Rare sites of breast cancer metastasis: a review.

Breast cancer (BC) metastasis accounts for the majority of deaths from BC. The rate of metastasis to uncommon sites is on the rise due to the more effective therapy prolonging survival and to the early detection on imaging. The evaluation of patient-reported symptoms is essential in detecting a recurrence as early as possible, which may impact survival. Hence, the knowledge of even the rare sites of BC metastasis is of paramount importance for the clinical interpretation of new symptoms in BC survivors. The term "unusual metastasis" defines a systemic failure with a frequency of ≤1% at each site and according to this unusual metastasis involve the central nervous system, secretory/endocrine organs and glands, internal organs and structures, and gynecological organs. The literature search was performed using the electronic database PubMed up to December 2018, with the following key words: {[rare(Title/Abstract)] OR [unusual(Title/Abstract)] OR [unconventional(Title/Abstract)]} AND {[metastases(Title/Abstract)] OR [metastasis(Title/Abstract)]} AND {[breast(Title/Abstract)]} AND {[cancer(Title/Abstract)] OR [tumor(Title/Abstract)] OR [tumour(Title/Abstract)] OR [neoplasm(Title/Abstract)]}. The search was limited to papers in English language. Of the 3,086 papers found, 757 were excluded as reporting animal models, 378 were not in English language, 1 was a duplicate of the same research, 1,414 did not report on BC metastases, 108 were previous review reviews on BC or tumour to tumour metastases; 428 papers were included in this review. Despite the improvements in BC management, most deaths from cancer result from metastases that are resistant to conventional therapies. In general, it is uncommon to find isolated rare metastases, the vast majority of these develops together with metastases in other sites, thus highlighting a worsening systemic disease. However, the early detection of even rare metastases represents the only chance to control the disease and prolong survival while waiting for the development of more effective systemic therapies. 2019 Translational Cancer Research. All rights reserved.

Introduction

Breast cancer (BC) metastasis accounts for the majority of deaths from BC. The rate of metastasis even in sites known as uncommon is on the rise. On one side this is due to the more effective therapy which have prolonged the overall survival of BC patients, on the other side due to the development of new imaging techniques and early detection (1). The American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline recommends that primary care clinicians should educate and counsel all women about the signs and symptoms of recurrence, including new lumps, pain in the bone, chest or abdomen, dyspnea and constant headaches (2). There is no evidence that routine laboratory tests or imaging (exception for mammography, when indicated) in asymptomatic patients gives any survival advantage, thus advanced imaging should be offered when recurrence is suspected (3,4). The evaluation of patient-reported symptoms is essential in detecting a recurrence as early as possible, which may impact survival (5,6). Hence, the knowledge of even the rare sites of BC metastasis is of paramount importance for the clinical interpretation of new symptoms in BC survivors.

BC can metastasize to several organs, the most frequent metastatic sites include bone, lungs, liver and skin (7). Additionally, more and more sites of BC metastasis have been reported in literature. The definition of “unusual metastasis” is not universally accepted, however it defines a systemic failure with a frequency of ≤1% at each site and according to this unusual metastasis involve the central nervous system, secretory/endocrine organs and glands, internal organs and structures, and gynaecological organs.

This review reports on the rare anatomical regions where BC can spread forming metastases.

Methods

The literature search was performed using the electronic database PubMed up to December 2018, with the following key words: {[rare(Title/Abstract)] OR [unusual(Title/Abstract)] OR [unconventional(Title/Abstract)]} AND {[metastases(Title/Abstract)] OR [metastasis(Title/Abstract)]} AND {[breast(Title/Abstract)]} AND {[cancer(Title/Abstract)] OR [tumor(Title/Abstract)] OR [tumour(Title/Abstract)] OR [neoplasm(Title/Abstract)]}. The search did not include editorials, letters, comments, conference letters, systematic reviews and meta-analyses and it was limited to papers in English language.

All studies on rare sites of metastases from BC were eligible to be included.

All data were extracted in a standard pre-determined format including information on: first author’s name, publication year, number of cases and site of metastases. We considered rare the sites different from nodes, bone, lung, liver and skin.

Results

The flow chart of the study selection was shown in . Of the 3,086 papers found, 757 were excluded as reporting animal models, 378 were not in English language, 1 was a duplicate of the same research, 1,414 did not report on BC metastases, 108 were previous review on BC or tumour to tumour metastases, 428 papers were included in this review. shows the distribution per sites of all cases of rare metastases reported in literature.

Figure 1

Flow chart of studies included in the review.

