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Periampullary Metastases from Breast Cancer: A Case Report and Literature Review

Periampullary Metastases from Breast Cancer: A Case Report and Literature Review Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 3479568, 6 pages https://doi.org/10.1155/2019/3479568 Case Report Periampullary Metastases from Breast Cancer: A Case Report and Literature Review 1 2 1 1 1 Yi Lin , Sio In Wong, Yuzhou Wang, Chileong Lam, and Xianghong Peng Department of Medical Oncology, Centro Hospitalar Conde de São Januário, Sé, Macau Department of Pathology, Centro Hospitalar Conde de São Januário, Sé, Macau Correspondence should be addressed to Xianghong Peng; xianghongpeng@hotmail.com Received 10 September 2018; Accepted 10 December 2018; Published 9 January 2019 Academic Editor: Su Ming Tan Copyright © 2019 Yi Lin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We presented a metastatic breast cancer case who was afflicted with obstructive jaundice caused by an ampullary neoplasm. Since jaundice due to periampullary metastasis from breast cancer was a rare entity, a literature review of similar cases through the PubMed database was done. A total of 23 additional cases were found. Among these 24 cases, 5 presented with periampullary metastasis synchronously with the diagnosis of breast cancer, while 19 had metachronous periampullary metastasis with an interval ranging between 1.3 and 23 years from the initial diagnosis of breast cancer to the emergence of jaundice. It is intriguing to establish a differential diagnosis for common bile tract stricture prior to tissue biopsy, even with diagnostic workups including serum tumor markers, MRI plus MRCP, ERCP with intraductal brushing, and endoscopic ultrasound, in that the clinical, radiological, and endoscopic findings of metastatic lesions overlapped extensively with those found with primary periampullary malignancies. An immunohistochemical portfolio including cytokeratin7/20 (CK7/20), homeobox protein CDX2, human epidermal growth factor receptor 2 (HER2/neu), estrogen receptor alfa (ERα), progesterone receptor (PgR), mammaglobin, gross cystic disease fluid protein-15 (GCDFP-15), and transacting T-cell-specific transcription factor (GATA-3) was helpful for differential diagnosis among cases with ambiguous microscopic features. 1. Introduction 2. Case Report Obstructive jaundice caused by extrahepatic biliary tract A 42-year-old woman presented with right breast invasive metastases from breast cancer is a rare clinical scenario. ductal carcinoma (TNM stage: cT3N1M0) which was human Accurate and prompt differentiation between primary epidermal growth factor receptor 2 (Her2) overexpressed and and secondary periampullary malignancies is essential for estrogen receptor (ER) and progesterone receptor (PR) further treatment decision-making and will exert a major negative in August 2013. Modified radical mastectomy was impact on the prognosis. We presented a case with breast performed in November 2014 after finishing 8 cycles of pre- cancer who developed metachronous metastasis to the operative chemotherapy with trastuzumab incorporated. The ampulla of Vater while other distant metastatic lesions surgical specimen had resection margins clear of tumor cells subsided completely after systemic treatment. A literature and was staged as ypT2N2a. She was afflicted with right chest review through the PubMed database yielded a total of wall local recurrence less than two months after the mastec- 23 similar cases of breast cancer with periampullary tomy. Complete remission of the recurrence was achieved metastases. Differential diagnosis between periampullary by local external beam irradiation. Administration of trastu- metastasis from breast cancer and a primary periampullary zumab was continued to a total of one year. Nonetheless, cancer was discussed thoroughly regarding patient history, seven months after completion of locoregional radiotherapy, serum tumor markers, imaging study plus biopsy procedures, some right chest wall skin lesions appeared in October 2015 and histopathology. with enlarged ipsilateral supraclavicular lymph nodes, which 2 Case Reports in Oncological Medicine obstructive jaundice due to disseminated intrahepatic metas- were both confirmed to be recurrent breast cancer by biopsy. She received salvage chemotherapy with paclitaxel plus per- tasis or extrahepatic biliary tract compression by enlarged tuzumab and trastuzumab every 3 weeks. The disease pro- peritoneal lymph nodes or biliary tract stricture of undeter- gressed with multiple liver and lung metastases in April mined site were excluded since we intended only to include 2016. Ado-trastuzumab emtansine was administered every the cases that featured clinical characteristics indistinguish- 3 weeks, and the metastatic lesions subsided completely on able from primary periampullary cancer. Supplementary 2 serial contrast-enhanced CT scans in August and Septem- Table 1 listed our case in addition to 23 cases found