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.

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

NA

Neg

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

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

0

0

90%

12

AWD

 

4

66

BL

BM

HypBM

Neg

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

Neg

Bio

NO

BCS + SLNB

Ana

No

T1cN0M0

1,9

0/16

NET

-

+

95%

95%

1+

25%

76

NED

 

6

78

BL

BM

SBM

Neg

Neg

Bio

NO

BCS + SLNB

Ana

Yes

T1cN0M0

2

0/2

NEC

NA

+

95%

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

MBM

Neg

NO

Bio

NO

Mast + ALND

VP-16

NO

T4N1M0

10

25/25

SCNC

NA

NA

NA

NA

NA

NA

NA

NA

Jundt[24]

1984

52

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

TXN1M1

NA

+/?

NA

NA

NA

NA

NA

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

-

NA

NA

NA

21

DUC

Chua[26]

1997

45

BM

NA

NA

NA

NA

Bio

NO

BCS

NA

NO

T2N0MX

4,5

NA

SCNC

-

+

-

-

NA

NA

<1

NED

Yalcin[27]

1997

63

BM

BM

BM

Neg

NA

Bio

NO

Mast + ALND

NO

NO

T2N0M0

5

0/?

NET

+

NA

NA

NA

NA

NA

18

NED

Fukunaga[28]

1998

51

BM

Neg

BM

Neg

NO

NA

NA

Mast + ALND

NA

NA

T2N0M0

2,5

0/29

NET

+

-

+

-

-

NA

16

NED

Fukunaga[29]

1998

38

BM

BM

BM

Neg

NO

NA

NO

Mast + ALND

NO

NO

T2N1M0

2,5

1/7

NEC

+

+

-

-

-

12%

72

NED

Sebenik[30]

1998

67

NA

NA

NA

NA

NA

NA

Yes

Mast + ALND

NA

NA

T2NXM0

4

NA

NA

NA

NA

NA

NA

NA

NA

33

NED

Samli[31]

2000

60

PBM

BM

BM

Neg

NO

Bio

Yes

Mast + ALND

CDDP/VP-16+

5-FU/CPA/EPI

Yes

T4N1M0

4,5

10/11

SCNC

+

+

+

+

NA

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

NA

16

NED

Hoang[33]

2001

41

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

T3NXMX

14,5

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

51

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

T3NXMX

8

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

Salmo[34]

2001

46

NA

NA

NA

NA

NA

NA

NO

BCS

ChT

YES

T2N0M0

4

NA

NA

NA

NA

NA

NA

NA

NA

9

NED

Berruti[35]

2004

59

LMet

Neg

Neg

LMet

NO

NA

Yes

LMet resection

Tam

NO

TXNXM1

NA

NA

NEC

+

+

+

-

-

12

144

NED

Bigotti[36]

2004

56

CM

BM

BM

NA

Neg

Bio

Yes

NO

ChT + Som

NO

T3N1M0

18

2/9

SCNC

-

+

-

-

-

NA

15

DOD

Bergman[37]

2004

61

BL

BM

BM

Neg

Neg

Bio

NO

Mast + ALND

NO

NO

T2N1M0

2,5

2/5

SCNC

-

-

-

-

-

-

NA

NA

Jochems[38]

2004

71

BM

NA

BM

Neg

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

Neg

Bio

Yes

BCS + ALND

HoT

NO

T3N1M0

5,5

1/?

SCNC

NA

+

NA

NA

NA

NA

6

NED

Sridhar[40]

2004

58

NA

NA

NA

NA

NA

NA

NO

BCS

ChT

YES

T2N1M0

2

NA

NA

NA

NA

NA

NA

NA

NA

18

NED

Yamamoto [41]

2004

53

NA

NA

NA

Neg

Neg

NA

NO

NA

NO

NO

T3N2M0

6,5

NA

NA

NA

NA

-

NA

NA

NA

34

NED

75

NA

NA

NA

Neg

Neg

NA

NO

NA

CPA/MTX/5-FU + HoT

NO

T2N1M0

2,5

NA

NA

NA

NA

+

NA

NA

NA

43

NED

Adegbola[42]

2005

46

BL

NA

NA

Neg

NO

NO

NO

BCS

CDDP/VP-16+

Yes

T1NXM0

1

0

SCNC

+

+

-

NA

-

NA

48

NED

60

BM

NA

NA

Neg

NO

NO

NO

BCS

CDDP/VP-16+

Yes

T1NxM0

1,7

0

SCNC

+

+

-

NA

-

NA

20

DOD

61

BM, N+

NA

NA

Neg

NO

NO

NO

BCS

CDDP/VP-16+

Yes

T1NxM1

1,7

0

SCNC

+

-

-

NA

-

NA

6

AWD

Stein[43]