Table 1

Site distribution of rare metastasis cases reported in literature

Anatomical region	Site	Reference	Number	Tot.
Eye	Orbital soft tissue	Reeves et al., 2002 (8)	1
		Asproudis et al., 2004 (9)	1
		Eckardt et al., 2011 (10)	1
		Mora-Guzmán et al., 2018 (11)	1
		Maliepaard et al., 2017 (12)	2
		Spraker et al., 2017 (13)	1
		Pinto Proença et al., 2018 (14)	1
		Gondim et al., 2017 (15)	5
		Kim et al., 2011 (16)	1 (bilateral)
		Pierson et al., 2016 (17)	6
		Raap et al., 2015 (18)	8
		Zwicker et al., 2008 (19)	7
		Torres et al., 2007 (20)	2
		Schick et al., 2006 (21)	3
		Dieing et al., 2004 (22)	2
		Amemiya et al., 2002 (23)	20
		Rossi et al., 2014 (24)	1	61
	Intraocular	Bajcsay et al., 2003 (25)	11	11
	Extraocular muscles	Murthy et al., 2011 (26)	1
		Chang et al., 2017 (27)	1
		Nifosì et al., 2018 (28)	1
		Framarino-Dei-Malatesta et al., 2019 (29)	1
		Weiss et al., 1984 (30)	2
		Lell et al., 2004 (31)	1
		Kouvaris et al., 2008 (32)	1 (bilateral)
		Spitzer et al., 2005 (33)	1
		Van der Heijden et al., 1991 (34)	1
		Glazer et al., 1991 (35)	1
		Pierson et al., 2016 (17)	6	17
	Retina	Correa de Mello et al., 2017 (36)	1
		Shields et al., 2014 (37)	2
		Shah et al., 2017 (38)	1
		Pierson et al., 2016 (17)	9
		Biswas et al., 2007 (39)	1 (bilateral)
		Sirimaharaj et al., 2006 (40)	1
		Schlaen et al., 1986 (41)	1	16
	Conjunctiva	Skalicky et al., 2007 (42)	1
		Sánchez Orgaz et al., 2017 (43)	1
		Radovanović et al., 2013 (44)	1
		Kiratli et al., 1996 (45)	4	7
	Eyelid	Kaur et al., 2005 (46)	1
		Martorell-Calatayud et al., 2010 (47)	1 (bilateral)
		Goodier et al., 2010 (48)	1
		Kuo et al., 2008 (49)	1
		Douglas et al., 2002 (50)	1 (bilateral)
		Claessens et al., 2000 (51)	1
		Rosenblum et al., 1983 (52)	2
		Lawton et al., 1980 (53)	1	9
	Iris and ciliar body	Ozturk et al., 2007 (54)	1
		Shields et al., 1995 (37)	16
		Mennel et al., 2001 (55)	2
		Reddy et al., 2000 (56)	1	20
	Choroid	Williams et al., 2000 (57)	1
		Solav et al., 2010 (58)	1
		Arya et al., 2018 (59)	1
		Luo et al., 2018 (60)	1
		Antosz et al., 2014 (61)	1
		Liu et al., 2012 (62)	1
		Hood et al., 2011 (63)	3
		Oleksy et al., 2010 (64)	1
		Kosmas et al., 2000 (65)	1
		Kreusel et al., 1999 (66)	2
		Chen et al., 1998 (67)	1
		Paoli et al., 1998 (68)	1
		Gupta et al., 1991 (69)	1
		Thatcher et al., 1975 (70)	42	58
Genital organs	Cervix	Pambuccian et al., 2000 (71)	1
		Nair et al., 2009 (72)	1
		Proença et al., 2016 (73)	2
		Toyoshima et al., 2015 (74)	1
		Bogliolo et al., 2010 (75)	1
		Mousavi et al., 2007 (76)	1
		Green et al., 2004 (77)	1
		Pauer et al., 2003 (78)	1
		Sinkre et al., 2000 (79)	1
		Kesavan et al., 2000 (80)	1
		Hepp et al., 1999 (81)	1
		Kennebeck et al., 1998 (82)	2
		Taxy et al., 1994 (83)	1
		Sanuki-Fujimoto et al., 2008 (84)	4	19
	Endometrium	Kemp et al., 1997 (85)	1
		Moey et al., 2016 (86)	1
		Çift et al., 2016 (87)	1
		Rahmani et al., 2018 (88)	1
		Aytekin et al., 2018 (89)	1
		Briki et al., 2018 (90)	2
		Franco-Màrquez et al., 2019 (91)	1
		Ertas et al., 2012 (92)	1
		D’souza et al., 2010 (93)	1
		Karvouni et al., 2009 (94)	1
		Scopa et al., 2005 (95)	2
		Chehal et al., 2002 (96)	1
		Horn et al., 2000 (97)	1	16
	Vulva	Gandhi et al., 2015 (98)	1