ber 2016. Nonetheless, the patient was afflicted with rapidly through literature review. worsening jaundice in late September 2016. Meanwhile, It has been reported that up to 21% of malignant extrahe- serial elevation of serum levels of carcinoembryonic antigen patic biliary obstructions resulted from distant metastases (CEA) was detected with fluctuating serum levels of carbohy- [2]. To our knowledge, the differential diagnosis between drate antigen 15.3 (CA15.3) and carbohydrate antigen 19.9 breast cancer metastasis to the periampullary region and (CA19.9). Magnetic resonance cholangiopancreatography primary periampullary cancer has not been discussed thor- (MRCP) showed segmental thickening of the common bile oughly in the published articles yet. We hereby summarized duct which was hypointense on T1WI and hyperintense on the data and focused on the differential diagnosis with regard T2WI with contrast enhancement. A swollen, hyperemic to patient history, serum tumor markers, imaging study plus major duodenal papilla and a well-demarcated luminal stric- biopsy procedures, and histopathology, etc. ture 7 cm in length spanning the middle and lower portions 3.1. History. Among the 24 cases in our review, 5 presented of the common bile duct were detected in endoscopic retro- grade cholangiopancreatography (ERCP). ERCP brushing with periampullary lesions causing jaundice while breast cytology yielded suspicious malignant cells. Forceps biopsy cancer was detected concurrently by subsequent diagnostic from the major duodenal papilla was consistent with poorly workups (described as “synchronous” in column 3 in differentiated adenocarcinoma (Figures 1(a) and 1(b)), of Supplementary Table 1). 16 cases developed metachronous which histopathologic features showed no overt similarity periampullary metastasis as the first sign of recurrence after to those of the prior mastectomy specimen. Immunohisto- curative resection of breast cancer, with a recurrence-free chemistry (IHC) profiling was positive for cytokeratin7 interval ranging from 1.5 years to 23 years (described as (CK7), Her2, transacting T-cell-specific transcription factor “metachronous” in column 3 in Supplementary Table 1). GATA-3 (Figure 1(c)) and negative for cytokeratin20 The remaining 3 cases had other sites of distant metastasis from the breast prior to the emerging of periampullary (CK20), ER, PR, and gross cystic disease fluid protein-15 (GCDFP-15) (Figures 1(d)–1(f)). The ampullary lesion was metastasis (also described as “metachronous” in column 3 in considered to be a metastasis from breast cancer. The Supplementary Table 1). As for these 3 cases, obstructive patient’s jaundice exacerbated in spite of papillosphincterect- jaundice presented in a scenario that all the formerly omy and bile tract stenting. She deceased in December 2016. detected distant metastasis subsided or remained stable during systemic treatment. Therefore, metastases should be taken into account for differential diagnosis among 3. Discussion patients with distal biliary stricture who has prior history Although adenocarcinoma of the periampullary region of breast cancer. Meanwhile, the possibility of a second consistently present with obstructive jaundice, this entity is primary periampullary malignancy in breast cancer survivors should also be considered. It has been reported composed of primary tumors derived from the pancreatic head, duodenum, distal biliary duct, and ampulla in addition that the standardized incidence ratio (SIR) estimates for to secondary deposits from distant sites including the lung, second primary cancer risk after breast cancer were 1.51 intestine, kidney, melanoma, and breasts. (95% CI: 1.35–1.70) for women younger than 50 years Cases presenting with obstructive jaundice due to metas- and 1.11 (95% CI: 1.02–1.21) for those who were older [3]. A population-based case-control study also showed tases to the periampullary region from breast cancer have been only occasionally reported in the literatures [1]. that breast cancer survivors were exposed to an excess In order to summarize the cases presenting with obstruc- risk of developing a second primary cancer, and the tive jaundice due to periampullary metastasis from breast, HER2-positive status increased cancer incidence risk of the key words including “breast cancer metastasis”, “secondary digestive system and thyroid, while BRCA1 or BRCA2 mutation increased the cancer incidence risk of the genital malignancies of/metastases to periampullary region/pancrea- tic head/ampulla of Vater/biliary tract/duodenum”, plus system [4]. “malignant obstructive jaundice” were used to search the PubMed database for related literatures in English with full 3.2. Serum Tumor Markers. Among the patients with avail- text available between 1995 and 2016. Cases included should able data in our review, elevated serum CEA level was detected in 4 out of 11 patients, elevated serum CA19.9 in 4 have all of the following data: (1) pathologically confirmed primary breast cancer and