2005

54

BM, N+

NA

NA

NA

NA

Bio

Yes

Mast + ALND

NO

Yes

T1N1M0

1,5

5/15

SCNC

+

NA

-

NA

NA

NA

24

NED

Tsai[44]

2005

42

BM

NA

NA

Neg

NA

Bio

NA

Mast

NA

NA

NA

NA

NA

NEC

+

+

+

+

NA

NA

NA

NA

Fujimoto[45]

2007

40

BL, BND

HyBM

Neg

NO

NO

Bio

NO

Mast + SLNB

Ana

NO

T2(m)N0

M0

2

0/1

NEC

+

+

+

NA

+

NA

NA

NA

Hennessy[46]

2007

63

PAMet

Neg

Neg

BMet

PAMet

NO

Bio

NO

Mast + SLNB

ChT/Tam

NO

TXNXM1

NA

NA

NEC

+

+

NA

NA

NA

NA

NA

AWD

Kitakata[47]

2007

44

BL

HyBM

BM

BM

Neg

Neg

NO

Mast + ALND

CPA/Epi + DTX

NO

T2N1M0

4,5

2/15

SCNC

-

+

-

+

-

NA

22

NED

La Rosa[48]

2007

49

BL

Pos

Pos

NO

NO

Cit

NO

Mast

ChT

NO

T2NXMX

2,5

NA

NEC

+

+

+

+

-

NA

NA

NA

Vidulich[49]

2007

76

BM, N+, PE

BM, N+

NA

LMet

MMet

Cit, Bio

NO

NO

Oct/Ever, Bev/Erl

NO

T4N1M1

5

NA

NEC

+

+

+

+

-

NA

NA

AWD

Yaren[50]

2007

76

NA

NA

NA

Neg

NA

NA

NO

Mast + ALND

HoT

NO

T2N0M0

5

0/13

NA

NA

NA

+

NA

NA

NA

12

NED

Jeong[51]

2008

39

BL

IBM

HypBM

NO

NO

NO

NO

Mast + ALND

ChT / Hot

Yes

T2N1M1

2,2

2/14

NEC

+

+

+

+

NA

NA

32

NED

Kim[52]

2008

27

BM

HeBM

BM

Neg

Neg

Bio

NO

BCS + ALND

ChT

Yes

T2NXM0

3,2

NA

NEC

+

+

-

NA

NA

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

NA

NA

NA

Neg

NA

NO

Mast + ALND

NO

YES

T3N1MX

10

2/15

NA

NA

NA

-

NA

NA

NA

15

DOD

Mecca[55]

2008

70

PLM

NA

NA

NA

NO

NA

NO

BCS + SLNB

NO

NO

T4N1M0

1,9

2/2

NEC

NA

+

+

+

+

NA

12

NED

Ogawa[11]

2008

34

BM

HeBM

HypBM

Neg

NA

Bio

NA

BCS

NA

NA

T2NXM0

2,7

NA

NET

+

-

+

+

NA

NA

7

NED

Pagani[56]

2008

62

NA

NA

NA

NA

NA

NA

NA

BCS + ALND

NA

NA

T1N2MX

1,5

19/20

NA

NA

NA

+

NA

NA

NA

NA

NA

41

NA

NA

NA

NA

NA

NA

NA

Mast + ALND

NA

NA

T2N1MX

4,1

1/18

NA

NA

NA

NA

NA

NA

NA

NA

NA

Sadanaga[57]

2008

33

NA

NA

NA

NA

NA

NA

Yes

Mast  ALND

ChT

YES

T2N0M0

4

0/?

NA

NA

NA

NA

NA

NA

NA

60

NED

Ulamec[58]

2008

60

Hematuria

BM

NA

NA

NA

NA

Yes

Mast + ALND

HoT

Yes

T4N2M1

4,5

9/9

NEC

-

+

+

+

+

5%

18

NED

Akhtar[59]

2009

40

BL, N+

NA

NA

NA

NA

Cit, Bio

NA

Mast + ALND

NA

NA

T3NXMX

8,5

NA

NEC

NA

+

NA

NA

NA

NA

NA

NA

Burckhardt[60]

2009

84

NA

NA

NA

NA

NA

NA

Yes

Mast + ALND

HoT

NO

T2N1M0

3

+/?