		Engelstaedter et al., 2011 (99)	1
		Sheen-Chen et al., 2004 (100)	1
		Curtin et al., 1997 (101)	1
		Valenzano Menada et al., 2003 (102)	1	5
	Vagina	Pineda et al., 1978 (103)	1
		Bellati et al., 2012 (104)	1	2
	Ovaries	Pambuccian et al., 2000 (71)	1
		Durga et al., 2018 (105)	1
		Fujii et al., 2006 (106)	1
		Sanuki-Fujimoto et al., 2008 (84)	6	9
	Clitoris	Julien et al., 2012 (107)	1	1
Placenta		Alexander et al., 2003 (108)	15
		Froehlich et al., 2018 (109)	1
		Eltorky et al., 1995 (110)	2
		Sanuki-Fujimoto et al., 2008 (84)	1	19
Soft tissue	Skeletal muscle	Liu et al., 2015 (111)	1
		Khettab et al., 2017 (112)	1
		Almusarhed et al., 2017 (113)	1
		Salemis et al., 2015 (114)	1
		Khandelwal et al., 2012 (115)	10
		Surov et al., 2010 (116)	2	16
	Subcutaneous tissue	Purkayastha et al., 2016 (117)	1
		Rao et al., 2015 (118)	1
		Metere et al., 2012 (119)	1
		Plaza et al., 2008 (120)	13	16
	Intra-articular	Jaffe et al., 2016 (121)	1	1
Head and neck	Paranasal sinus	Monserez et al., 2001 (122)	1
		Pignataro et al., 2001 (123)	1
		Asproudis et al., 2004 (9)	1
		Fyrmpas et al., 2008 (124)	1
		Reimann et al., 2011 (125)	1
		Xiong et al., 2017 (126)	1
		Walker et al., 2013 (127)	1
		Marchioni et al., 2004 (128)	1
		Pitkäranta et al., 2001 (129)	1
		Austin et al., 1995 (130)	9
		Gondim et al., 2017 (15)	2
		Tiwari et al., 2014 (131)	1
		Namad et al., 2014 (132)	1
		Imre et al., 2013 (133)	1
		Atasoy et al., 2013 (134)	1	24
	Parotid gland	Ando et al., 2011 (135)	1
		Agrawal et al., 2018 (136)	1
		Cao et al., 2018 (137)	1
		Rawet et al., 2017 (138)	1
		Sellinger et al., 2011 (139)	1
		Dangore-K et al., 2009 (140)	1
		Perez-Fidalgo et al., 2007 (141)	1
		Zhang et al., 2003 (142)	1
		Sanuki-Fujimoto et al., 2008 (84)	3	11
	Minor Salivary glands	Erra et al., 2011 (143)	1
		Cain et al., 2001 (144)	1	2
	Tongue and lip	Suárez Roa et al., 2007 (145)	2
		Owosho et al., 2016 (146)	1	3
	Tonsils	Bar et al., 2011 (147)	1
		Sera et al., 2017 (148)	1
		Maruzzo et al., 2012 (149)	1
		Barton et al., 1980 (150)	1
		Gondim et al., 2017 (15)	1	5
	Pharynx and parapharyngeal space	Saab et al., 1987 (151)	1
		Copson et al., 2018 (152)	1
		Murhekar et al., 2015 (153)	1
		Raut et al., 2001 (154)	1
		Nguyen et al., 1983 (155)	1
		Agrawal et al., 2015 (156)	1	6
	Larynx	Schuler et al., 2010 (157)	1
		Wanamaker et al., 1993 (158)	1	2
	Nasal cavity	Weng et al., 2014 (159)	1
		Gondim et al., 2017 (15)	1
		Wanamaker et al., 1993 (158)	1	3
	Ear	Pusiol et al., 2013 (160)	1
		Marques et al., 2002 (161)	1	2
	Glomus	Çelik et al., 2017 (162)	1	1
	Intravascular carcinomatosis	Takei et al., 2015 (163)	1	1
	Lacrimal gland	Sanuki-Fujimoto et al., 2008 (84)	1	1
	Oral cavity	Cooney et al., 1988 (164)	1
		Scipio et al., 2001 (165)	1
		Malhotra et al., 2006 (166)	1
		Eichhorn et al., 2010 (167)	1
		Kechagias et al., 2012 (168)	1
		Gondim et al., 2017 (15)	3
		Friedrich et al., 2010 (169)	6
		Rajesh et al., 1998 (170)	1	15
	Thyroid	Yang et al., 2014 (171)	1
		Bourcier et al., 2018 (172)	1
		Ghias et al., 2019 (173)	1
		Kho et al., 2018 (174)	1
		Plonczak et al., 2017 (175)	1
		Debnam et al., 2017 (176)	8
		Magers et al., 2016 (177)	1
		Rossi et al., 2015 (178)	5
		HooKim et al., 2015 (179)	3