secondary periampullary metasta- out of 10 patients, elevated serum CA15.3 in 6 out of 11 ses involving ampulla of Vater, duodenum, pancreatic head, patients, and combination of elevated level of CA15.3 and or extrahepatic biliary tract; and (2) tomography imaging normal level of CA19.9 in 1 out of 7 patients. Elevated serum studies such as CT, MR, or PET to evaluate metastasis to CEA could be detected in gastrointestinal, pancreaticobiliary, lung, breast, medullary thyroid carcinoma, and multiple other parts of body. Metastatic breast cancer cases that had Case Reports in Oncological Medicine 3 HE (10×) HE (40×) (a) (b) IHC (GATA-3) IHC (ER) (c) (d) IHC (PR) IHC (HER2) (e) (f) Figure 1: Histologic sections of the duodenal major papilla tumor biopsy. (a) Hematoxylin and eosin, 10× amplification. (b) Hematoxylin and eosin, 40× amplification. (c) GATA-3 (IHC), 40× amplification. (d) ER (IHC), 40× amplification. (e) PR (IHC), 40× amplification. (f) HER2 (IHC), 40× amplification. Isolated tumor cells and tumor cells clustered in solid pattern were seen in the lamina propria of the duodenal mucosa. The tumor cells have pleomorphic nuclei with prominent nucleoli. IHC profiling was weakly positive for GATA-3 (c), strongly positive for HER2 (f), and negative for ER (d) and PR (e). nonneoplastic conditions. CA19.9 is an established serum imaging study for patients presenting with painless jaundice. marker for the diagnosis of pancreaticobiliary carcinoma, The majority of these 24 cases were found to have a mass in with a sensitivity and a specificity of 76.7% and 87.1%, the head of the pancreas with or without involvement of the duodenum and common biliary tract on CT scan. Indirect respectively, for pancreatic cancer, as well as 77.6% and 83% for biliary cancer without cholangitis or cholestasis at signs of the biliary stricture as dilated proximal biliary tract a cutoff value of 37 units/ml [5]. Elevated serum CA19.9 were seen universally in all the cases, including those without levels were also found in breast cancer patients with only axil- overt periampullary mass on CT scan. It may be difficult to lary lymph nodes recurrence [6]. Therefore, the significance differentiate a solitary pancreatic metastasis from a primary of serum levels of CEA and CA19.9 remain uncertain in the pancreatic tumor only via CT scan. Metastatic masses may differentiation between periampullary breast cancer metasta- be hypo- or isoattenuating at nonenhanced CT, and their ses and primary pancreatobiliary cancer among patients with margins might be clearly demarcated, ill-defined, or extrahepatic biliary stricture. Moreover, there are no evi- lobulated. MRI scan usually showed tumor which was dences that showed that the serum tumor marker CA 15.3 hypointense on T1-weighted images and had intermediate could be used for diagnosis of metastatic breast cancer [7]. or high signal intensity on T2-weighted images. On contrast enhancement CT/MRI scan, primary pancreatic adenocarci- 3.3. Imaging/Endoscopic Diagnostic Workups and Procedures noma generally manifests as a hypoenhancing mass. In con- for Biopsy. Contrast-enhanced CT scan was usually the initial trast, 3 cases with pancreatic metastases from invasive 4 Case Reports in Oncological Medicine and ductal breast carcinoma, while the CK7+ve/CK 20-ve or lobular breast cancer in a case report unanimously showed rim enhancement [8]. However, the enhancement pattern CK7+ve/CK 20+ve could be observed in primary biliary of hypovascular pancreatic metastases from the lung, breast, tract, ampulla, duodenal, or pancreatic carcinoma [21]. Among 4 of these 24 patients having both CK7 and CK20 and colon may also resemble that of the primary pancreatic adenocarcinoma [9]. IHC staining data, 3 were found to have CK7+ve/CK 20-ve MRCP has a high sensitivity for detecting bile duct steno- phenotype, the remaining 1 had CK7-ve/CK 20-ve pheno- sis and filling defects associated with bile duct carcinoma. type. Since CK 20 was usually not observed in metastatic However, it cannot reliably distinguish malignant strictures breast cancer, it can be used to rule out metastatic breast car- cinoma. Moreover, homeobox protein CDX2 expression was from benign strictures nor differentiate between metastases and primary biliary malignancy [10]. considered specific for enterocytes and was found in 97% of Biopsy of the malignant biliary stricture is essential colorectal cancer, 61% of gastric cancer, and 16% of pancre- for diagnosis, which may be obtained by forceps biopsy, atic cancer, whereas its expression in breast cancer has never brush cytology, endoscopic ultrasound-guided fine-needle been reported [22]. Approximately 75% to 80% of human breast tumors aspiration (EUS-FNA), and cholangioscopy-directed biopsy. Among the 24 cases summarized in our review, 19 express ER and/or PR [23]. Amplification of HER2 gene or (78.16%) underwent upper gastrointestinal endoscopy and overexpression of Her2 protein was detected in 18% to 20% 13 (54.17%) underwent ERCP. The neoplasms of the