breast cancer is the most common malignancy after lung cancer and the leading cause of cancer - related deaths among women worldwide .
although the incidence of breast cancer has been increasing , male breast cancer is a rare and uncommon disease , accounting for only 0.5% to 1% of all cases .
male patients are diagnosed at late stages and usually have a worse prognosis , mainly due to the lack of screening for disease prevention and less awareness of pathognomonic symptoms .
nonetheless , there have been several studies where male sex was not reported as an independent prognostic factor for worse clinical outcome and there were no meaningful differences between the 5- and 15-year excess mortalities of men and women . among the histological subtypes of breast cancer , invasive lobular carcinomas have a high capacity to metastasize to uncommon sites such as the skin , pleura , peritoneum , ovaries , and the gastrointestinal ( gi ) tract . in such cases ,
the stomach is the most affected segment of the digestive tract , detected in 3% to 18% of patients with metastatic disease . on the other hand ,
importantly , metastatic spread to the stomach may occur many years after the initial treatment for breast cancer , and it may be extremely difficult to distinguish from a primary gastric cancer based on clinical , endoscopic , radiological , and histopathological features .
however , this discrimination is imperative to establish the best treatment strategy for our patients .
herein , we report the first case of ductal breast carcinoma metastatic to the stomach mimicking primary linitis plastica in a male patient .
a 65-year - old man presented to the emergency room of santa maria della misericordia hospital ( perugia , italy ) with the primary complaints of hematemesis and epigastric pain in april 2015 .
twelve years ago , he had undergone total mastectomy with complete axillary dissection for invasive ductal carcinoma .
postoperative histology showed a completely excised invasive ductal carcinoma with the following immunohistochemistry ( ihc ) profile : estrogen receptor ( er ) , 90% ; progesterone receptor ( pr ) , 0% ; ki-67 , > 10% ; and human epidermal growth factor receptor 2 ( her2 ) , 1 + ( figure 1 ) .
the patient was treated with four cycles of adjuvant doxorubicin and cyclophosphamide , followed by 5 years of tamoxifen with no signs of recurrence . in august 2011 ,
the relapse was observed at the surgical mastectomy site and the patient underwent radical surgical excision of the nodule , which was diagnosed as metastasis from invasive ductal breast carcinoma with the same ihc profile as the primary tumor ( er , 100% ; pr , 0% ; ki-67 , 14% ; her2 , 1 + ) . following these findings ,
the patient was treated with 12 cycles of doxorubicin , cyclophosphamide , and paclitaxel , followed by tamoxifen with no signs of recurrence until september 2014 , when a positron emission tomography / computed tomography ( pet / ct ) image showed new bone lesions .
subsequently , tamoxifen treatment was stopped and the patient was started on anastrozole ; he showed stable disease on the subsequent follow - up visits and instrumental evaluations . at the time of hospitalization in april 2015 ,
the patient had undergone an esophagogastroduodenoscopy , which had revealed a borrmann type 4 tumor that was characterized by diffuse thickening and sclerosis of the gastric wall and marked hypertrophy of the mucosal folds .
a subsequent pet / ct scan showed wall thickening of both the gastric antrum and the body of the stomach with a significant 18f - fluorodeoxyglucose ( fdg ) uptake , indicating linitis plastica ( figure 2 ) .
based on these findings , the patient was diagnosed with primary gastric adenocarcinoma , although the possibility of a metastatic progression of invasive ductal carcinoma to the stomach could not be eliminated . however , considering the poorer prognosis associated with primary diffuse gastric carcinoma compared to oligometastatic breast cancer and the different treatment strategies associated with these diagnoses , after a multidisciplinary discussion , it was decided that surgery was the most suitable treatment strategy .
therefore , the patient underwent gastrectomy with roux - en - y esophagojejunal anastomosis with both diagnostic and therapeutic intention .
on macroscopic examination , the stomach measured 163 mm with wall thickening ( up to 10 mm ) of the antrum and corpus .
the internal surface of the thickened wall showed a diffuse loss of mucosal rugae in an 88-mm region without mucosal ulceration .