		Kolarević et al., 2012 (180)	1
		Calzolari et al., 2008 (181)	1
		Saber et al., 2007 (182)	1
		Leboeuf et al., 2006 (183)	1
		Gong et al., 2005 (184)	1
		Lam et al., 1998 (185)	7
		Ferrara et al., 1997 (186)	1
		Rosen et al., 1978 (187)	1	39
		Sanuki-Fujimoto et al., 2008 (84)	3
	Parathyroid glands	Lee et al., 2013 (188)	1
		Watanabe et al., 1983 (189)	1	2
	Pituitary gland	Ghosn et al., 1991 et al., (190)	1
		Fukunaga et al., 2014 (191)	1
		Rozen et al., 2007 (192)	1
		Poursadegh Fard et al., 2011 (193)	1
		Nose et al., 2018 (194)	1
		Castle-Kirszbaum et al., 2018 (195)	4
		Kam et al., 2017 (196)	1
		Ravnik et al., 2016 (197)	1
		Burkhardt et al., 2016 (198)	6
		Gormally et al., 2014 (199)	1
		Magalhães et al., 2014 (200)	1
		Spinelli et al., 2012 (201)	1
		Naqi et al., 2012 (202)	1
		Dogan et al., 2008 (203)	1
		Gołkowski et al., 2007 (204)	1
		Kurkjian et al., 2005 (205)	2
		Sturm et al., 2004 (206)	1
		Ruiz Hernández et al., 1996 (207)	1
		Paulus et al., 1990 (208)	1
		Yap et al., 1979 (209)	39
		Sanuki-Fujimoto et al., 2008 (84)	2
		Teears et al., 1975 (210)	35	104
	Jugular foramen (Villaret syndrome)	Flis et al., 2015 (211)	1	1
	Cavernous sinus	Khaw et al., 2012 (212)	1	1
Thoracic organs	Mediastinum	Kim et al., 2018 (213)	1
		Rampado et al., 2007 (214)	25	26
	Thymus	Fukunaga et al., 2017 (215)	1
		Fujioka et al., 2013 (216)	1
		Park et al., 2007 (217)	1	3
	Heart	Bhojwani et al., 2016 (218)	1
		Sandhu et al., 2017 (219)	1
		Bhambhani et al., 2014 (220)	1
		Katalinic et al., 2013 (221)	1
		Eminowicz et al., 2011 (222)	1
		Garg et al., 2011 (223)	1
		Kawase et al., 2009 (224)	1
		Broom et al., 2006 (225)	1
		Lieberman et al., 1993 (226)	1
		Labib et al., 1992 (227)	2	11
Gastrointestinal tract	Esophagus	Wada et al., 2009 (228)	1
		Anaya et al., 2006 (229)	1
		Koike et al., 2005 (230)	2
		McLemore et al., 2005 (231)	4
		Sunada et al., 2005 (232)	1
		Erman et al., 2002 (233)	1
		Simchuk et al., 2001 (234)	4
		Varanasi et al., 1995 (235)	4
		Herrera et al., 1992 (236)	1
		Biller et al., 1982 (237)	2
		Sanuki-Fujimoto et al., 2008 (84)	2	23
	Stomach	Ghosn et al., 1991 (190)	1
		Malhotra et al., 2009 (238)	1
		Hara et al., 2010 (239)	1
		Dòria et al., 2015 (240)	1
		Geredeli et al., 2015 (241)	1
		Ricciuti et al., 2016 (242)	1
		Dos Santos Fernandes et al., 2016 (243)	4
		Villa Guzmán et al., 2017 (244)	1
		Jmour et al., 2017 (245)	4
		Khan et al., 2017 (246)	1
		Kliiger et al., 2017 (247)	1
		Ulmer et al., 2018 (248)	1
		Bushan et al., 2018 (249)	1
		Güler et al., 2019 (250)	1
		Woo et al., 2018 (251)	1
		Kim et al., 2018 (213)	1
		Gurzu et al., 2018 (252)	2
		Yim et al., 2017 (253)	1
		Choi et al., 2017 (254)	1
		Mullally et al., 2017 (255)	1
		Rodrigues et al., 2016 (256)	1
		Zuhair et al., 2015 (257)	1
		Rachan Shetty et al., 2015 (258)	2
		Wysocka et al., 2011 (259)	1
		Critchley et al., 2011 (260)	1
		Almubarak et al., 2011 (261)	35
		Ghirarduzzi et al., 2010 (262)	3
		Yamamoto et al., 2010 (263)	1
		Trouillet et al., 2010 (264)	4
		Ellis et al., 2009 (265)	4
		Ciulla et al., 2008 (266)	1
		Jhaveri et al., 2006 (267)	1
		Savanis et al., 2006 (268)	1
		Whitty et al., 2005 (269)	1
		Akcali et al., 2005 (270)	1
