VP-16

Yes

T4bN3aM1

12

9/14

NEC

+

0

90%

12

AWD

4

66

BL

BM

HypBM

Neg

Bio

NO

BCS + ALND

ADR/CPA + DTX + Ana

Yes

T1N3aM0

0,8

13/15

ICNE

NA

+

80%

70%

0

12%

53

AWD

5

78

BL

HyBM

SBM

Neg

Bio

NO

BCS + SLNB

Ana

No

T1cN0M0

1,9

0/16

NET

-

+

95%

1+

25%

76

NED

6

78

BL

BM

SBM

Neg

Bio

NO

BCS + SLNB

Ana

Yes

T1cN0M0

2

0/2

NEC

NA

+

95%

0

20%

70

NED

HeadingS: NA = Not available data; Clin Pres = Clinical presentation; US = breast Ultrasound; MX = mammography; Bio = biopsy; Cit = citology; Ad treat = adjuvant treatment (chemotherapy and/or hormone therapy); Adj RT = adjuvant radiotherapy; Tum size = tumor size (centimeters); LNs = lymph nodes removed; CrA = Chromogranin A; Syn = Synaptophisin; ER = Estrogen receptor; PR = Progesterone receptor; Her2 = her2-neu receptor; FUP = follow-up (months).

Clinical and radiological findings: Pos = positive for malignancy; Neg = negative for malignancy; BM = Breast Mass; CM = carcinomatous mastitis; N+ = axillary adenopathy, PBM = Painful breast mass; BL = breast lump; SR = Skin retraction, NR = nipple retraction, PLM = Paget-like Mass; BND = Bloody nipple discharge; UBM = Ulcerated Breast Mass; MBM = Multilobulated breast mass; HyBM = Hypoechoic (US) / Hypodense (MX) breast mass; Hyp = Hyperechoic (US) / Hyperdense breast mass = HeBM = Heterogeneous breast mass, SBM = Spiculated breast mass, Mic = microcalcifications, BoMet = Bone Metastases; LMet = Lung metastasis; PAMet = Perianal metastases, PiMet = Pituitary metastases; PaMet = Pancreatic metastases; PE = Pleural effusion; MMet = Multiple metastases; IBM = Isoechoic breast mass
Neg = Negative; Sus = suspicious; LMet = lung metastasis.
Mast = Mastectomy; BCS = Breast Conservative Surgery; SLNB = Sentinel Lymph Node Biopsy; ALND = Axillary Lymph Node Dissection.

Chemotherapy: ChT = chemotherapy (not defined); HoT = hormone therapy (not defined); CDDP = Cisplatin, CBL = Carboplatin, VP-16 = Etoposide, CPT-11 = Irinotecan, 5-FU = Fluorouracil, EPI = Epirubicin, CAP = Capecitabine, DTX = Docetaxel, 5’-DFUR = 50 deoxy-5-fluorouridine, Tor = Toremifene, CPA = Cyclophosphamide, EPI = Epirubicin, Tam = Tamoxifen, Tor = Torenifene, Let = Letrozole, S = Streptozotocin, MTX = Methotrexate, Ana = Anastrazole, AI = Aromatase inhibitor, LHRH = Leutinising hormone releasing hormone analogue, UFT = Uracil & Tegafur, PTX = Paclitaxel, ADR = Adriamycin (Doxorubicin), Sando = Sandostatin, Som = Somatostatin; Ever = Everolimus, Bev = Bevacizumab, Erl = Erlotinib; Palb = Palbociclib; Oct = Octreotide.

Histology: SCNC = Small Cell Neuroendocrine Carcinoma, ICNE = Invasive carcinoma with neuroendocrine differentiation; NET = well-differentiated neuroendocrine tumor; NEC = poorly differentiated neuroendocrine carcinoma.

Follow-up: NED = No evidence of disease; AWD = Alive with disease; DOD = Died of disease; DUC = Died of Uncertain cause †Median follow-up.

Table 1B: Case reports available in literature.

Author

Preoperative diagnosis

Treatment

Tumor biology

Follow-up

Author

(year)

Year

Age

Clin pres

US

MX

CT

PET

Bio / Cit

Nadj

treat

Surgery

Adj treat

Adj RT

pTNM

Tum size

LNs

Histo-type

CrA

Syn

ER

PR

Her2

Ki67

FUP

(mo)

Alive status

Wade[23]

1983

52

UBM N+

MBM

Neg

NO

Bio

NO

Mast + ALND

VP-16

NO

T4N1M0

10

25/25

SCNC

NA

Jundt[24]

1984

52

NA

TXN1M1

NA

+/?

NA

14

DOD

Francois[25]

1995

68

BM

HeBM

HBM

Neg

NO

Cit

NO

Mast + ALND

CPA/ADR/VP-16

Yes

T2N0M0

4

0/12

SCNC

NA

-

NA

21

DUC

Chua[26]

1997

45

BM

NA

Bio

NO

BCS

NA

NO

T2N0MX

4,5

NA

SCNC

-

+

-

NA

<1

NED

Yalcin[27]

1997

63

BM

Neg

NA

Bio

NO

Mast + ALND

NO

T2N0M0

5

0/?

NET

+

NA

18

NED

Fukunaga[28]

1998

51

BM

Neg

BM

Neg

NO

NA

Mast + ALND

NA

T2N0M0

2,5

0/29

NET

+

-

+

-

NA

16

NED

Fukunaga[29]

1998

38

BM

Neg

NO

NA

NO

Mast + ALND

NO

T2N1M0

2,5

1/7

NEC

+

-

12%

72

NED

Sebenik[30]

1998

67

NA

Yes

Mast + ALND

NA

T2NXM0

4

NA

33

NED

Samli[31]

2000

60

PBM

BM

Neg

NO

Bio

Yes

Mast + ALND

CDDP/VP-16+

5-FU/CPA/EPI

Yes

T4N1M0

4,5

10/11

SCNC

+

NA

6

AWD

Yamasaki[32]

2000

41

BM

Neg

SBM

Neg

Sus

Cit

NO

Mast + ALND

CPA/MTX/5-FU

NO

T2N0M0

3,5

0/5

SCNC

+

-

NA

16

NED

Hoang[33]

2001

41

NA

T3NXMX

14,5

NA

51

NA

T3NXMX

8

NA

Salmo[34]

2001

46

NA

NO

BCS

ChT

YES

T2N0M0

4

NA

9

NED

Berruti[35]

2004

59

LMet

Neg

LMet

NO

NA

Yes

LMet resection

Tam

NO

TXNXM1

NA

NEC

+

-

12

144

NED

Bigotti[36]

2004

56

CM

BM

NA

Neg

Bio

Yes

NO

ChT + Som

NO

T3N1M0

18

2/9

SCNC

-

+

-

NA

15

DOD

Bergman[37]

2004

61

BL

BM

Neg

Bio

NO

Mast + ALND

NO

T2N1M0

2,5

2/5

SCNC

-

NA

Jochems[38]

2004

71

BM

NA

BM

Neg

Bio

NO

Mast + ALND

Tam

NO

T2N0M0

3

0/10

NEC

+

-

NA

12

NED

Mariscal[39]

2004

53

BM, SR, N+

HyBM

BM, N+

Neg

Bio

Yes

BCS + ALND

HoT

NO

T3N1M0

5,5

1/?