NA

NA

NA

+

NA

NA

NA

NA

NED

El Hassani[61]

2009

40

BM

NA

BM

Neg

NO

Bio

Yes

NO

VP16-CDDP

NA

T4NXMX

NA

NA

NEC

+

+

+

+

NA

NA

1

DOD

Ersahin[62]

2009

50

NA

NA

NA

NA

NA

NA

NA

BCS

NA

NA

T3NXM0

2,5

NA

NA

NA

NA

NA

NA

NA

NA

12

NED

Haji[63]

2009

68

NA

NA

NA

NA

NA

NA

YES

Mast + ALND

NO

NO

T3N1M0

5,8

NA

NA

NA

NA

NA

NA

NA

NA

6

DOD

Hojo[64]

2009

60

NA

NA

NA

NA

NA

NA

NO

Mast + ALND

NO

NO

T3N0M1

3

0/?

NA

NA

NA

NA

NA

NA

NA

26

AWD

Lee[65]

2009

65

BM

HyBM

HypBM

NO

Neg

Neg

NO

BCS + SLNB

HoT

NO

T1N0M0

1,6

0/1

NEC

NA

+

+

-

-

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

NA

NA

NA

NA

NA

YES

BCS

NO

Yes

T3N0M0

6

0/?

NA

NA

NA

NA

NA

NA

NA

20

NED

Rineer[68]

2009

81

NA

NA

NA

NA

NA

NA

YES

BCS

NO

Yes

T3N1M0

5

NA

NA

NA

NA

NA

NA

NA

NA

26

AWD

Salama[69]

2009

48

BoMet

NA

NA

NA

NA

NA

YES

NO

NO

NO

T4NXMX

2,5

NA

NA

+

+

NA

NA

NA

NA

<1

AWD

Sartori[70]

2009

70

NA

NA

NA

NA

Neg

NA

NO

BCS + ALND

Som

Yes

T1N3M0

1,8

34/?

NA

NA

NA

+

NA

NA

NA

12

NED

Stita[71]

2009

64

BM

BM

BM

Neg

NO

NA

NO

Mast + ALND

ChT

NO

T2N0M0

3

0/?

NET

+

+

+

+

NA

NA

8

NED

Yamaguchi[72]

2009

51

BM

BM

BM

NA

Neg

Bio

NO

Mast + ALND

PTX

NO

T2N0M0

2,5

NA

SCNC

+

+

-

-

-

85%

12

AWD

Christie[73]

2010

61

NA

NA

NA

NA

NA

NA

NO

BCS

NO

NO

T3N2M0

3

NA

NA

NA

NA

NA

NA

NA

NA

3

DOD

Goucha[74]

2010

40

NA

NA

NA

NA

NA

NA

NO

BCS + ALND

NO

Yes

T1N0MX

1,8

0/15

NA

NA

NA

+

NA

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

NA

NA

Neg

Neg

NA

NO

Mast + ALND

DTX/Bev

NO

T3N1M1

9

NA

NA

NA

NA

NA

NA

NA

NA

NA

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

NA

NA

Saglam[78]

2010

60

NA

NA

NA

NA

Neg

NA

NO

NO

NO

NO

T4N1M1

0,6

1/1

NA

NA

NA

+

NA

NA

NA

26

DOD

Salman[79]

2010

72

NA

NA

NA

Neg

Neg

NA

NO

Mast + ALND

Letr

NO

TXNXM1

NA

NA

NA

NA

NA

+

NA

NA

NA

12

NED

Buttar[80]

2011

63

Jaundice

NA

NA

Pos

NO

Bio

NO

NO

Tam/Ana

NO

T2N0M1

NA

0/1

NEC

-

+

+

NA

-

NA

12

NED

Cesaretti[81]

2011

68

BM, N+

BL

HypBM

NA

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

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

NA

NA

Bio

NO

BCS + ALND

ADR + Tam

YES

T1N0M0

1,1

0/4

ICNE

+

NA

+

+

NA

40%

NA

NA

Kavasaki[84]

2011

43

BND

BM

NA

NA

NA

NA

NO

BCS

NA

NA

T1N0M0

1,2

0/4

NEC

+

+

+

NA

+

NA

NA

NA

Kawanishi [85]

2011

67

UBM

HyBM

BM

NA

NA

Cit, Bio

NO

BCS + SLNB

Ana

NO

T1N0M0

0,8

0/1

NEC

+

+

+

NA

-

NA

12

NED

Navrozoglou[86]

2011

73

NO

BN

BN

NA

Neg

Bio

NO

Mast + ALND

NO

NO

T1N0M0

1,1

0/17

NET

+

+

NA

NA

NA

NA

48

NED

Nicoletti[87]

2011

40

BM

BN

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

NA

NA

NO

Mast + ALND

CMF + AI

NA

NA

3

0/?