		Tremblay et al., 2002 (271)	1
		Oda et al., 2001 (272)	61 (autopsy)
		Pera et al., 2001 (273)	1
		Washington et al., 1995 (274)	20
		McLemore et al., 2005 (231)	11
		Sanuki-Fujimoto et al., 2008 (84)	6	185
	Duodenum	Houghton et al., 1987 (275)	1
		Sarkar et al., 2002 (276)	1
		Sato et al., 2007 (277)	1
		Jones et al., 2015 (278)	1
		Giestas et al., 2016 (279)	1
		Lin et al., 2019 (280)	1
		Wang et al., 2018 (281)	1
		Zhao et al., 2012 (282)	1
		Asoglu et al., 2006 (283)	1
		Lottini et al., 2002 (284)	1
		Titus et al., 1997 (285)	1	11
	Small bowel	Hernández et al., 2000 (286)	1
		Choi et al., 2011 (287)	1
		Khan et al., 2017 (246)	1
		Liu et al., 2018 (288)	1
		Bilen et al., 2012 (289)	1
		Cho et al., 2011 (290)	1
		Mouawad et al., 2011 (291)	1
		Kelly et al., 2009 (292)	1
		Oyasiji et al., 2009 (293)	1
		Al-Qahatani et al., 2007 (294)	1
		McLemore et al., 2005 (231)	14	24
	Colon-rectum	Wang et al., 2014 (159)	1
		Haberstich et al., 2005 (295)	1
		Malhotra et al., 2009 (238)	1
		Titi et al., 2010 (296)	1
		Okido et al., 2011 (297)	1
		Saranovic et al., 2011 (298)	1
		Mistrangelo et al., 2011 (299)	1
		Villa Guzmán et al., 2016 (244)	1
		Cherian et al., 2017 (300)	1
		Khan et al., 2017 (246)	1
		Falco et al., 2018 (301)	1
		Blachman-Braun et al., 2019 (302)	1
		Samra et al., 2019 (303)	1
		Schellenberg et al., 2018 (304)	1
		Ruymbeke et al., 2018 (305)	1
		Tsujimura et al., 2017 (306)	1
		Buka et al., 2016 (307)	1
		Rengifo et al., 2016 (308)	1
		Mroz et al., 2015 (309)	1
		Zhou et al., 2012 (310)	1
		Takeuchi et al., 2012 (311)	1
		Bochicchio et al., 2012 (312)	1
		Gerova et al., 2012 (313)	1
		Nikolic et al., 2012 (314)	1
		Amin et al., 2011 (315)	1
		Razzetta et al., 2011 (316)	1
		Critchley et al., 2011 (260)	1
		Efthimiadis et al., 2011 (317)	1
		Balja et al., 2010 (318)	1
		Thèraux et al., 2009 (319)	1
		Birla et al., 2008 (320)	1
		Uygun et al., 2006 (321)	1
		Savanis et al., 2006 (268)	1
		Signorelli et al., 2005 (322)	1
		McLemore et al., 2005 (231)	18
		Law et al., 2003 (323)	1
		Dhar et al., 2003 (324)	1
		Bamias et al., 2001 (325)	1
		Koutsomanis et al., 2000 (326)	1
		Flamme et al., 1994 (327)	1
		Rabau et al., 1988 (328)	1
		Balibrea et al., 2007 (329)	1	59
Abdominal organs	Appendix	Dirksen et al., 2010 (330)	1	1
	Pancreas	Hardt et al., 1993 (331)	1
		Stoeckler et al., 2007 (332)	1
		Bonapasta et al., 2010 (333)	1
		Takamizawa et al., 2011 (334)	1
		Inoue et al., 2018 (335)	1
		Sun et al., 2017 (336)	1
		Song et al., 2014 (337)	1
		Molino et al., 2014 (338)	1
		Razzetta et al., 2011 (316)	1
		Lam et al., 2011 (339)	1
		Mourra et al., 2010 (340)	1
		Ang et al., 2007 (341)	1
		Crippa et al., 2006 (342)	3
		Haque et al., 2005 (343)	1
		Z'graggen et al., 1998 (344)	1
		Mountney et al., 1997 (345)	1
		Sanuki-Fujimoto et al., 2008 (84)	6
		Kliiger et al., 2017 (247)	1	25
	Peritoneum	Saranovic et al., 2011 (298)	1
		Shan et al., 2016 (346)	1
		Osaku et al., 2015 (347)	1
		Cardi et al., 2013 (348)	5
		D’Annibale et al., 2007 (349)	1
		Kobayashi et al., 2007 (350)	1
		McLemore et al., 2005 (231)	50
		Sanuki-Fujimoto et al., 2008 (84)	27	87
	Gallbladder	Doval et al., 2006 (351)	1
		Markelov et al., 2011 (352)	1