SCNC

NA

+

NA

6

NED

Sridhar[40]

2004

58

NA

NO

BCS

ChT

YES

T2N1M0

2

NA

18

NED

Yamamoto [41]

2004

53

NA

Neg

NA

NO

NA

NO

T3N2M0

6,5

NA

-

NA

34

NED

75

NA

Neg

NA

NO

NA

CPA/MTX/5-FU + HoT

NO

T2N1M0

2,5

NA

+

NA

43

NED

Adegbola[42]

2005

46

BL

NA

Neg

NO

BCS

CDDP/VP-16+

Yes

T1NXM0

1

0

SCNC

+

-

NA

-

NA

48

NED

60

BM

NA

Neg

NO

BCS

CDDP/VP-16+

Yes

T1NxM0

1,7

0

SCNC

+

-

NA

-

NA

20

DOD

61

BM, N+

NA

Neg

NO

BCS

CDDP/VP-16+

Yes

T1NxM1

1,7

0

SCNC

+

-

NA

-

NA

6

AWD

Stein[43]

2005

54

BM, N+

NA

Bio

Yes

Mast + ALND

NO

Yes

T1N1M0

1,5

5/15

SCNC

+

NA

-

NA

24

NED

Tsai[44]

2005

42

BM

NA

Neg

NA

Bio

NA

Mast

NA

NEC

+

NA

Fujimoto[45]

2007

40

BL, BND

HyBM

Neg

NO

Bio

NO

Mast + SLNB

Ana

NO

T2(m)N0

M0

2

0/1

NEC

+

NA

+

NA

Hennessy[46]

2007

63

PAMet

Neg

BMet

PAMet

NO

Bio

NO

Mast + SLNB

ChT/Tam

NO

TXNXM1

NA

NEC

+

NA

AWD

Kitakata[47]

2007

44

BL

HyBM

BM

Neg

NO

Mast + ALND

CPA/Epi + DTX

NO

T2N1M0

4,5

2/15

SCNC

-

+

-

+

-

NA

22

NED

La Rosa[48]

2007

49

BL

Pos

NO

Cit

NO

Mast

ChT

NO

T2NXMX

2,5

NA

NEC

+

-

NA

Vidulich[49]

2007

76

BM, N+, PE

BM, N+

NA

LMet

MMet

Cit, Bio

NO

Oct/Ever, Bev/Erl

NO

T4N1M1

5

NA

NEC

+

-

NA

AWD

Yaren[50]

2007

76

NA

Neg

NA

NO

Mast + ALND

HoT

NO

T2N0M0

5

0/13

NA

+

NA

12

NED

Jeong[51]

2008

39

BL

IBM

HypBM

NO

Mast + ALND

ChT / Hot

Yes

T2N1M1

2,2

2/14

NEC

+

NA

32

NED

Kim[52]

2008

27

BM

HeBM

BM

Neg

Bio

NO

BCS + ALND

ChT

Yes

T2NXM0

3,2

NA

NEC

+

-

NA

18

NED

Kinoshita[53]

2008

31

BL

HyBM

Neg

MMet

NO

Bio

Yes

Mast + ALND

CDDP/CPT-11

NO

T2N1M1

3,7

7/30

SCNC

+

-

+

-

NA

1

AWD

Lopez Garcia[54]

2008

31

NA

Neg

NA

NO

Mast + ALND

NO

YES

T3N1MX

10

2/15

NA

-

NA

15

DOD

Mecca[55]

2008

70

PLM

NA

NO

NA

NO

BCS + SLNB

NO

T4N1M0

1,9

2/2

NEC

NA

+

NA

12

NED

Ogawa[11]

2008

34

BM

HeBM

HypBM

Neg

NA

Bio

NA

BCS

NA

T2NXM0

2,7

NA

NET

+

-

+

NA

7

NED

Pagani[56]

2008

62

NA

BCS + ALND

NA

T1N2MX

1,5

19/20

NA

+

NA

41

NA

Mast + ALND

NA

T2N1MX

4,1

1/18

NA

Sadanaga[57]

2008

33

NA

Yes

Mast ALND

ChT

YES

T2N0M0

4

0/?

NA

60

NED

Ulamec[58]

2008

60

Hematuria

BM

NA

Yes

Mast + ALND

HoT

Yes

T4N2M1

4,5

9/9

NEC

-

+

5%

18

NED

Akhtar[59]

2009

40

BL, N+

NA

Cit, Bio

NA

Mast + ALND

NA

T3NXMX

8,5

NA

NEC

NA

+

NA

Burckhardt[60]

2009

84

NA

Yes

Mast + ALND

HoT

NO

T2N1M0

3

+/?

NA

+

NA

NED

El Hassani[61]

2009

40

BM

NA

BM

Neg

NO

Bio

Yes

NO

VP16-CDDP

NA

T4NXMX

NA

NEC

+

NA

1

DOD

Ersahin[62]

2009

50

NA

BCS

NA

T3NXM0

2,5

NA

12

NED

Haji[63]

2009

68

NA

YES

Mast + ALND

NO

T3N1M0

5,8

NA

6

DOD

Hojo[64]

2009

60

NA

NO

Mast + ALND

NO

T3N0M1

3

0/?

NA

26

AWD

Lee[65]

2009

65

BM

HyBM

HypBM

NO

Neg

NO

BCS + SLNB

HoT

NO

T1N0M0

1,6

0/1

NEC

NA

+

-

NA

NED

Okoshi[66]

2009

63

BM

HyBM

HypBM

Neg

No

Cit

NO

BCS + ALND

ChT

Yes

T2N0M0

2

0/?

NET

-

+

-

+

NA

44

NED

Rivero[67]

2009

41

NA

YES

BCS

NO

Yes

T3N0M0

6

0/?

NA

20

NED

Rineer[68]

2009

81

NA

YES

BCS

NO

Yes

T3N1M0

5

NA

26

AWD

Salama[69]

2009

48

BoMet

NA

YES

NO

T4NXMX

2,5

NA

+

NA

<1

AWD

Sartori[70]

2009

70

NA

Neg

NA

NO

BCS + ALND

Som

Yes

T1N3M0

1,8

34/?

NA

+

NA

12

NED

Stita[71]

2009

64

BM

Neg

NO

NA

NO

Mast + ALND

ChT

NO

T2N0M0

3

0/?

NET

+

NA

8

NED

Yamaguchi[72]

2009

51

BM

NA

Neg

Bio

NO

Mast + ALND

PTX

NO

T2N0M0

2,5

NA

SCNC

+

-

85%

12

AWD

Christie[73]

2010

61

NA

NO

BCS

NO

T3N2M0

3

NA

3

DOD

Goucha[74]

2010

40

NA

NO

BCS + ALND

NO

Yes

T1N0MX

1,8

0/15

NA

+

NA

12

NED

Honami[75]

2010

54

BND

HyBM

Neg

NO

No

Bio

NO

BCS

HoT

Yes

T1NXMX

1,5

NA

ICNE

+

NA

-

NA

18

NED

Huettemann [76]

2010

65

NA

Neg

NA

NO

Mast + ALND

DTX/Bev

NO

T3N1M1

9

NA

Latif[77]

2010

53

BM

Neg

BM

NO

Neg

Cit, Bio

Yes

BCS + SLNB

Tam/Som

Yes

T3N0M0

1 cm

0/1

SCNC

+

-

NA

-

NA

Saglam[78]

2010

60

NA

Neg

NA

NO

T4N1M1

0,6

1/1

NA

+

NA

26

DOD

Salman[79]

2010

72

NA

Neg

NA

NO

Mast + ALND

Letr

NO

TXNXM1

NA

+

NA

12

NED

Buttar[80]

2011

63

Jaundice

NA

Pos

NO

Bio

NO

Tam/Ana

NO

T2N0M1

NA

0/1

NEC

-

+

NA

-

NA

12

NED

Cesaretti[81]

2011

68

BM, N+

BL

HypBM

NA

Cit, Bio

NO

BCS + ALND

ADR/CPA + Ana

Yes

T1cN0Mx

1,1

0/19

NEC

+

-

7%

34

NED

Ghanem[82]

2011

64

BM, N+

BN

Neg

NA

Bio

Yes

Mast + ALND

ADR/CPA + Ana

YES

T3N2M0

8

16/23

NA

+

NA

+

-

10%

32

AWD

Jach[83]

2011

28

BL

BN

NA

Bio

NO

BCS + ALND

ADR + Tam

YES

T1N0M0

1,1

0/4

ICNE

+

NA

+

NA

40%

NA

Kavasaki[84]

2011

43

BND

BM

NA

NO

BCS

NA

T1N0M0

1,2

0/4

NEC

+

NA

+

NA

Kawanishi [85]

2011

67

UBM

HyBM

BM

NA

Cit, Bio

NO

BCS + SLNB

Ana

NO

T1N0M0

0,8

0/1

NEC

+

NA

-

NA

12

NED

Navrozoglou[86]

2011

73

NO

BN

NA

Neg

Bio

NO

Mast + ALND

NO

T1N0M0

1,1

0/17

NET

+

NA

48

NED

Nicoletti[87]

2011

40

BM

BN

Neg

NO

Bio

NO

Mast + ALND

ADR/CPA + CBL/VP-16 + Tam/LHRH

NO

T2N1M0

3

1/16

SCNC

+

-

+

96

NED

Nozoe[88]

2011

57

BL

HyBM

BM

NA

NO

Mast + ALND

CMF + AI

NA

3

0/?