duo- of human breast cancers [24]. ER/PR and Her2 status may denum major papilla or ampulla were visualized endo- show significant discordance between primary breast lesion and metastatic sites [25]. Changes in ER, PR, and HER2 sta- scopically in 3 and 4 cases, respectively. Brush cytology is one of the most frequently used biopsy techniques with tus have also been observed in a large number of patients a sensitivity for diagnosing cholangiocarcinoma (23 to 80%) over the course of disease progression [26]. On the other higher than that for pancreatic cancer (0 to 66%) [11]. ERCP hand, expressions of ERα and ERβ were also detected in a forceps biopsy can provide a sample deep into the epithelium variety of nonbreast cancers including gastric cancer [27], cholangiocarcinoma [28], gallbladder cancer [29], and pan- and theoretically avoids inadequate sampling that may occur with brushing [12]. 5 of the 24 patients underwent ERCP for- creatic cancer [30]. Since Her2 overexpression was also ceps biopsy, whereas it failed to obtain diagnostic specimen reported in pancreaticobiliary tract cancer [31] and periam- for only 1 case with the target lesion located in the head of pullary carcinoma [32], the potency of Her2 status for pancreas. A recent study showed that the sensitivity of for- differentiating between primary periampullary cancer and metastatic breast cancer was diminished. ceps biopsies for malignant biliary strictures was about 73.53% in cholangiocarcinoma, 29.17% for pancreatic head Mammaglobin was reported to be expressed in 70% to cancer, and 42.86% for other etiologies (metastasis from 80% of primary and metastatic breast tumors with the expression level unaltered at the metastatic site in compari- colon cancer, hepatocellular carcinoma, gallbladder cancer, and lung cancer) [13]. son with the primary tumor, which made it a useful marker for identifying breast carcinoma especially localized in rare Endoscopic ultrasound-guided fine-needle biopsy (EUS-FNA) was performed in 3 patients with lesion in metastatic sites [33]. GCDFP-15 is a major protein constitu- the head of the pancreas. Adequate diagnostic specimens ent of breast cysts, of which expression was found in breast cancer and other cancers originating from nonmammary were obtained for all of them. It has been reported that the sensitivity for diagnosing primary biliary duct malig- tissues such as the skin, salivary gland, bronchial gland, prostate, and seminal vesicle [34]. The expressions of the nancy via EUS-FNA was 43 to 86% [14–16], while the sensitivity and specificity for diagnosing pancreatic metas- two human milk fat globule membrane protein epitopes, tases via EUS-FNA was 75% to 93.8% and 60% to 100%, HMFG1 and HMFG2, were found in the lactating human mammary epithelial cells, as well as in neoplasms derived respectively [17, 18]. from the breast and ovary [35]. The combination of HMFG 3.4. Histopathology and Immunohistochemistry Profile. with GCDFP-15 was used to confirm the breast origin of Microscopic histopathology features resembling those of the pancreatic lesion in 1 case [36]. GATA-3 was reported primary breast cancer in the periampullary specimen were to be expressed in primary and metastatic breast ductal and lobular carcinoma (>90%), pancreatic ductal carcinoma considered to be an essential clue for diagnosis in 17 among these 24 cases. The metastasis usually featured disaggregated (37%), gastric, and colon adenocarcinoma (<10%), which tumor cells or tumor cells in single file pattern in the pancrea- may be used to differentiate the tumor origin in combination ticobiliary parenchyma. The primary breast lesion was lobu- with other related IHC markers [37]. lar carcinoma in 11 of the aforementioned 17 cases. Invasive ductal carcinomas and invasive lobular carcinoma, as the 3.5. Treatment and Prognosis. Jaundice in patients with most prevalent two types, account for 50–80% and 5–15% breast carcinoma is usually attributed to extensive hepatic of all the breast cancer cases, respectively [19]. Infiltrating metastases and is associated with poor prognosis. However, lobular carcinoma seems to have a metastatic pattern distinct from that of the ductal type, with an apparent predilection for the overall survival in patients who had extrahepatic metasta- tic obstruction without liver parenchymal involvement was the gastrointestinal tract due to unidentified mechanism [20]. IHC played an important role in differential diagnosis. significantly longer (median: 6 months) than that of patients The CK7+ve/CK 20-ve phenotype was found in both lobular with liver involvement (median: 1.8 months) [38]. Case Reports in Oncological Medicine 5 10 out of 13 cases with a solitary periampullary metastasis References in this series underwent radical resection of metastasis and [1] S. Giestas, S. Lopes, P. Souto et al., “Ampullary metastasis from achieved postoperative survival of 5 months to more than breast cancer: a rare cause of obstructive jaundice,” GE Portu- 48 months (median: 15 months). 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Periampullary Metastases from Breast Cancer: A Case Report and Literature Review