NEC

NA

+

+

+

-

NA

NA

NA

Zhang[89]

2011

29

BND

BM

BM

NO

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

Neg

NO

Pos

Bio

Yes

NO

Letr - Ana

NA

TXNXM1

NA

NA

SCNC

-

+

+

NA

NA

NA

12

NED

Flessas[91]

2012

59

NO

NA

Mic

NO

NO

Bio

NO

BCS +ALND

NA

NA

T2N1M0

2,8

1/?

ICNE

+

+

NA

NA

NA

NA

NA

NA

Graça[92]

2012

83

BM

BN

BM

Neg

Neg

Cit

NO

BCS + SLNB

HoT

NO

T2N0M0

2,4

0/1

NEC

NA

+

+

NA

NA

NA

NA

NED

Menéndez [93]

2012

44

NO

NA

BM

NA

NA

NA

NO

BCS + ALND

5-FU/EPI/CPA

Yes

T2N0M0

2

1/?

NEC

NA

NA

+

+

-

NA

48

NED

68

NO

NA

BM

NA

NA

NA

NO

BCS + SLNB

5-FU/EPI/CPA + DTX + Ana

Yes

 

3,6

NA

NEC

+

NA

NA

NA

NA

NA

24

NED

58

NO

NA

BM

NO

NO

Bio

NO

BCS + SLNB

5-FU/EPI/CPA

Yes

T1N0M0

1

0/1

NEC

NA

NA

+

-

-

NA

8

AWD

69

NO

HyBM

BM

NA

NA

NA

NA

BCS + SLNB

NA

NA

T1N0M0

1,4

0/1

ICNE

+

+

+

+

-

10%

2

NED

Miura[94]

2012

72

NO

NA

NA

Neg

NA

Cit, Bio

NO

BCS + SLNB

NA

NA

 

1,5

0/1

NEC

+

+

+

+

-

1%

NA

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

NA

NA

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

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

NO

T2N1M0

3

5/16

ICNE

NA

+

+

+

+

NA

15

NED

Abbasi[99]

2013

37

BL, N+

NA

NA

BoMet

NA

Bio

NO

Mast + ALND

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

NO

T3N2M1

7,5

9/19

ICNE

+

+

NA

NA

NA

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

NA

T2N1M0

NA

+/?

NEC

+

+

+

NA

-

NA

NA

NA

Hanna[102]

2013

60

PBM

Neg

Neg

Neg

NO

Bio

NO

BCS

CBL/VP-16

NO

T1N2M0

1,4

4/11

NEC

-

+

+

NA

-

NA

NA

NA

Senetta[103]

2013

82

Asthenia

BM

NA

PiMet

NO

Bio

NO

BCS + SLNB

HoT

NO

T1NXM1

2,3

NA

NEC

+

+

+

+

-

10

NA

NA

Yoon[8]

2013

44

BM

HyBM

HyBM

Neg

Neg

Bio

NA

Mast + ALND

CPA/ADR

NA

T2NXM0

2

NA

NEC

+

+

+

+

NA

NA

2

NED

Cinkir[104]

2014

75

BM

BM

BM

NA

NA

Bio

NO

Mast + ALND

CDDP/VP-16

Yes

T0N0M0

0

0/?

SCNC

+

+

+

+

-

5%

30%

NED

2014

77

PBM

SBM

SBM

NA

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

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

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

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

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

NA

Neg

NO

Bio

NA

Mast + ALND

NA

NA

T3N2M0

6

4/20

NEC

+

+

+

+

-

NA

NA

NA

Santos-Juanez[110]

2015

80

BM

Neg

Neg

Pos

NO

Bio

Yes

NO

NO

Yes

T4NXM1

17

NA

NET

+

+

+

+

-

10%

5

NED

Sherwell-Cabello[111]

2015

60

BL, N+

NA

NA

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

NO

Bio

Yes

Mast + ALND

NA

NA

T2N1M0

3

1/?

NET

+

+

+

-

+

10%

NA

NA

Alva[113]

2016

53

BL

Neg

SBM

Neg

NO

Cit

NO

Mast + ALND

NA

NA

T2N0M0

5

0/10

NEC

+

+

-

NA

-

NA

 

 

Christensen [114]

2016

73

SR

BM

BM

PaMet

NA

NA

NA

BCS + ALND

NA

NA

T2N3M1

3,8

18/21

ICNE

-

+

NA

NA

NA

 

4,5

AWD

D'antonio [115]

2016

50

BL

BL

Neg

Neg

Neg

Bio

NO

BCS + ALND

NO

NO

T1N0M0

1,5

0/?

ICNE

+

+

-

+

-

<5%

12

NED

Mečiarová[116]

2016

42

BL

HyBM

HypBM, Mic

Neg

NA

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

NA

Pos

NA

Bio

NA

Mast + ALND

NA

NA

T2N0M0

NA

NA

NET

NA

NA

NA

NA

NA

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

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