NEC

NA

+

-

NA

Zhang[89]

2011

29

BND

BM

NO

Cit

NO

BCS + SLNB

CPA/EPI/5-FU + DTX + Tor

NA

T2N0M0

2

0/2

NET

+

-

1%

20

NED

Alkaied[90]

2012

83

Anorexia

Neg

NO

Pos

Bio

Yes

NO

Letr - Ana

NA

TXNXM1

NA

SCNC

-

+

NA

12

NED

Flessas[91]

2012

59

NO

NA

Mic

NO

Bio

NO

BCS +ALND

NA

T2N1M0

2,8

1/?

ICNE

+

NA

Graça[92]

2012

83

BM

BN

BM

Neg

Cit

NO

BCS + SLNB

HoT

NO

T2N0M0

2,4

0/1

NEC

NA

+

NA

NED

Menéndez [93]

2012

44

NO

NA

BM

NA

NO

BCS + ALND

5-FU/EPI/CPA

Yes

T2N0M0

2

1/?

NEC

NA

+

-

NA

48

NED

68

NO

NA

BM

NA

NO

BCS + SLNB

5-FU/EPI/CPA + DTX + Ana

Yes

3,6

NA

NEC

+

NA

24

NED

58

NO

NA

BM

NO

Bio

NO

BCS + SLNB

5-FU/EPI/CPA

Yes

T1N0M0

1

0/1

NEC

NA

+

-

NA

8

AWD

69

NO

HyBM

BM

NA

BCS + SLNB

NA

T1N0M0

1,4

0/1

ICNE

+

-

10%

2

NED

Miura[94]

2012

72

NO

NA

Neg

NA

Cit, Bio

NO

BCS + SLNB

NA

1,5

0/1

NEC

+

-

1%

NA

Psoma[95]

2012

46

BM

HyBM

HypBM

Neg

NO

NA

NO

Mast + ALND

CDDP/EPI/VP-16

Yes

T3N0M0

6,5

NA

NET

+

NA

6

NED

Su[96]

2012

75

PBM

HyBM

HypBM

Neg

NA

Bio

NO

Mast + ALND

Let

NO

T2N0M0

4

0/?

ICNE

+

-

NA

20

NED

Watrowski [97]

2012

56

BM

HyBM

NA

NO

Bio

NO

BCS + SLNB

CPA/EPI/5-FU + HoT

Yes

T1N0M0

1,7

0/1

NET

NA

+

-

46%

15

NED

Yavas[98]

2012

77

BM, N+

BM

HypBM

Neg

NO

NA

NO

Mast + ALND

NO

T2N1M0

3

5/16

ICNE

NA

+

NA

15

NED

Abbasi[99]

2013

37

BL, N+

NA

BoMet

NA

Bio

NO

Mast + ALND

5-FU/ADR/CPA + CDDP + VP-16

NO

T3N2M1

7,5

9/19

ICNE

+

NA

6

NED

Angarita[100]

2013

51

BL

Neg

SBM

Neg

NO

Bio

Yes

BCS + ALND

CDDP/VP-16 + PTX

NA

T2N0M0

3,2

0/?

ICNE

+

-

NA

-

>20%

13

AWD

Chang[101]

2013

42

BL

MBM

HypBM

NO

Neg

Cit

No

NO

NA

T2N1M0

NA

+/?

NEC

+

NA

-

NA

Hanna[102]

2013

60

PBM

Neg

NO

Bio

NO

BCS

CBL/VP-16

NO

T1N2M0

1,4

4/11

NEC

-

+

NA

-

NA

Senetta[103]

2013

82

Asthenia

BM

NA

PiMet

NO

Bio

NO

BCS + SLNB

HoT

NO

T1NXM1

2,3

NA

NEC

+

-

10

NA

Yoon[8]

2013

44

BM

HyBM

Neg

Bio

NA

Mast + ALND

CPA/ADR

NA

T2NXM0

2

NA

NEC

+

NA

2

NED

Cinkir[104]

2014

75

BM

NA

Bio

NO

Mast + ALND

CDDP/VP-16

Yes

T0N0M0

0

0/?

SCNC

+

-

5%

30%

NED

2014

77

PBM

SBM

NA

Bio

NO

Mast + ALND

AI

NO

T2NXM0

2,3

NA

NEC

+

-

10%

9%

NED

Pagano[105]

2014

51

BL, NR

NA

BM

Neg

NA

Bio

NO

Mast + ALND

CPA/MTX/5-FU + Tam

NA

T2N2M0

3,5

5/28

NET

+

-

30

126

AWD

Suhani[106]

2014

66

BL

NA

Neg

NA

Bio

NO

Mast + ALND

CPA/ADR/5-FU + AI

Yes

T3N1M0

6,5

1/15

NET

+

-

+

-

NA

48

NED

55

BL

NA

Neg

NA

Bio

NO

Mast + ALND

CPA/ADR/5-FU + AI

Yes

T2N1M0

4,5

2/16

NET

+

-

+

-

NA

36

NED

50

BL

NA

Neg

NA

Bio

NO

Mast + ALND

CPA/ADR/5-FU + AI

Yes

T2N0M0

4

0/18

NET

+

-

NA

18

NED

60

BL, BND

NA

Neg

NA

Bio

NO

Mast + ALND

CPA/ADR/5-FU + AI

Yes

T3N1M0

5,5

1/16

NET

-

+

-

NA

9

NED

Janosky[107]

2015

34

BL

Neg

HypBM

NA

Neg

Bio

Yes

BCS + ALND

CBL/PTX

Yes

T2N0M0

3,5

0/?

NEC

+

-

NA

-

100%

2

AWD

Kawasaki[108]

2015

60

SR

HyBM

NA

Neg

NO

Bio

NO

BCS + ALND

Ana

NO

T1N0M0

1,2

0/4

NEC

+

-

+

NA

0

6.3%

48

AWD

Rana[109]

2015

65

BL

NA

Neg

NO

Bio

NA

Mast + ALND

NA

T3N2M0

6

4/20

NEC

+

-

NA

Santos-Juanez[110]

2015

80

BM

Neg

Pos

NO

Bio

Yes

NO

Yes

T4NXM1

17

NA

NET

+

-

10%

5

NED

Sherwell-Cabello[111]

2015

60

BL, N+

NA

Neg

NA

NO

Mast + ALND

CBL/VP-16

Yes

T3N3M0

6

11/15

NET

-

+

-

70%

6

NED

Wei[112]

2015

43

BM

HyBM

MBM

NO

Bio

Yes

Mast + ALND

NA

T2N1M0

3

1/?