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Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 3479568, 6 pages https://doi.org/10.1155/2019/3479568 Case Report Periampullary Metastases from Breast Cancer: A Case Report and Literature Review 1 2 1 1 1 Yi Lin , Sio In Wong, Yuzhou Wang, Chileong Lam, and Xianghong Peng Department of Medical Oncology, Centro Hospitalar Conde de São Januário, Sé, Macau Department of Pathology, Centro Hospitalar Conde de São Januário, Sé, Macau Correspondence should be addressed to Xianghong Peng; xianghongpeng@hotmail.com Received 10 September 2018; Accepted 10 December 2018; Published 9 January 2019 Academic Editor: Su Ming Tan Copyright © 2019 Yi Lin et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We presented a metastatic breast cancer case who was afflicted with obstructive jaundice caused by an ampullary neoplasm. Since jaundice due to periampullary metastasis from breast cancer was a rare entity, a literature review of similar cases through the PubMed database was done. A total of 23 additional cases were found. Among these 24 cases, 5 presented with periampullary metastasis synchronously with the diagnosis of breast cancer, while 19 had metachronous periampullary metastasis with an interval ranging between 1.3 and 23 years from the initial diagnosis of breast cancer to the emergence of jaundice. It is intriguing to establish a differential diagnosis for common bile tract stricture prior to tissue biopsy, even with diagnostic workups including serum tumor markers, MRI plus MRCP, ERCP with intraductal brushing, and endoscopic ultrasound, in that the clinical, radiological, and endoscopic findings of metastatic lesions overlapped extensively with those found with primary periampullary malignancies. An immunohistochemical portfolio including cytokeratin7/20 (CK7/20), homeobox protein CDX2, human epidermal growth factor receptor 2 (HER2/neu), estrogen receptor alfa (ERα), progesterone receptor (PgR), mammaglobin, gross cystic disease fluid protein-15 (GCDFP-15), and transacting T-cell-specific transcription factor (GATA-3) was helpful for differential diagnosis among cases with ambiguous microscopic features. 1. Introduction 2. Case Report Obstructive jaundice caused by extrahepatic biliary tract A 42-year-old woman presented with right breast invasive metastases from breast cancer is a rare clinical scenario. ductal carcinoma (TNM stage: cT3N1M0) which was human Accurate and prompt differentiation between primary epidermal growth factor receptor 2 (Her2) overexpressed and and secondary periampullary malignancies is essential for estrogen receptor (ER) and progesterone receptor (PR) further treatment decision-making and will exert a major negative in August 2013. Modified radical mastectomy was impact on the prognosis. We presented a case with breast performed in November 2014 after finishing 8 cycles of pre- cancer who developed metachronous metastasis to the operative chemotherapy with trastuzumab incorporated. The ampulla of Vater while other distant metastatic lesions surgical specimen had resection margins clear of tumor cells subsided completely after systemic treatment. A literature and was staged as ypT2N2a. She was afflicted with right chest review through the PubMed database yielded a total of wall local recurrence less than two months after the mastec- 23 similar cases of breast cancer with periampullary tomy. Complete remission of the recurrence was achieved metastases. Differential diagnosis between periampullary by local external beam irradiation. Administration of trastu- metastasis from breast cancer and a primary periampullary zumab was continued to a total of one year. Nonetheless, cancer was discussed thoroughly regarding patient history, seven months after completion of locoregional radiotherapy, serum tumor markers, imaging study plus biopsy procedures, some right chest wall skin lesions appeared in October 2015 and histopathology. with enlarged ipsilateral supraclavicular lymph nodes, which 2 Case Reports in Oncological Medicine obstructive jaundice due to disseminated intrahepatic metas- were both confirmed to be recurrent breast cancer by biopsy. She received salvage chemotherapy with paclitaxel plus per- tasis or extrahepatic biliary tract compression by enlarged tuzumab and trastuzumab every 3 weeks. The disease pro- peritoneal lymph nodes or biliary tract stricture of undeter- gressed with multiple liver and lung metastases in April mined site were excluded since we intended only to include 2016. Ado-trastuzumab emtansine was administered every the cases that featured clinical characteristics indistinguish- 3 weeks, and the metastatic lesions subsided completely on able from primary periampullary cancer. Supplementary 2 serial contrast-enhanced CT scans in August and Septem- Table 1 listed our case in addition to 23 cases found ber 2016. Nonetheless, the patient was