microscopic examination revealed diffuse growth of a poorly differentiated carcinoma with a full - thickness extension through the stomach wall .
the neoplasm appeared to grow from the serous surface toward the overlying gastric mucosa , which appeared normal but infiltrated .
foci of dysplasia were not found in the surrounding gastric mucosa , leading to the suspicion that the gastric involvement was of metastatic origin .
the tumor cells had large vesicular nuclei with prominent nucleoli , and they were arranged in solid and tubular patterns of growth ( figure 3a , b ) . the mitotic count was elevated ( up to 20 mitosis/10 high power fields ) .
importantly , the tumor cells showed immunore - activity for cytokeratin 7 ( ck7 ) , e - cadherin , gross cystic disease fluid protein 15 ( gcdfp15 ) , and gata binding protein 3 ( gata3 ) , consistent with the findings for metastatic breast carcinoma of no special type ( figure 3c - e ) .
the er , pr , ck20 , and synaptophysin statuses were negative , whereas ihc staining for her2 revealed a 3 + positivity ( figure 3f ) . a pet / ct scan performed after the gastric resection showed no fdg uptake ( figure 2 g , h ) .
following diagnosis of her2 positive gastric metastasis of breast carcinoma , the patient received six cycles of docetaxel plus trastuzumab , thus achieving stable disease .
presently , the patient is receiving maintenance therapy with trastuzumab , without any signs of progression .
breast cancer metastases to the gi tract are very rare occurrences ; the most common metastatic sites are the bones , liver , lungs , and brain .
the estimated overall incidence of breast cancer metastasis to the stomach during either long - term follow - up or post mortem analyses is 2% to 18% , with 90% to 94% of the patients having concurrent breast cancer metastases .
importantly , metastases to the gi tract can represent the first manifestation of metastatic breast cancer , as well as late recurrence even years after the diagnosis of the primary neoplasm , similar to the present case . of note ,
the potential of metastasis to the stomach is higher among patients with lobular histologies . in this respect ,
a retrospective analysis conducted over a period of 15 years demonstrated that 83% of patients with gastric metastases had lobular histologies .
these findings were confirmed in a larger series , which demonstrated that the lobular type accounted for at least 83% to 85% of the cases with gastric metastases form breast cancer .
the biological mechanism underlying the unusual spread of lobular breast carcinoma to the gi tract is not clearly understood ; however , some authors have hypothesized that it might be linked to a specific tropism of the lobular cells .
intriguingly , in the mixed histology subtype ( ductal and lobular ) , only the lobular component potentially metastasizes to the stomach .
clinically , metastatic gastric linitis plastica is indistinguishable from a primary gastric linitis plastica , similar to the present case .
in fact , the clinical presentation of gastric involvement is completely a specific ; it commonly manifests as epigastric pain , indigestion , lack of appetite , and occasional gastric obstruction and bleeding .
although rare , linitis plastica represents the most frequent type of gastric metastasis from lobular breast cancer .
conversely , the evidence for the association of ductal breast carcinoma with gastric metastases is insufficient , and its association with linitis plastica is very rare as it usually manifests as a polyp , ulcer erosion , or stenosis . in the present case ,
the patient showed tumor recurrence in the gi tract , presenting as secondary linitis plastica from a primary breast ductal carcinoma , as the second case reported in medical literature , and the first ever described case among male patients . in order to obtain an accurate differential diagnosis between breast cancer metastasis to the stomach and primary gastric cancer , ihc analysis
is strongly recommended , because clinical , radiological , and endoscopic findings are generally unhelpful .
importantly , even though the detection of er and pr expression in biopsy samples and surgical gastric specimens is indicative of breast cancer metastasis to the stomach , early studies with first - generation antibodies documented er and pr positivity in 32% and 12% of the cases , respectively , in patients with primary gastric cancer .
later , van velthuysen et al .   demonstrated that second - generation anti - er antibodies are sensitive and specific biomarkers for determining breast origin , because they are not usually expressed by gastric cancer cells .