NET

+

-

+

10%

NA

Alva[113]

2016

53

BL

Neg

SBM

Neg

NO

Cit

NO

Mast + ALND

NA

T2N0M0

5

0/10

NEC

+

-

NA

-

NA

Christensen [114]

2016

73

SR

BM

PaMet

NA

BCS + ALND

NA

T2N3M1

3,8

18/21

ICNE

-

+

NA

4,5

AWD

D'antonio [115]

2016

50

BL

Neg

Bio

NO

BCS + ALND

NO

T1N0M0

1,5

0/?

ICNE

+

-

+

-

<5%

12

NED

Mečiarová[116]

2016

42

BL

HyBM

HypBM, Mic

Neg

NA

NO

BCS + SLNB

VP-16/CDDP

Yes

T2N1M0

3,2

1/1

NEC

+

-

50%

36

NED

Nakai[117]

2016

46

PBM

HyBM, N+

NA

Neg

NA

Bio

NO

Mast + ALND

CPA/EPI/5-FU

NA

T2N2M0

2,3

9/17

NET

+

61%

4

NED

Takanami [118]

2016

57

Neuralgia

NA

Pos

NA

Bio

NA

Mast + ALND

NA

T2N0M0

NA

NET

NA

180

AWD

Abou Dalle[119]

2017

47

NO

NA

BM

NO

Neg

Bio

NO

Mast + SLNB

CDDP/VP-16 + 5-FU/EPI/CPA + Tam

NO

T2N0M0

3

0/4

SCNC

+

NA

-

50%

10

NED

Maqsood [120]

2017

67

Neuralgia

HyBM

BM

MMet

Bio

Yes

NO

Let + Palb

NO

T1NXM1

1

NEC

-

+

NA

-

NA

3

AWD

Soe[121]

2017

57

BL

HyBM

HypBM

NA

BoMet

NA

NO

BCS

CDDP/VP-16 + Oct

NO

T2NXM1

4

NA

NET

+

NA

15%

18

NED

Headings: NA = Not available data; Clin Pres = Clinical presentation; US = breast Ultrasound; MX = mammography; Bio = biopsy; Cit = citology; Ad treat = adjuvant treatment (chemotherapy and/or hormone therapy); Adj RT = adjuvant radiotherapy; Tum size = tumor size (centimeters); LNs = lymph nodes removed; CrA = Chromogranin A; Syn = Synaptophisin; ER = Estrogen receptor; PR = Progesterone receptor; Her2 = her2-neu receptor; FUP = follow-up (months)

Clinical and radiological findings: Pos = positive for malignancy; Neg = negative for malignancy; BM = Breast Mass; CM = carcinomatous mastitis; N+ = axillary adenopathy, PBM = Painful breast mass; BL = breast lump; SR = Skin retraction, NR = nipple retraction, PLM = Paget-like Mass; BND = Bloody nipple discharge; UBM = Ulcerated Breast Mass; MBM = Multilobulated breast mass; HyBM = Hypoechoic (US) / Hypodense (MX) breast mass; Hyp = Hyperechoic (US) / Hyperdense breast mass = HeBM = Heterogeneous breast mass, SBM = Spiculated breast mass, Mic = microcalcifications, BoMet = Bone Metastases; LMet = Lung metastasis; PAMet = Perianal metastases, PiMet = Pituitary metastases; PaMet = Pancreatic metastases; PE = Pleural effusion; MMet = Multiple metastases; IBM = Isoechoic breast mass
Neg = Negative; Sus = suspicious; LMet = lung metastasis
Mast = Mastectomy; BCS = Breast Conservative Surgery; SLNB = Sentinel Lymph Node Biopsy; ALND = Axillary Lymph Node Dissection

Chemotherapy: ChT = chemotherapy (not defined); HoT = hormone therapy (not defined); CDDP = Cisplatin, CBL = Carboplatin, VP-16 = Etoposide, CPT-11 = Irinotecan, 5-FU = Fluorouracil, EPI = Epirubicin, CAP = Capecitabine, DTX = Docetaxel, 5’-DFUR = 50 deoxy-5-fluorouridine, Tor = Toremifene, CPA = Cyclophosphamide, EPI = Epirubicin, Tam = Tamoxifen, Tor = Torenifene, Let = Letrozole, S = Streptozotocin, MTX = Methotrexate, Ana = Anastrazole, AI = Aromatase inhibitor, LHRH = Leutinising hormone releasing hormone analogue, UFT = Uracil & Tegafur, PTX = Paclitaxel, ADR = Adriamycin (Doxorubicin), Sando = Sandostatin, Som = Somatostatin; Ever = Everolimus, Bev = Bevacizumab, Erl = Erlotinib; Palb = Palbociclib; Oct = Octreotide

Histology: SCNC = Small Cell Neuroendocrine Carcinoma, ICNE = Invasive carcinoma with neuroendocrine differentiation; NET = well-differentiated neuroendocrine tumor; NEC = poorly differentiated neuroendocrine carcinoma

Follow-Up: NED = No evidence of disease; AWD = Alive with disease; DOD = Died of disease; DUC = Died of Uncertain cause
†Median follow-up

Table 2: Case series and retrospective studies reported in literature.

Author	Year	Study type	N. patients	Mean age (range)	Only breast	N+ (%)	M1 (%)	ER+	PR+	Her2+	CrA+	Syn+	Mast	BCS	No surgery	Adj RT	Adj CHT	Adj OT	Mean FUP (range)
Papotti[122]	1992	CS*	4	56 (41-64)	25,00%	75,00%	50,00%	NA	NA	NA	NA	NA	100,00%	0,00%	0,00%	25,00%	25,00%	25,00%	20,5(9-44)
Shin[123]	2000	CS*	9	55,4 (43-70)	44,44%	55,56%	0,00%	66,67%	55,56%	0,00%	44,44%	44,44%	33,33%	66,67%	0,00%	44,44%	77,78%	0,00%	20,3(3-35)
Zekioglu[124]	2003	CS**	12	65,0 (43-49)	91,67%	8,33%	0,00%	91,67%	91,67%	16,67%	41,67%	91,67%	50,00%	50,00%	0,00%	NA	NA	NA	24,1(1-54)
Bonet[125]	2008	CS**	7	61,3 (35-88)	57,14%	42,86%	NA	100,00%	100,00%	14,29%	0%	100%	71,43%	14,29%	14,29%	28,57%	28,57%	100,00%	51,64(2, 7-115,5)
Tian[126]	2011	Ret**	74	61 (29-82)	52,70%	41,89%	8,11%	95,00%	80,00%	9,00%	NA	NA	40,54%	57,81%	17,27%	NA	NA	NA	46,92 (0-260)
Kanat[127]	2011	CS**	7	43,8 (29-56)	14,29%	85,71%	28,57%	28,57%	28,57%	0,00%	57,14%	100%	85,71%	14,29%	0,00%	71,43%	85,71%	28,57%	22,4(9-48)
Kawasaki[128]	2011	Ret**	27	47,8 (28-74)	95,83%	4,17%	0,00%	100,00%	100,00%	54,17%	NA	NA	37,50%	62,50%	0,00%	NA	NA	NA	83,7 (64-101)
Zhang[129]	2013	Ret**	107	65 (25-95)	NA	NA	NA	94,39%	85,05%	2,80%	NA	NA	NA	NA	NA	NA	NA	NA	27† (3-134)
Wu[130]	2012	Ret**	13	55,4 (36-78)	92,31%	7,69%	7,69%	100,00%	100,00%	0,00%	69,23%	30,77%	100,00%	0,00%	0,00%	NA	NA	100,00%	67,5 (41-89)
Rovera[131]	2013	Ret**	96	70,1 (40-94)	NA	NA	NA	90,00%	75,00%	1,04%	NA	NA	30,21%	31,25%	36,46%	48,00%	5,00%	75,00%	88† (4-242)
Zhu[132]	2013	Ret**	22	52,5 (29-77)	NA	NA	NA	90,91%	95,00%	25,00%	95,00%	14,29%	68,18%	31,82%	0,00%	0,00%	63,64%	90,91%	64,5 (4-89)
Charfi[133]	2013	Ret***	15	62,3 (37-78)	73,33%	26,67%	0,00%	80,00%	93,33%	0,00%	73,33%	6,67%	80,00%	20,00%	0,00%	86,67%	46,67%	60,00%	40,14 (3-125)
Cloyd[134]	2014	Ret***	284	NA	43,40%	36,20%	20,40%	46,5%	35,6%	NA	NA	NA	35,20%	36,60%	27,80%	41,50%	NA	NA	NA
Jeon[135]	2014	Ret***	11	54,7 (29-79)	NA	NA	NA	100,00%	100,00%	0,00%	54,55%	0,00%	36,36%	63,64%	0.00%	NA	NA	NA	38,6 (21-76)
Roininen[136]	2017	Ret***	43	66 (NA)	55,8%	39,53%	9,3%	97,70%	86,10%	4,70%	69,80%	0,00%	58,20%	39,60%	2,27%	74,40%	34,09%	75,00%	NA