afflicted with rapidly through literature review. worsening jaundice in late September 2016. Meanwhile, It has been reported that up to 21% of malignant extrahe- serial elevation of serum levels of carcinoembryonic antigen patic biliary obstructions resulted from distant metastases (CEA) was detected with fluctuating serum levels of carbohy- [2]. To our knowledge, the differential diagnosis between drate antigen 15.3 (CA15.3) and carbohydrate antigen 19.9 breast cancer metastasis to the periampullary region and (CA19.9). Magnetic resonance cholangiopancreatography primary periampullary cancer has not been discussed thor- (MRCP) showed segmental thickening of the common bile oughly in the published articles yet. We hereby summarized duct which was hypointense on T1WI and hyperintense on the data and focused on the differential diagnosis with regard T2WI with contrast enhancement. A swollen, hyperemic to patient history, serum tumor markers, imaging study plus major duodenal papilla and a well-demarcated luminal stric- biopsy procedures, and histopathology, etc. ture 7 cm in length spanning the middle and lower portions 3.1. History. Among the 24 cases in our review, 5 presented of the common bile duct were detected in endoscopic retro- grade cholangiopancreatography (ERCP). ERCP brushing with periampullary lesions causing jaundice while breast cytology yielded suspicious malignant cells. Forceps biopsy cancer was detected concurrently by subsequent diagnostic from the major duodenal papilla was consistent with poorly workups (described as “synchronous” in column 3 in differentiated adenocarcinoma (Figures 1(a) and 1(b)), of Supplementary Table 1). 16 cases developed metachronous which histopathologic features showed no overt similarity periampullary metastasis as the first sign of recurrence after to those of the prior mastectomy specimen. Immunohisto- curative resection of breast cancer, with a recurrence-free chemistry (IHC) profiling was positive for cytokeratin7 interval ranging from 1.5 years to 23 years (described as (CK7), Her2, transacting T-cell-specific transcription factor “metachronous” in column 3 in Supplementary Table 1). GATA-3 (Figure 1(c)) and negative for cytokeratin20 The remaining 3 cases had other sites of distant metastasis from the breast prior to the emerging of periampullary (CK20), ER, PR, and gross cystic disease fluid protein-15 (GCDFP-15) (Figures 1(d)–1(f)). The ampullary lesion was metastasis (also described as “metachronous” in column 3 in considered to be a metastasis from breast cancer. The Supplementary Table 1). As for these 3 cases, obstructive patient’s jaundice exacerbated in spite of papillosphincterect- jaundice presented in a scenario that all the formerly omy and bile tract stenting. She deceased in December 2016. detected distant metastasis subsided or remained stable during systemic treatment. Therefore, metastases should be taken into account for differential diagnosis among 3. Discussion patients with distal biliary stricture who has prior history Although adenocarcinoma of the periampullary region of breast cancer. Meanwhile, the possibility of a second consistently present with obstructive jaundice, this entity is primary periampullary malignancy in breast cancer survivors should also be considered. It has been reported composed of primary tumors derived from the pancreatic head, duodenum, distal biliary duct, and ampulla in addition that the standardized incidence ratio (SIR) estimates for to secondary deposits from distant sites including the lung, second primary cancer risk after breast cancer were 1.51 intestine, kidney, melanoma, and breasts. (95% CI: 1.35–1.70) for women younger than 50 years Cases presenting with obstructive jaundice due to metas- and 1.11 (95% CI: 1.02–1.21) for those who were older [3]. A population-based case-control study also showed tases to the periampullary region from breast cancer have been only occasionally reported in the literatures [1]. that breast cancer survivors were exposed to an excess In order to summarize the cases presenting with obstruc- risk of developing a second primary cancer, and the tive jaundice due to periampullary metastasis from breast, HER2-positive status increased cancer incidence risk of the key words including “breast cancer metastasis”, “secondary digestive system and thyroid, while BRCA1 or BRCA2 mutation increased the cancer incidence risk of the genital malignancies of/metastases to periampullary region/pancrea- tic head/ampulla of Vater/biliary tract/duodenum”, plus system [4]. “malignant obstructive jaundice” were used to search the PubMed database for related literatures in English with full 3.2. Serum Tumor Markers. Among the patients with avail- text available between 1995 and 2016. Cases included should able data in our review, elevated serum CEA level was detected in 4 out of 11 patients, elevated serum CA19.9 in 4 have all of the following data: (1) pathologically confirmed primary breast cancer and secondary periampullary metasta- out of 10 