		Di Vita et al., 2011 (353)	1
		Urade et al., 2019 (354)	1
		Zamkowski et al., 2017 (355)	1
		Abdelilah et al., 2014 (356)	1
		Manouras et al., 2008 (357)	1
		Zagouri et al., 2007 (358)	1	8
	Spleen	Bartolotti et al., 2012 (359)	1
		El Fadli et al., 2017 (360)	1
		Sufficool et al., 2013 (361)	1
		Foroudi et al., 1999 (362)	1
		Chapel et al., 1999 (363)	1
		Cummings et al., 1992 (364)	2
		Sanuki-Fujimoto et al., 2008 (84)	2	9
	Kidney	Kykalos et al., 2010 (365)	1
		Mhamdi et al., 2017 (366)	1
		Nasu et al., 2015 (367)	1
		Karczmarek-Borowska et al., 2015 (368)	1
		Wu et al., 2015 (369)	6
		Herzberg et al., 1991 (370)	1
		Sanuki-Fujimoto et al., 2008 (84)	1	12
	Bladder	Al Ibraheemi et al., 2016 (371)	1
		Jordan et al., 2018 (372)	1
		Kase et al., 2018 (373)	1
		Xiao et al., 2012 (374)	3
		Vulcano et al., 2010 (375)	1
		Gatti et al., 2005 (376)	1
		Soon et al., 2004 (377)	1
		Elia et al., 1999 (378)	1	10
	Ureter	Gabsi et al., 2018 (379)	1
		Zunarelli et al., 1995 (380)	1	2
	Adrenal gland	Mizuyama et al., 2013 (381)	1
		Andjelic-Dekic et al., 2014 (382)	1
		Paunovic et al., 2014 (383)	1
		Demirci et al., 2011 (384)	1
		Liu et al., 2010 (385)	1
		Bausewein et al., 2006 (386)	1
		Davì et al., 1996 (387)	1
		Sanuki-Fujimoto et al., 2008 (84)	2	9
	Retroperitoneum	Sanuki-Fujimoto et al., 2008 (84)	16
		Kim et al., 2018 (213)	1	17
	Pelvis	Shan et al., 2016 (346)	1
		Colak et al., 2005 (388)	1	2
Nervous System	Meninges	Kashiwagi et al., 2012 (389)	4
		Laurencet et al., 2000 (390)	1
		Higashi et al., 2000 (391)	1
		Mego et al., 2011 (392)	2
		Rao et al., 2017 (393)	15
		Alnajar et al., 2017 (394)	19
		Seki et al., 2016 (395)	1
		Pan et al., 2015 (396)	1
		Meattini et al., 2012 (397)	33
		Tseng et al.,H. 2003 (398)	1
		Kosmas et al., 2000 (65)	1
		Jayson et al., 1994 (399)	35
		Sanuki-Fujimoto et al., 2008 (84)	16
		Madgula et al., 2014 (400)	1	125
	Intramedullary spinal cord	Higashi et al., 2000 (391)	1
		Gasser et al., 2001 (401)	1
		Choi et al., 2010 (402)	1
		Garcia et al., 2016 (403)	1
		Aiello et al., 2017 (404)	1
		Payer et al., 2015 (405)	3
		Hsu et al., 2013 (406)	1
		Zebrowski et al., 2010 (407)	3
		Watanabe et al., 2006 (408)	1
		Villegas et al., 2004 (409)	1
		Chen et al., 1995 (410)	1
		Schwechheimer et al., 1985 (411)	1
		Moffie et al., 1980 (412)	1
		West et al., 1979 (413)	1	18
	Intraventricular	Della Puppa et al., 2010 (414)	1
		Sajko et al., 2009 (415)	1	2
	Cerebellum	Saha et al., 2018 (416)	1
		Singh et al., 2015 (417)	1
		Rowe et al., 2015 (418)	1
		Higashi et al., 2000 (391)	1	4
	Peripheral nervous system	Artico et al., 1991 (419)	1
		Backhouse et al., 1998 (420)	1
		Cherekaev et al., 2013 (421)	1
		Suryanarayanan et al., 2005 (422)	1
		Ito et al., 2010 (423)	1
		Schulz et al., 2009 (424)	1
		Zingale et al., 2002 (425)	1
		Hirota et al., 1998 (426)	1
		Breadon et al., 1977 (427)	1	9
	Brainstem	Reyes et al., 2011 (428)	1	1
	Brain	de Ceuster et al., 2016 (429)	1
		Chakrabarti et al., 2013 (430)	1
		Kashiwagi et al., 2012 (389)	3
		Low et al., 2012 (431)	1
		Modi et al., 2006 (432)	1
		Saisho et al., 2005 (433)	2
		Higashi et al., 2000 (391)	4
		Chou et al., 1998 (434)	1
		Koller et al., 1986 (435)	1	15