Headings: Ret = retrospective; CS = Case Series;
*Previous to 2003 criteria, ** According to 2003 criteria, *** According to WHO 2012 criteria
†Median follow-up

Figure 1: Flowchart of literature eligibility assessment process.

Figure 2: Proposal of diagnostic and therapeutic algorithm for NEN.

References

Feyrter F, Hartmann G (1963) [on the Carcinoid Growth Form of the Carcinoma Mammae, Especially the Carcinoma Solidum (Gelatinosum) Mammae]. Frankf Z Pathol 73: 24-39. [Crossref]
Ellis P, Schnitt S, Sastre-Garau X (2003) Invasive breast carcinoma. In Tavassoli FA, Deyilee P, editors Tumors of the Breast and Female Genital Organ: Pathology and Genetics Lyon: France, IARC Press; .
Lakhani SR, Ellis IO, Schnitt SJ, Tan P, Van de Vijver M (2012) WHO Classification of Tumours of the Breast. Fourth Edition. In WHO Classification of Tumours Volume 4.
Tavassoli F, Devilee P (2003) Pathology and Genetics: Tumours of the Breast and Female Genital Organs. WHO Classification of Tumours series, Volume 4 3 Lyon, France: IARC Press: 32-34.
Wang J, Wei B, Albarracin CT, Hu J, Abraham SC et al. (2014) Invasive neuroendocrine carcinoma of the breast: a population-based study from the surveillance, epidemiology and end results (SEER) database. BMC Cancer 14: 147. [Crossref]
Brask JB, Talman ML, Wielenga VT (2014) Neuroendocrine carcinoma of the breast - a pilot study of a Danish population of 240 breast cancer patients. APMIS 122: 585-592. [Crossref]
Bogina G, Munari E, Brunelli M, Bortesi L, Marconi M et al. (2016) Neuroendocrine differentiation in breast carcinoma: clinicopathological features and outcome. Histopathology 68: 422-432. [Crossref]
Yoon YS, Kim SY, Lee JH, Kim SY, Han SW (2014) Primary neuroendocrine carcinoma of the breast: radiologic and pathologic correlation. Clin Imaging 38: 734-738. [Crossref]
Adams RW, Dyson P, Barthelmes L (2014) Neuroendocrine breast tumours: breast cancer or neuroendocrine cancer presenting in the breast? Breast 23: 120-127. [Crossref]
Gradishar WJ, Anderson BO, Balassanian R, Blair SL, Burstein HJ et al. (2017) NCCN Guidelines Insights: Breast Cancer, Version 1.2017. J Natl Compr Canc Netw 15: 433-451. [Crossref]
Ogawa H, Nishio A, Satake H, Naganawa S, Imai T et al. (2008) Neuroendocrine tumor in the breast. Radiat Med 26: 28-32.
Zhang P, Yu J, Li J, Shen L, Li N et al. (2018) Clinical and Prognostic Value of PET/CT Imaging with Combination of (68)Ga-DOTATATE and (18)F-FDG in Gastroenteropancreatic Neuroendocrine Neoplasms. Contrast Media Mol Imaging 2018: 2340389. [Crossref]
Papotti M, Macri L, Finzi G, Capella C, Eusebi V et al. (1989) Neuroendocrine differentiation in carcinomas of the breast: a study of 51 cases. Semin Diagn Pathol 6: 174-188. [Crossref]
Miremadi A, Pinder SE, Lee AH, Bell JA, Paish EC et al. (2002) Neuroendocrine differentiation and prognosis in breast adenocarcinoma. Histopathology 40: 215-222. [Crossref]
Castaneda SA, Strasser J (2017) Updates in the Treatment of Breast Cancer with Radiotherapy. Surg Oncol Clin N Am 26: 371-382. [Crossref]
Yildirim Y, Elagoz S, Koyuncu A, Aydin C, Karadayi K (2011) Management of neuroendocrine carcinomas of the breast: A rare entity. Oncol Lett 2: 887-890. [Crossref]
Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J et al. (2016) ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology 103: 153-171. [Crossref]
O'Toole D, Kianmanesh R, Caplin M (2016) ENETS 2016 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: An Update. Neuroendocrinology 103: 117-118. [Crossref]
Delle Fave G, O'Toole D, Sundin A, Taal B, Ferolla P et al. (2016) ENETS Consensus Guidelines Update for Gastroduodenal Neuroendocrine Neoplasms. Neuroendocrinology 103: 119-124. [Crossref]
Reubi JC, Waser B, Schaer JC, Laissue JA (2001) Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med 28: 836-846. [Crossref]
Setyono-Han B, Henkelman MS, Foekens JA, Klijn GM (1987) Direct inhibitory effects of somatostatin (analogues) on the growth of human breast cancer cells. Cancer Res 47: 1566-1570. [Crossref]
Szepeshazi K, Milovanovic S, Lapis K, Groot K, Schally AV (1992) Growth inhibition of estrogen independent MXT mouse mammary carcinomas in mice treated with an agonist or antagonist of LH-RH, an analog of somatostatin, or a combination. Breast Cancer Res Treat 21: 181-192. [Crossref]
Wade PM Jr, Mills SE, Read M, Cloud W, Lambert MJ 3rd et al. (1983) Small cell neuroendocrine (oat cell) carcinoma of the breast. Cancer 52: 121-125. [Crossref]
Jundt G, Schulz A, Heitz PU, Osborn M (1984) Small cell neuroendocrine (oat cell) carcinoma of the male breast. Immunocytochemical and ultrastructural investigations. Virchows Arch A Pathol Anat Histopathol 404: 213-221. [Crossref]
Francois A, Chatikhine VA, Chevallier B, Ren GS, Berry M et al. (1995) Neuroendocrine primary small cell carcinoma of the breast. Report of a case and review of the literature. Am J Clin Oncol 18: 133-138.
Chua RS, Torno RB, Vuletin JC (1997) Fine needle aspiration cytology of small cell neuroendocrine carcinoma of the breast. A case report. Acta Cytol 41: 1341-1344. [Crossref]
Yalcin S, Zengin N, Tekuzman G, Kucukali T (1997) Primary neuroendocrine tumor of the breast. Med Oncol 14: 121-123. [Crossref]
Fukunaga M (1998) Neuroendocrine carcinoma of the breast: a case report of pure type. APMIS 106: 1095-1100. [Crossref]
Fukunaga M (1998) Neuroendocrine carcinoma of the breast with Merkel cell carcinoma-like features. Pathol Int 48: 557-561. [Crossref]
Sebenik M, Nair SG, Hamati HF (1998) Primary small cell anaplastic carcinoma of the breast diagnosed by fine needle aspiration cytology: a case report. Acta Cytol 42: 1199-1203. [Crossref]
Samli B, Celik S, Evrensel T, Orhan B, Tasdelen I (2000) Primary neuroendocrine small cell carcinoma of the breast. Arch Pathol Lab Med 124: 296-298. [Crossref]
Yamasaki T, Shimazaki H, Aida S, Tamai S, Tamaki K et al. (2000) Primary small cell (oat cell) carcinoma of the breast: report of a case and review of the literature. Pathol Int 50: 914-918. [Crossref]
Hoang MP, Maitra A, Gazdar AF, Albores-Saavedra J (2001) Primary mammary small-cell carcinoma: a molecular analysis of 2 cases. Hum Pathol 32: 753-757. [Crossref]