patients, elevated serum CA15.3 in 6 out of 11 ses involving ampulla of Vater, duodenum, pancreatic head, patients, and combination of elevated level of CA15.3 and or extrahepatic biliary tract; and (2) tomography imaging normal level of CA19.9 in 1 out of 7 patients. Elevated serum studies such as CT, MR, or PET to evaluate metastasis to CEA could be detected in gastrointestinal, pancreaticobiliary, lung, breast, medullary thyroid carcinoma, and multiple other parts of body. Metastatic breast cancer cases that had Case Reports in Oncological Medicine 3 HE (10×) HE (40×) (a) (b) IHC (GATA-3) IHC (ER) (c) (d) IHC (PR) IHC (HER2) (e) (f) Figure 1: Histologic sections of the duodenal major papilla tumor biopsy. (a) Hematoxylin and eosin, 10× amplification. (b) Hematoxylin and eosin, 40× amplification. (c) GATA-3 (IHC), 40× amplification. (d) ER (IHC), 40× amplification. (e) PR (IHC), 40× amplification. (f) HER2 (IHC), 40× amplification. Isolated tumor cells and tumor cells clustered in solid pattern were seen in the lamina propria of the duodenal mucosa. The tumor cells have pleomorphic nuclei with prominent nucleoli. IHC profiling was weakly positive for GATA-3 (c), strongly positive for HER2 (f), and negative for ER (d) and PR (e). nonneoplastic conditions. CA19.9 is an established serum imaging study for patients presenting with painless jaundice. marker for the diagnosis of pancreaticobiliary carcinoma, The majority of these 24 cases were found to have a mass in with a sensitivity and a specificity of 76.7% and 87.1%, the head of the pancreas with or without involvement of the duodenum and common biliary tract on CT scan. Indirect respectively, for pancreatic cancer, as well as 77.6% and 83% for biliary cancer without cholangitis or cholestasis at signs of the biliary stricture as dilated proximal biliary tract a cutoff value of 37 units/ml [5]. Elevated serum CA19.9 were seen universally in all the cases, including those without levels were also found in breast cancer patients with only axil- overt periampullary mass on CT scan. It may be difficult to lary lymph nodes recurrence [6]. Therefore, the significance differentiate a solitary pancreatic metastasis from a primary of serum levels of CEA and CA19.9 remain uncertain in the pancreatic tumor only via CT scan. Metastatic masses may differentiation between periampullary breast cancer metasta- be hypo- or isoattenuating at nonenhanced CT, and their ses and primary pancreatobiliary cancer among patients with margins might be clearly demarcated, ill-defined, or extrahepatic biliary stricture. Moreover, there are no evi- lobulated. MRI scan usually showed tumor which was dences that showed that the serum tumor marker CA 15.3 hypointense on T1-weighted images and had intermediate could be used for diagnosis of metastatic breast cancer [7]. or high signal intensity on T2-weighted images. On contrast enhancement CT/MRI scan, primary pancreatic adenocarci- 3.3. Imaging/Endoscopic Diagnostic Workups and Procedures noma generally manifests as a hypoenhancing mass. In con- for Biopsy. Contrast-enhanced CT scan was usually the initial trast, 3 cases with pancreatic metastases from invasive 4 Case Reports in Oncological Medicine and ductal breast carcinoma, while the CK7+ve/CK 20-ve or lobular breast cancer in a case report unanimously showed rim enhancement [8]. However, the enhancement pattern CK7+ve/CK 20+ve could be observed in primary biliary of hypovascular pancreatic metastases from the lung, breast, tract, ampulla, duodenal, or pancreatic carcinoma [21]. Among 4 of these 24 patients having both CK7 and CK20 and colon may also resemble that of the primary pancreatic adenocarcinoma [9]. IHC staining data, 3 were found to have CK7+ve/CK 20-ve MRCP has a high sensitivity for detecting bile duct steno- phenotype, the remaining 1 had CK7-ve/CK 20-ve pheno- sis and filling defects associated with bile duct carcinoma. type. Since CK 20 was usually not observed in metastatic However, it cannot reliably distinguish malignant strictures breast cancer, it can be used to rule out metastatic breast car- cinoma. Moreover, homeobox protein CDX2 expression was from benign strictures nor differentiate between metastases and primary biliary malignancy [10]. considered specific for enterocytes and was found in 97% of Biopsy of the malignant biliary stricture is essential colorectal cancer, 61% of gastric cancer, and 16% of pancre- for diagnosis, which may be obtained by forceps biopsy, atic cancer, whereas its expression in breast cancer has never brush cytology, endoscopic ultrasound-guided fine-needle been reported [22]. Approximately 75% to 80% of human breast tumors aspiration (EUS-FNA), and cholangioscopy-directed biopsy. Among the 24 cases summarized in our review, 19 express ER and/or PR [23]. Amplification of HER2 gene or (78.16%) underwent upper gastrointestinal endoscopy and overexpression of Her2 protein was detected in 18% to 20% 13 (54.17%) underwent ERCP. The neoplasms of the duo- of human breast cancers [24]. ER/PR