Discussion

In the war against BC, metastasis remains a primary clinical challenge as it is unpredictable in onset and it exponentially increases the clinical impact to the patient. The process of tumour metastasis is still controversial. Starting from Paget’s hypothesis of “seed and soil” (436), numerous studies have partially confirmed his observations and integrated new findings with the idea of a multistage process dependent on both the intrinsic properties of the tumour cells and the host response (437). In 1889 the surgeon Stephen Paget had already raised the question of “What is that decides what organs shall suffer in a case of disseminated cancer?” and contradicted the prevailing theory of Virchow (438) on metastasis originating from the arrest of tumour-cell emboli in the vasculature. Paget’s hypothesis is now widely accepted and enriched by new studies. The current definition of “seed” is a progenitor cell, cancer stem cell, or metastatic cell within the heterogeneous subpopulations forming the primary tumour, and the “soil” is the host factor, stroma, niche or organ microenvironment where selected metastatic cells can live and grow (439,440).

Translating Paget’s theory into clinical practice, findings show that BC preferentially spreads to some organs, whilst it is less common to find BC metastasis in other remote sites. In this review we mainly focused on anatomical sites where few cases of metastases have been reported in literature.

In clinical practice the knowledge of common sites of metastases helps the physician to detect early symptoms corresponding to secondary lesions, however when BC metastasizes in less expected sites the diagnosis could be delayed.

BC is amongst the most common tumours to metastasize to the head and neck, it constitutes ~15–20% of all metastases to this region and has been described in almost every head and neck anatomic subsite. However, since metastases to the head and neck are uncommon to begin with, breast carcinoma metastases are still relatively rare in clinical practice. Parenchymal metastases to the submandibular and parotid glands can be difficult to distinguish from new primary tumors arising there, specifically salivary duct carcinoma. In these cases immuno-histochemistry only can help differential diagnosis (15). Among metastatic orbital neoplasms, BC is the most common primary tumour, in particular, 55 cases were reported as affecting orbital soft tissue and 55 cases choroid, being bilateral in less than 1% of cases (1/55). A median time to onset of orbital metastases from BC diagnosis is 4.5–6.5 years and the majority of these patients have ER positive Her2 positive BC. A biological explanation for this tropism might be that steroid hormones, needed for tear production are produced in the orbital fat or in alternative, orbital metastases could be a late complication in patients with slow growing ER positive disease (17). Whether there is a tropism of lobular cancer cells to the orbital tissue or this is purely due to the more infiltrative nature of this tumor type along with its general tendency for spreading to myriad body sites is a matter of speculation (18). Prognosis in cases of orbital metastases from BC is determined by metastatic burden. A mean survival time of 5–22 months after orbital diagnosis has been reported in the literature. Furthermore, orbital metastases can cause various local problems, such as exophthalmos, exposure keratitis, optic neuropathy, and limited extraocular muscle motion. As enucleation confers no benefit in terms of survival, external beam radiotherapy is the most commonly used palliative treatment (16). Although BC rarely metastasizes to the head and neck region, awareness should be raised when BC patients experience headache or have sinus-related symptoms. The most of these patients have very poor prognosis, however chemotherapy and radiotherapy may be effective to prolong survival (126). Despite the principle that metastatic deposits have a predilection for highly vascularized organs, the thyroid is rarely a metastatic site. We found 39 cases of BC metastasis to the thyroid gland reported in literature, the true prevalence oscillates from 3% to 34% of all thyroid metastases, whilst it is much more common to find synchronous or metachronous malignancies (84,170-187). The suspicion of metastatic disease should be raised by thyroid lumps in BC survivors, although indicating poor prognosis, the role of surgery in these lesions should be considered for local disease to control, palliate and prevent the potential morbidity on the airway (441,442).

Despite the well-known BC propensity to spread to the central nervous system, the prevalence of symptomatic central nervous system metastases among patients with BC ranges from 5% to 16%, although autoptic studies have reported prevalence rates of up to 30% (414). In our review we found 18 cases of intramedullary spinal cord metastases (see ). The mechanism of intramedullary spread is not well established but it may involve lymphatic or haematological transit, direct spread from the vertebrae or ‘drop-down’ metastases from the brain. The most common symptoms are paresis and dysesthesia or bladder dysfunction, both surgery and radiotherapy are recommended both for diagnosis and treatment of brain metastases (405). Interestingly, Zebrowski et al. (407) suggested a potential association between the inability of trastuzumab to cross the blood-brain barrier and the occurrence of intramedullary metastases in Her2 positive disease. Additionally, some studies report a predisposition of lobular histotype to leptomeningeal carcinomatosis, whilst in the case of ductal carcinoma spreading to the meninges a high histological grade and triple-negative biology seems to be prevalent (394).

Although very rare (9 cases reported), metastasis to the spinal nerve root ganglion can be the first manifestation of distant hematogenous metastases of BC. The clinical course is characterized by increasing radicular symptoms-especially intractable pain. Surgical intervention with tumour debulking followed by radiotherapy provides local tumour control and palliation from pain (422-425).

Soft tissue metastasis from any primary malignancy is considered very rare, it can be in subcutaneous and muscular tissue (117). In this review we found 33 cases of soft tissues metastases involving skeletal muscle or subcutaneous tissue or both of the upper and lower limbs, trunk, shoulders, and buttocks (117-120). Some studies have reported a frequency of 0.8% based on autopsies while few reported an incidence of 0.2% based on clinical studies (443,444). This rarity can be due to the fact that soft tissues produce anti-carcinogenic factors like lactic acid, beta adrenergic receptors or protease inhibitors which serve as a deterrent for metastatic invasion (116,445,446). As for other metastatic sites a multimodality approach generally is adopted depending upon the performance status of the patient, any comorbid condition, type of primary malignancy, site and size of the metastatic lesion. RT and chemotherapy have been generally considered the primary modality of therapy either in combination or separately while surgery is reserved for patients not responding to radiation or chemotherapy. A high degree of clinical suspicion and immuno-histopathological confirmation are required to identify and diagnose any soft tissue swelling of the body in a previously treated primary breast cancer patient to prevent any inappropriate treatment causing undue morbidity or even mortality (117).