Salmo EN, Connolly CE (2001) Primary small cell carcinoma of the breast: report of a case and review of the literature. Histopathology 38: 277-278. [Crossref]
Berruti A, Saini A, Leonardo E, Cappia S, Borasio P et al. (2004) Management of neuroendocrine differentiated breast carcinoma. Breast 13: 527-529. [Crossref]
Bigotti G, Coli A, Butti A, del Vecchio M, Tartaglione R et al. (2004) Primary small cell neuroendocrine carcinoma of the breast. J Exp Clin Cancer Res 23: 691-696.
Bergman S, Hoda SA, Geisinger KR, Creager AJ, Trupiano JK (2004) E-cadherin-negative primary small cell carcinoma of the breast. Report of a case and review of the literature. Am J Clin Pathol 121: 117-121. [Crossref]
Jochems L, Tjalma WA (2004) Primary small cell neuroendocrine tumour of the breast. Eur J Obstet Gynecol Reprod Biol 115: 231-233. [Crossref]
Mariscal A, Balliu E, Diaz R, Casas JD, Gallart AM (2004) Primary oat cell carcinoma of the breast: imaging features. AJR Am J Roentgenol 183: 1169-1171. [Crossref]
Sridhar P, Matey P, Aluwihare N (2004) Primary carcinoma of breast with small-cell differentiation. Breast 13: 149-151. [Crossref]
Yamamoto J, Ohshima K, Nabeshima K, Ikeda S, Iwasaki H et al. (2004) Comparative study of primary mammary small cell carcinoma, carcinoma with endocrine features and invasive ductal carcinoma. Oncol Rep 11: 825-831.
Adegbola T, Connolly CE, Mortimer G (2005) Small cell neuroendocrine carcinoma of the breast: a report of three cases and review of the literature. J Clin Pathol 58: 775-778. [Crossref]
Stein ME, Gershuny A, Abdach L, Quigley MM (2005) Primary small-cell carcinoma of the breast. Clin Oncol (R Coll Radiol) 17: 201-202. [Crossref]
Tsai WC, Yu JC, Lin CK, Hsieh CT (2005) Primary alveolar-type large cell neuroendocrine carcinoma of the breast. Breast J 11: 487.
Fujimoto Y, Yagyu R, Murase K, Kawajiri H, Ohtani H et al. (2007) A case of solid neuroendocrine carcinoma of the breast in a 40-year-old woman. Breast Cancer 14: 250-253. [Crossref]
Hennessy BT, Gilcrease MZ, Kim E, Gonzalez-Angulo AM (2007) Breast carcinoma with neuroendocrine differentiation and myocardial metastases. Clin Breast Cancer 7: 892-894. [Crossref]
Kitakata H, Yasumoto K, Sudo Y, Minato H, Takahashi Y (2007) A case of primary small cell carcinoma of the breast. Breast Cancer 14: 414-419. [Crossref]
La Rosa S, Usellini L, Riva C, Capella C (2007) Well-differentiated neurotensin-producing neuroendocrine carcinoma of the breast. Report of a case. Histopathology 51: 846-847.
Vidulich KA, Donley SE, Duvic M (2007) Multinodular cutaneous spread in neuroendocrine tumor of the breast : an unusual presentation. Am J Clin Dermatol 8: 379-383. [Crossref]
Yaren A, Kelten C, Akbulut M, Teke Z, Duzcan E et al. (2007) Primary neuroendocrine carcinoma of the breast: a case report. Tumori 93: 496-498.
Jeong AK, Cha HJ, Ko BK, Park SB, Kang BS et al. (2008) Primary neuroendocrine carcinoma of the breast involving the nipple-areolar complex. J Ultrasound Med 27: 1401-1405. [Crossref]
Kim JW, Woo OH, Cho KR, Seo BK, Yong HS et al. (2008) Primary large cell neuroendocrine carcinoma of the breast: radiologic and pathologic findings. J Korean Med Sci 23: 1118-1120. [Crossref]
Kinoshita S, Hirano A, Komine K, Kobayashi S, Kyoda S et al. (2008) Primary small-cell neuroendocrine carcinoma of the breast: report of a case. Surg Today 38: 734-738.
Lopez Garcia J, Mesas Lorenzo R, de la Morena Valenzuela E (2008) [Pure neuroendocrine breast tumour]. Cir Esp 83: 273-274. [Crossref]
Mecca P, Busam K (2008) Primary male neuroendocrine adenocarcinoma involving the nipple simulating Merkel cell carcinoma - a diagnostic pitfall. J Cutan Pathol 35: 207-211. [Crossref]
Pagani A, Iandolo M (2008) [Invasive breast carcinoma with features of neuroendocrine carcinoma and carcinoma with osteoclastic cells: fine-needle aspiration cytology and histology of two cases]. Pathologica 100: 176-180. [Crossref]
Sadanaga N, Okada S, Shiotani S, Morita M, Kakeji Y et al. (2008) Clinical characteristics of small cell carcinoma of the breast. Oncol Rep 19: 981-985.
Ulamec M, Tomas D, Peric-Balja M, Spajic B, Hes O et al. (2008) Neuroendocrine breast carcinoma metastatic to renal cell carcinoma and ipsilateral adrenal gland. Pathol Res Pract 204: 851-855. [Crossref]
Akhtar K, Zaheer S, Ahmad SS, Hassan MJ (2009) Primary neuroendocrine carcinoma of the breast. Indian J Pathol Microbiol 52: 71-73. [Crossref]
Burckhardt O MM, Fiche M, Demartines N (2009) Primary Neuroendocrine criteria. Neuroendocrinology 90: 101-102.
El Hassani LK, Bensouda Y, M'Rabti H, Boutayeb S, Kamouni M et al. (2009) Primary neuroendocrine carcinoma of the breast, which chemotherapy? Indian J Cancer 46: 352-354.
Ersahin C, Bandyopadhyay S, Bhargava R (2009) Thyroid transcription factor-1 and "basal marker"--expressing small cell carcinoma of the breast. Int J Surg Pathol 17: 368-372. [Crossref]
Haji AG, Sharma S, Vijaykumar DK, Mukherjee P, Babu RM et al. (2009) Primary mammary small-cell carcinoma: A case report and review of the literature. Indian J Med Paediatr Oncol 30: 31-34.
Hojo T, Kinoshita T, Shien T, Terada K, Hirose S et al. (2009) Primary small cell carcinoma of the breast. Breast Cancer 16: 68-71.
Lee YC, Chen YL, Chan SE, Tseng HS, Chen DR (2009) Neuroendocrine Carcinoma of the Breast: Case Report and Literature Review. Breast Care (Basel) 4: 324-327.
Okoshi K, Saiga T, Hisamori S, Iwaisako K, Kobayashi H et al. (2012) A case of cytokeratin 20-positive large-cell neuroendocrine carcinoma of the breast. Breast Cancer 19: 360-364. [Crossref]
Quiros Rivero J, Munoz Garcia JL, Cabrera Rodriguez JJ, Gonzalez Ferreira JA, Samper Ots P et al. (2009) Extrapulmonary small cell carcinoma in breast and prostate. Clin Transl Oncol 11: 698-700.
Rineer J, Choi K, Sanmugarajah J (2009) Small cell carcinoma of the breast. J Natl Med Assoc 101: 1061-1064. [Crossref]
Salama AR, Jham BC, Papadimitriou JC, Scheper MA (2009) Metastatic neuroendocrine carcinomas to the head and neck: report of 4 cases and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 108: 242-247. [Crossref]