and Her2 status may denum major papilla or ampulla were visualized endo- show significant discordance between primary breast lesion and metastatic sites [25]. Changes in ER, PR, and HER2 sta- scopically in 3 and 4 cases, respectively. Brush cytology is one of the most frequently used biopsy techniques with tus have also been observed in a large number of patients a sensitivity for diagnosing cholangiocarcinoma (23 to 80%) over the course of disease progression [26]. On the other higher than that for pancreatic cancer (0 to 66%) [11]. ERCP hand, expressions of ERα and ERβ were also detected in a forceps biopsy can provide a sample deep into the epithelium variety of nonbreast cancers including gastric cancer [27], cholangiocarcinoma [28], gallbladder cancer [29], and pan- and theoretically avoids inadequate sampling that may occur with brushing [12]. 5 of the 24 patients underwent ERCP for- creatic cancer [30]. Since Her2 overexpression was also ceps biopsy, whereas it failed to obtain diagnostic specimen reported in pancreaticobiliary tract cancer [31] and periam- for only 1 case with the target lesion located in the head of pullary carcinoma [32], the potency of Her2 status for pancreas. A recent study showed that the sensitivity of for- differentiating between primary periampullary cancer and metastatic breast cancer was diminished. ceps biopsies for malignant biliary strictures was about 73.53% in cholangiocarcinoma, 29.17% for pancreatic head Mammaglobin was reported to be expressed in 70% to cancer, and 42.86% for other etiologies (metastasis from 80% of primary and metastatic breast tumors with the expression level unaltered at the metastatic site in compari- colon cancer, hepatocellular carcinoma, gallbladder cancer, and lung cancer) [13]. son with the primary tumor, which made it a useful marker for identifying breast carcinoma especially localized in rare Endoscopic ultrasound-guided fine-needle biopsy (EUS-FNA) was performed in 3 patients with lesion in metastatic sites [33]. GCDFP-15 is a major protein constitu- the head of the pancreas. Adequate diagnostic specimens ent of breast cysts, of which expression was found in breast cancer and other cancers originating from nonmammary were obtained for all of them. It has been reported that the sensitivity for diagnosing primary biliary duct malig- tissues such as the skin, salivary gland, bronchial gland, prostate, and seminal vesicle [34]. The expressions of the nancy via EUS-FNA was 43 to 86% [14–16], while the sensitivity and specificity for diagnosing pancreatic metas- two human milk fat globule membrane protein epitopes, tases via EUS-FNA was 75% to 93.8% and 60% to 100%, HMFG1 and HMFG2, were found in the lactating human mammary epithelial cells, as well as in neoplasms derived respectively [17, 18]. from the breast and ovary [35]. The combination of HMFG 3.4. Histopathology and Immunohistochemistry Profile. with GCDFP-15 was used to confirm the breast origin of Microscopic histopathology features resembling those of the pancreatic lesion in 1 case [36]. GATA-3 was reported primary breast cancer in the periampullary specimen were to be expressed in primary and metastatic breast ductal and lobular carcinoma (>90%), pancreatic ductal carcinoma considered to be an essential clue for diagnosis in 17 among these 24 cases. The metastasis usually featured disaggregated (37%), gastric, and colon adenocarcinoma (<10%), which tumor cells or tumor cells in single file pattern in the pancrea- may be used to differentiate the tumor origin in combination ticobiliary parenchyma. The primary breast lesion was lobu- with other related IHC markers [37]. lar carcinoma in 11 of the aforementioned 17 cases. Invasive ductal carcinomas and invasive lobular carcinoma, as the 3.5. Treatment and Prognosis. Jaundice in patients with most prevalent two types, account for 50–80% and 5–15% breast carcinoma is usually attributed to extensive hepatic of all the breast cancer cases, respectively [19]. Infiltrating metastases and is associated with poor prognosis. However, lobular carcinoma seems to have a metastatic pattern distinct from that of the ductal type, with an apparent predilection for the overall survival in patients who had extrahepatic metasta- tic obstruction without liver parenchymal involvement was the gastrointestinal tract due to unidentified mechanism [20]. IHC played an important role in differential diagnosis. significantly longer (median: 6 months) than that of patients The CK7+ve/CK 20-ve phenotype was found in both lobular with liver involvement (median: 1.8 months) [38]. Case Reports in Oncological Medicine 5 10 out of 13 cases with a solitary periampullary metastasis References in this series underwent radical resection of metastasis and [1] S. Giestas, S. Lopes, P. Souto et al., “Ampullary metastasis from achieved postoperative survival of 5 months to more than breast cancer: a rare cause of obstructive jaundice,” GE Portu- 48 months (median: 15 months). 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