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D'Angelo et al. J Cancer Metastasis Treat 2019;5:30 I http://dx.doi.org/10.20517/2394-4722.2018.86 Page 9 of 18

Incidence
Gastrointestinal metastases from breast cancer are rare, among them the stomach is the second most
[53]
common site. In McLemore et al. , 2005 study, which regarded 12,001 patients, gastric involvement
represents 28% of all cases. The incidence of breast cancer metastasis to the stomach is reported to be
[3,4]
from 0.1% to 6%, but in autopsy series the estimated incidence is found to be higher, from 5% to 18% .
Gastrointestinal metastases are usually associated with other concurrent tumor localization: in a
[3]
retrospective study lead by Taal et al. , 1992 up to 94% of patients present with disseminated disease, that
[4]
involve the skeleton (60%), liver (20%), and also the lung (18%) . In our study 81% of the patients had other
metastases at time of diagnosis.

Metastasis
Gastrointestinal metastasis from breast cancer can be synchronous or more frequently metachronous,
[5]
with a mean time of presentation reported to be from 6 to 7 years , but in literature time can vary from 2
[5,6]
to 30 years . In our study there were 54 cases with metachronous presentation and only 10 patients with
synchronous disease.

Studies report three main mechanisms of dissemination of malignant breast cells to the upper GI tract:
lymphatic spread, hematogeneous route, and direct invasion from surrounding organs [3,4,54,55] . The first
type is more common in esophageal metastasis: the typical presentation is stricture or submucosal nodules
with normal overlying mucosa, that makes endoscopic diagnosis difficult [54,55] . Also the infiltration of
paraesophageal lymphonodes can result in compression of the esophageal lumen with consequent intramural
[56]
infiltration . Hematogenous spread is typical of esophagus, stomach or duodenum which results in stenosis
or mass localized intramural or in the submucosal layer, that may become ulcerated. The most common
pattern of presentation is linitis plastica-like; in this situation malignant cells are trapped from blood stream
to the submucosal or subserosal layer with diffuse infiltration that cause diffuse thickening and rigidity of
the organ wall [4,54,55,57] .

An important role in metastatic pathway is played by chemokines. CXCR4 and CXCR7 are the main
chemokine receptor expressed in breast cancer cells involved in transendothelial migration (TEM), and they
[58]
are responsible for the chemotaxis to certain target organs . CXCR4+ tumors are associated with more
[59]
distant metastasis than CXCR4-tumors, even though this association is not statistically significant . Their
ligandsareCXCL12 and CCL21; the first is implied in modulating integrin expression, metalloproteinase
production, tumor angiogenesis, tumor cell adhesion and apoptosis [60,61] . Metalloproteinases are essential to
degrade extracellular matrix to permit invasion of the cells attracted in metastatic sites by chemokines from
[60]
the bloodstream . CXCL12 promotes homing of tumor cells to secondary sites and then recall endothelial
[61]
stem cells for blood vessel formation and subsequent proliferation .
Circulating breast tumor cells pass from blood or lymphatic stream to areas that express CXCL12, thereby
metastatizing in many organs such as bone marrow, lymph nodes, liver and lung [59,61] .

An interesting hypothesis suggested by an article by J. Carlos Villa Guzman highlights the implication of
inflammation response in tumorigenesis. Chronic inflammation induced by Helicobacter Pylori is associated
with higher expression of chemokines and interleukins that may attract tumor cells to gastric or colon
[9]
mucosa with subsequent proliferation and develop of metastatic disease . Even though these mechanisms
are not fully understood, this hypothesis offers an interesting start point for other future studies.

Lobular breast cancer
Breast cancer metastases are more frequently related to lobular type then ductal type; in 83% of all
[62]
[4]
metastases the primary breast cancer has lobular histotype . According to the study of Borst et al. , 1993