Gastrointestinal (GI) tract metastases from BC are also considered rare, their incidence in autopsy series varied from 8% to 35% (274,447). This localization can easily simulate a primary GI cancer and any region of the GI tract can be involved, from the tongue (145) to the anus (448). Most series report a greater propensity of lobular carcinoma to metastasize to the GI tract and peritoneum, but data on this tropism are poor and inconclusive (231,449,450). The most common site of GI tract metastasis is the stomach, 185 cases in our review. Colon involvement is quite common (59 cases), whilst small intestine involvement has been reported in 24 cases and is more frequently diagnosed at autopsy. In particular, ductal carcinoma seems to produce nodular stomach lesions, while lobular BC tend to cause more diffuse disease (451). The GI tract metastases are uncommon and peculiar, the main issue is to identify symptoms like nausea, vomiting, diarrhoea or abdominal pain and start the differential diagnosis with CT scan, endoscopy and biopsy. According to literature reports, surgery is crucial when possible, nevertheless chemotherapy and endocrine therapy were commonly used, very rarely radiotherapy can also play a role (452). Other abdominal organs are also rare sites of BC metastasis often mimicking primary tumours, so the final diagnosis occurs after biopsy or surgical excision.

BC metastases can also involve genital organs and the placenta. Most cases of uterine metastases presents as vaginal bleeding or abdominal discomfort, although the vast majority of these have been diagnosed during autopsy (78,453). Studies have showed that the incidence of ovarian metastases in BC patients is 13–47%. It seems that the metastatic lesions reach the ovaries and genital organs through the lymphatic and blood vessels, or through trans-coelomic spread, then the reciprocal interaction between intrinsic BC molecular characteristics and the local microenvironment explains the metastatic organotropism (103,454). The most common sign of uterine or vaginal metastases is vaginal bleeding, while ovarian metastases frequently present as an asymptomatic ovarian mass (455,456). In any case, the central task is to differentiate primary versus secondary tumours, as this will affect the clinical decision process, treatment and prognosis. The surgical metastasis excision, hysterectomy or oophorectomy not only provide diagnostic information, but they could also have a curative effect along with systemic therapy (104). The local control of bleeding can also benefit from radiation therapy, uterine artery embolization and conisation (73). However, genital tract and ovarian metastases represent the late stage of a systemic disease, for instance BC patients with ovarian metastases have a 6–26% 5-year survival rate (106,454,457). The lack of symptoms and poor outcomes emphasize the relevance of a regular gynaecological surveillance in all BC survivors, despite guidelines citing different approaches (73). In 2003, Alexander et al. (108) have reported the most comprehensive review of placental involvement (15 cases), where BC cells were located in the intervillous space without any involvement of the fetal villous stroma and vascular circulation. Fetal immune response seems to play a key role in avoiding the fetal involvement when possible, although maternal prognosis remains very poor (109,110). Malignant disease in pregnancy provoke a challenging situation for gynaecologists, breast surgeons, oncologists and neonatologists, all placentas should be evaluated by pathologists and each single case of metastasis should be discussed within a multidisciplinary team (109).

The analysis of BC metastatic pattern has shown that lobular tumours were more likely to metastasize to the peritoneum, adrenal glands, uterus and pleural surface (458). Additionally, the aggressiveness of lobular carcinoma seems to be associated to metastasis at unusual sites, in particular meningeal dissemination was more frequently associated to lobular BC (459-462). A retrospective study on 3783 patients about the distribution and frequency of metastases at unusual sites showed that the majority of unusual metastases are associated with prior metastases at more unusual sites, which appear, on average, 1 year before. The prognosis of metastatic BC patients was the same irrespective of the metastasis site and no risk factors for unusual metastasis were identified (84). In general, it is uncommon to find isolated rare metastases, the vast majority of the rare metastases described develop together with metastases in other sites, thus highlighting a worsening systemic disease.

Conclusions

Despite the improvements in diagnosis, surgical techniques, general patient care, and local and systemic adjuvant therapies, most deaths from cancer result from metastases that are resistant to conventional therapies. The process of cancer metastasis is sequential and selective and incorporates stochastic elements, hence the growth of metastases represents the endpoint of the interplay of tumour cells with host factors.

On the research level, the recent advances in our understanding of the metastatic process at the cellular and molecular level provide unprecedented potential for the improvement and the development of effective adjuvant therapies.

On the clinical level, the early diagnosis of secondary lesions represents the only chance to control the disease and prolong survival, hence the knowledge of the common as well as rare sites of metastases can help the physician to detect symptoms and plan the most appropriate treatment.