Sartori A, Scomersi S, Spivach A, Vigna S (2009) [Neuroendocrine carcinoma of the breast: a rare entity]. Chir Ital 61: 265-267. [Crossref]
Stita W, Trabelsi A, Gharbi O, Mokni M, Korbi S (2009) Primary solid neuroendocrine carcinoma of the breast. Can J Surg 52: E289-E290. [Crossref]
Yamaguchi R, Tanaka M, Otsuka H, Yamaguchi M, Kaneko Y et al. (2009) Neuroendocrine small cell carcinoma of the breast: report of a case. Med Mol Morphol 42: 58-61.
Christie M, Chin-Lenn L, Watts MM, Tsui AE, Buchanan MR (2010) Primary small cell carcinoma of the breast with TTF-1 and neuroendocrine marker expressing carcinoma in situ. Int J Clin Exp Pathol 3: 629-633. [Crossref]
Goucha A, Rekik W, Ben Mna N, Ben Hassouna J, Debbabi B et al. (2010) [Primary neuroendocrine carcinoma of the breast]. Tunis Med 88: 290-292.
Honami H, Sotome K, Sakamoto G, Iri H, Tanaka Y et al. (2014) Synchronous bilateral neuroendocrine ductal carcinoma in situ. Breast Cancer 21: 508-513. [Crossref]
Huettemann U LE, Neumann M, Vesper A, Janni W, Nestle-Kraemling C (2010) Primary metastatic neuroendocrine breast cancer: an extraordinary case report. Arch Gynecol Obs 282: 102-103.
Latif N, Rosa M, Samian L, Rana F (2010) An unusual case of primary small cell neuroendocrine carcinoma of the breast. Breast J 16: 647-651. [Crossref]
Saglam S OKS, Dagoglu N, Turkmen C, Yavuz E, Ozturk N (2010) Neuroendocrine carincoma of the breast: a case presenting with Octreoscan positive skin metastases. Turk Onkol Derg 25: 63-66.
Salman B SO, Yılmaz U, Cakır A, Kerem M, Aydın A (2010) Primary neuroendocrine carcinoma in the breast: a case report. J Breast Cancer 13: 115-119.
Buttar A, Mittal K, Khan A, Bathini V (2011) Effective role of hormonal therapy in metastatic primary neuroendocrine breast carcinoma. Clin Breast Cancer 11: 342-345. [Crossref]
Cesaretti M, Guarnieri A, Gaggelli I, Tirone A, Francioli N et al. (2011) Small cell carcinoma of the breast. Report of a case. Ann Ital Chir 82: 61-64.
Ghanem S S GM, Naciri S , Khoyaali S , Kabbaj M , Khanoussi B , Errihani H (2011) A Rare Tumor Of The Breast: Solid Neuroendocrine Carcinoma. Webmed Central BREAST WMC001591.
Jach R, Piskorz T, Przeszlakowski D, Huras H, Pitynski K et al. (2011) Solid papillary carcinoma of the breast with neuroendocrine features in a pregnant woman: a case report. Neuro Endocrinol Lett 32: 405-407. [Crossref]
Kawasaki T, Suda M, Kondo T, Nakazawa T, Mochizuki K et al. (2011) Microinvasive neuroendocrine carcinoma arising from a central papilloma of the breast. J Clin Pathol 64: 549-551. [Crossref]
Kawanishi N, Norimatsu Y, Funakoshi M, Kamei T, Sonobe H et al. (2011) Fine needle aspiration cytology of solid neuroendocrine carcinoma of the breast: a case report. Diagn Cytopathol 39: 527-530. [Crossref]
Navrozoglou I, Vrekoussis T, Zervoudis S, Doukas M, Zinovieva I et al. (2011) Primary atypical carcinoid of the breast: a case report and brief overview of evidence. World J Surg Oncol 9: 52. [Crossref]
Nicoletti S, Papi M, Drudi F, Fantini M, Canuti D et al. (2010) Small cell neuroendocrine tumor of the breast in a 40 year-old woman: a case report. J Med Case Rep 4: 201. [Crossref]
Nozoe T, Sueishi K, Mori E, Iguchi T, Egashira A et al. (2011) Primary neuroendocrine carcinoma of the breast: report of a case. Surg Today 41: 829-831.
Zhang JY, Chen WJ (2011) Bilateral primary breast neuroendocrine carcinoma in a young woman: report of a case. Surg Today 41: 1575-1578. [Crossref]
Alkaied H, Harris K, Azab B, Dai Q (2012) Primary neuroendocrine breast cancer, how much do we know so far? Med Oncol 29: 2613-2618. [Crossref]
Flessas I, Tsamis D, Michalopoulos NV, Chrysikos D, Liakou P et al. (2012) Dual carcinoma of the breast with neuroendocrine differentiation. Am Surg 78: E457-E458.
Graca S, Esteves J, Costa S, Vale S, Maciel J (2012) Neuroendocrine breast cancer. BMJ Case Rep 2012 : bcr1220115343. [Crossref]
Menendez P, Garcia E, Rabadan L, Pardo R, Padilla D et al. (2012) Primary neuroendocrine breast carcinoma. Clin Breast Cancer 12: 300-303.
Miura K, Nasu H, Ogura H (2012) Double neuroendocrine ductal carcinomas in situ coexisting with a background of diffuse idiopathic neuroendocrine cell hyperplasia of breast: a case report and hypothesis of neuroendocrine tumor development. Pathol Int 62: 331-334. [Crossref]
Psoma E, Nikolaidou O, Stavrogianni T, Mavromati A, Lytras K et al. (2012) A rare case report of a primary large-cell neuroendocrine carcinoma of the breast with coexisting Paget disease. Clin Imaging 36: 599-601. [Crossref]
Su CH, Chang H, Chen CJ, Liu LC, Wang HC et al. (2012) The carcinoembryonic antigen as a potential prognostic marker for neuroendocrine carcinoma of the breast. Anticancer Res 32: 183-188. [Crossref]
Watrowski R, Jager C, Mattern D, Horst C (2012) Neuroendocrine carcinoma of the breast--diagnostic and clinical implications. Anticancer Res 32: 5079-5082. [Crossref]
Yavas G, Karabagli P, Araz M, Yavas C, Ata O (2015) HER-2 positive primary solid neuroendocrine carcinoma of the breast: a case report and review of the literature. Breast Cancer 22: 432-436. [Crossref]
Abbasi NZ, Zahur Z, Sheikh AS, Khan AA, Ali F et al. (2013) Solid neuroendocrine carcinoma of the breast. J Coll Physicians Surg Pak 23: 820-822.
Angarita FA, Rodriguez JL, Meek E, Sanchez JO, Tawil M et al. (2013) Locally-advanced primary neuroendocrine carcinoma of the breast: case report and review of the literature. World J Surg Oncol 11: 128. [Crossref]
Chang ED, Kim MK, Kim JS, Whang IY (2013) Primary neuroendocrine tumor of the breast: imaging features. Korean J Radiol 14: 395-399. [Crossref]
Hanna MY, Leung E, Rogers C, Pilgrim S (2013) Primary large-cell neuroendocrine tumor of the breast. Breast J 19: 204-206. [Crossref]
Senetta R, Castellano I, Garbossa D, Sapino A, Cassoni P (2013) Pituitary metastasis of an unknown neuroendocrine breast carcinoma mimicking a pituitary adenoma. Pathology 45: 422-424. [Crossref]
Cinkir HY DU, Helvaci K, Bal O, Demirici A, Alkis N, Oksuzoglu B (2014) Primary Neuroendocrine Carcinoma of The Breast. Int J Hematol Oncol 24: 281-283.