unfortunately , they are unhelpful in the case of er - negative primary breast cancer , and loss of er expression in the metastatic site of breast cancer has been widely reported , as observed in our patient .
therefore , in such cases , er and pr do not represent suitable biomarkers to discriminate between breast cancer metastasis to the stomach and primary gastric cancer . in the present study ,
the authors provide an ihc panel of selected antibodies that allowed a proper differential diagnosis ( ck20 , ck7 , er , pr , e - cadherin , gcdfp15 , and gata3 ) .
gcdfp15 has been proven an accurate biomarker for identifying a malignant lesion of breast origin , yielding 55% to 76% sensitivity , and 95% to 100% specificity .
additionally , combined ihc for ck7 and ck20 represents another useful tool , as breast carcinomas are ck7 positive in 90% of cases versus the 50% to 55% of primary gastric cancers , whereas ck20 is negative in all breast carcinomas and highly positive in gastric , colorectal , and pancreatic carcinomas .
notably , our panel also included gata3 , a member of the gata family of zinc - finger dna binding proteins , which is currently considered a reliable , sensitive , and specific immunomarker for the diagnosis of breast cancer , as it was found only in breast and urothelial carcinomas but not in other tumors .
aberrant e - cadherin expression is common in invasive ductal carcinomas that develop distant metastases .
intriguingly , distant metastases consistently express e - cadherin , often more strongly than the primary tumor .
when breast cancer metastasis to the gi tract is suspected , positive ihc for ck7 , gcdfp15 , and gata3 can effectively confirm the diagnosis , particularly in case of ck20 negativity .
in addition , e - cadherin expression further corroborates a ductal histology , whereas e - cadherin loss is peculiar of invasive lobular carcinomas . in the present case
, discordance was observed between the hormone receptor statuses of primary ( er , 90% ; pr , 0% ) and metastatic breast cancer ( er , 0% ; pr , 0% ) . loss of er and pr during disease progression is a well - recognized phenomenon , representing a consequence of disease progression or prolonged endocrine therapy . concerning the her2 status , we reported discordance between primary invasive ductal carcinoma and gastric recurrence as well .
as opposed to the primary tumor , the immunohistochemical staining for her2 on gastric specimens revealed 3 + positivity that supported targeted therapy with trastuzumab , which in turn resulted in stable disease .
data on treatment are extremely limited because of the lack of randomized trials and the lack of reports ; however , majority of the patients with gastric metastases from breast cancer usually receive chemotherapy or hormone therapy , based on the assessment of hormone receptor statuses in metastatic tissues . in case of isolated gi tract involvement
, surgery should be considered where appropriate , although it is often reserved for palliation purposes in cases of intestinal obstruction or bleeding .
conversely , in the multi - metastatic setting , surgery does not improve survival compared to systemic treatment . of note , to the best of our knowledge , trastuzumab - based therapy for her2
positive gastric metastasis from breast cancer has never been reported previously . beyond the rarity of the case and its presentation ,
this report further enlarges the growing body of evidence suggesting that hormone receptor and her2 status should be determined for all recurrences , in case the procedure is technically feasible and not unreasonably invasive , since any change in er , pr , and her2 statuses might grant new therapeutic possibilities for the patient , allowing us to tailor the treatment in the most accurate manner .
 breast cancer metastases to the gastrointestinal tract are very rare occurrences . among the histological subtypes of breast cancer , invasive lobular carcinomas have a high capacity of metastasis to uncommon sites including the stomach . 
 conversely , there has not been sufficient evidence supporting the gastric metastasis of invasive ductal carcinoma . 
 herein , we report a unique case of metastatic ductal breast carcinoma mimicking primary linitis plastica in a male patient , particularly focusing on the clinical and pathological features of presentation . 
 moreover , we propose a immunohistochemical panel of selected antibodies including those for cytokeratin 20 , cytokeratin 7 , estrogen receptor , progesterone receptor , e - cadherin , gross cystic disease fluid protein 15 , and gata binding protein 3 for an accurate differential diagnosis . 
INTRODUCTION
CASE REPORT
DISCUSSION