Pagano M, Asensio SN, Zanelli F, Lococo F, Cavazza A et al. (2014) Is there a role for hormonal therapy in neuroendocrine carcinoma of the breast? A Paradigmatic case report. Clin Breast Cancer 14: e99-e101. [Crossref]
Suhani, Ali S, Desai G, Thomas S, Aggarwal L et al. (2014) Primary neuroendocrine carcinoma breast: our experience. Breast Dis 34: 95-99.
Janosky M, Bian J, Dhage S, Levine J, Silverman J et al. (2015) Primary large cell neuroendocrine carcinoma of the breast, a case report with an unusual clinical course. Breast J 21: 303-307. [Crossref]
Kawasaki T, Ishida M, Tada T, Matsuya H, Saitoh M et al. (2015) Well-differentiated neuroendocrine tumor of the breast with recurrence due to needle tract seeding. Virchows Arch 466: 479-481. [Crossref]
Rana V, Kakkar S, Anand S, Singh Y (2015) Primary neuroendocrine carcinoma of breast: A rare tumor. Indian J Cancer 52: 85-86. [Crossref]
Santos-Juanes J, Fernandez-Vega I, Coto-Segura P, Vivanco-Allende B, Garcia-Pravia C (2015) Cutaneous spread of primary neuroendocrine breast carcinoma with apocrine differentiation. J Eur Acad Dermatol Venereol 29: 1440-1441. [Crossref]
Sherwell-Cabello S, Maffuz-Aziz A, Hernandez-Hernandez B, Bautista-Pena V, Rodriguez-Cuevas S (2015) Primary neuroendocrine tumor of the breast. Breast J 21: 312-313. [Crossref]
Wei X, Chen C, Xi D, Bai J, Huang W et al. (2015) A case of primary neuroendocrine breast carcinoma that responded to neo-adjuvant chemotherapy. Front Med 9: 112-116. [Crossref]
Alva KA, Tauro LF, Shetty P, Saldanha E (2015) Primary neuroendocrine carcinoma of the breast: A rare and distinct entity. Indian J Cancer 52: 636-637.
Christensen L, Mortensen MB, Detlefsen S (2016) Breast Carcinoma With Unrecognized Neuroendocrine Differentiation Metastasizing to the Pancreas: A Potential Diagnostic Pitfall. Int J Surg Pathol 24: 463-467. [Crossref]
D'Antonio A, Addesso M, Memoli D, Cascone A, Cremone L (2016) A case of multicentric low-grade neuroendocrine breast tumor with an unusual histological pattern. Breast Dis 36: 161-164. [Crossref]
Meciarova I, Sojakova M, Mego M, Mardiak J, Pohlodek K (2016) High-Grade Neuroendocrine Carcinoma of the Breast With Focal Squamous Differentiation. Int J Surg Pathol 24: 738-742. [Crossref]
Nakai T, Kawasaki T, Tada T, Ishida M, Iwakoshi A et al. (2016) Well-differentiated neuroendocrine tumor of the breast with extensive lymphatic and vascular infiltration. Pathol Int 66: 706-707. [Crossref]
Takanami T, Ota Y, Suzuki M (2017) Pterygopalatine fossa metastasis with severe trigeminal neuralgia from neuroendocrine carcinoma of the breast. Auris Nasus Larynx 44: 131-133. [Crossref]
Abou Dalle I, Abbas J, Boulos F, Salem Z, Assi HI (2017) Primary small cell carcinoma of the breast: a case report. J Med Case Rep 11: 290. [Crossref]
Maqsood A, Khoury T, Kumar P, Papanicolau-Sengos A, Early AP (2017) Neuroendocrine Carcinoma of the Breast With Endobronchial Metastases and Syndrome of Inappropriate Antidiuretic Hormone Secretion. Clin Breast Cancer 17: e229-e232. [Crossref]
Soe AM, Joseph G, Guevara E, Xiao P (2017) Primary Neuroendocrine Carcinoma of the Breast Metastatic to the Bones, Which Chemotherapy? Breast J 23: 589-593. [Crossref]
Papotti M, Gherardi G, Eusebi V, Pagani A, Bussolati G (1992) Primary oat cell (neuroendocrine) carcinoma of the breast. Report of four cases. Virchows Arch A Pathol Anat Histopathol 420: 103-108. [Crossref]
Shin SJ, DeLellis RA, Ying L, Rosen PP (2000) Small cell carcinoma of the breast: a clinicopathologic and immunohistochemical study of nine patients. Am J Surg Pathol 24: 1231-1238. [Crossref]
Zekioglu O, Erhan Y, Ciris M, Bayramoglu H (2003) Neuroendocrine differentiated carcinomas of the breast: a distinct entity. Breast 12: 251-257. [Crossref]
López-Bonet E, Alonso-Ruano, M, Barraza, G, Vazquez-Martin A, Bernadó L, Menendez JA (2008) Solid neuroendocrine breast carcinomas: Incidence, clinico-pathological features and immunohistochemical profiling. Oncol Rep 20: 1369-1374. [Crossref]
Tian Z, Wei B, Tang F, Wei W, Gilcrease MZ et al. (2011) Prognostic significance of tumor grading and staging in mammary carcinomas with neuroendocrine differentiation. Hum Pathol 42: 1169-1177. [Crossref]
Kanat O, Kilickap S, Korkmaz T, Ustaalioglu Oven BB, Canhoroz M et al. (2011) Primary small cell carcinoma of the breast: report of seven cases and review of the literature. Tumori 97: 473-478. [Crossref]
Kawasaki T, Nakamura S, Sakamoto G, Kondo T, Tsunoda-Shimizu H et al. (2011) Neuroendocrine ductal carcinoma in situ of the breast: cytological features in 32 cases. Cytopathology 22: 43-49. [Crossref]
Zhang Y, Chen Z, Bao Y, Du Z, Li Q et al. (2013) Invasive neuroendocrine carcinoma of the breast: a prognostic research of 107 Chinese patients. Neoplasma 60: 215-222. [Crossref]
Wu J, Yang QX, Wu YP, Wang DL, Liu XW et al. (2012) Solid neuroendocrine breast carcinoma: mammographic and sonographic features in thirteen cases. Chin J Cancer 31: 549-556. [Crossref]
Rovera F, Lavazza M, La Rosa S, Fachinetti A, Chiappa C et al. (2013) Neuroendocrine breast cancer: retrospective analysis of 96 patients and review of literature. Int J Surg 11: S79-S83. [Crossref]
Zhu Y, Li Q, Gao J, He Z, Sun R et al. (2013) Clinical features and treatment response of solid neuroendocrine breast carcinoma to adjuvant chemotherapy and endocrine therapy. Breast J 19: 382-387. [Crossref]
Charfi S, Ayed CB, Mnif H, Ellouze S, Chaabane K et al. (2013) Mammary neuroendocrine carcinoma with mucinous differentiation: a clinicopathological study of 15 cases. Breast Dis 34: 87-93. [Crossref]
Cloyd JM, Yang RL, Allison KH, Norton JA, Hernandez-Boussard T et al. (2014) Impact of histological subtype on long-term outcomes of neuroendocrine carcinoma of the breast. Breast Cancer Res Treat 148: 637-644. [Crossref]
Jeon CH, Kim SM, Jang M, Yun BL, Ahn HS et al. (2014) Clinical and radiologic features of neuroendocrine breast carcinomas. J Ultrasound Med 33: 1511-1518. [Crossref]
Roininen N, Takala S, Haapasaari KM, Jukkola-Vuorinen A, Mattson J et al. (2017) Primary neuroendocrine breast carcinomas are associated with poor local control despite favourable biological profile: a retrospective clinical study. BMC Cancer 17: 72. [Crossref]