Japanese Journal of Clinical Oncology 33:93-97 (2003)
© 2003 Foundation for Promotion of Cancer Research
Obstructive Jaundice in a Metastatic Tumor of the Pancreas from Breast Cancer: a Case Report
1 Department of Surgery and 2 First Department of Pathology, Shiga University of Medical Science, Otsu, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONIMMUNOHISTOCHEMICAL STAININGCASE REPORTDISCUSSIONREFERENCES |
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Metastatic pancreas tumors from breast cancer are comparatively uncommon and patients with this tumor usually remain asymptomatic during their life. A 55-year-old woman presented with obstructive jaundice following mastectomy for invasive ductal carcinoma. We diagnosed obstructive jaundice due to a pancreatic tumor demonstrated on computed tomography and performed percutaneous transhepatic cholangio-drainage. Although the patient recovered from the jaundice, she had exacerbation of pneumonia from which she died. At autopsy, invasive ductal carcinoma was found in the pancreas tumor. Immunohistochemical staining was performed to confirm whether the pancreatic tumor was primary or secondary. Human milk fat globules 1 and 2 and gross cystic disease fluid protein-15, which characteristically exist in normal breast tissue or breast carcinoma, were expressed both in the primary breast tumor and the pancreatic tumor. In contrast, both the anti-estrogen receptor and anti-progesterone receptor antibodies stained positively in the primary breast cancer; however, neither of them was positive in the metastatic pancreatic tumor. We report a rare case of a patient who presented with obstructive jaundice from a pancreatic tumor metastasizing from breast cancer and in whom immunohistochemical staining using the antibodies unique to the mammary gland was effective for the diagnosis of this secondary tumor.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONIMMUNOHISTOCHEMICAL STAININGCASE REPORTDISCUSSIONREFERENCES |
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Metastatic tumors of the pancreas are rarely found clinically, although their incidence has been reported to be about 3% among autopsies for malignant diseases (1,2). Metastatic pancreatic tumors from breast cancer are comparatively uncommon and patients with this tumor rarely have any signs and symptoms of the metastatic tumor during their life. Tumors in breast cancer are relatively slow growing. Recent combined adjuvant therapies for breast cancer patients have improved greatly and have increased the survival rates and times of these patients. The median survival of patients with breast cancer is 21.4 months even after having bone metastases (3,4). Therefore, uncommon metastatic tumors from breast cancer, for example, metastatic pancreatic tumors, may increase and the indication and choice of treatments for these metastatic tumors may become important. Indeed, recent reports have described three cases of obstructive jaundice from metastatic pancreas tumor from breast cancer and aggressive palliative treatments for these diseases (2,4,5).
We sometimes experience difficulty in distinguishing whether a tumor is primary or secondary and it is even more difficult when the metastatic site is unusual for the tumor. Immunohistochemical staining using antibodies targeted to the original organ for the primary tumor may be helpful for the diagnosis of metastatic tumors.
We report a rare case of a patient who presented with obstructive jaundice from a tumor of the head of the pancreas which metastasized from breast cancer 9 years after mastectomy and in which immunohistochemical staining using the antibodies characteristic of the mammary gland was effective for its correct diagnosis.
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IMMUNOHISTOCHEMICAL STAINING |
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TOPABSTRACTINTRODUCTIONIMMUNOHISTOCHEMICAL STAININGCASE REPORTDISCUSSIONREFERENCES |
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The tissues of the mammary gland and the pancreas were fixed in 10% neutral buffered formalin, embedded in paraffin and cut for hematoxylin–eosin (H&E) staining and the specific stainings described below. Immunohistochemical staining was carried out with the following monoclonal antibodies against (1) human milk fat globule 1 (HMFG1) (HMFG1, clone 1.10.F3; 1:100, Novocastra, Newcastle, UK); (2) human milk fat globule 2 (HMFG2) (HMFG2, clone 3.14.A3; 1:100, Novocastra); (3) anti-gross cystic disease fluid protein-15 (anti-GCDFP-15) (BRST-2, cloneD6; 1:100, Signet Laboratories, Dedham, MA); (4) anti-estrogen receptor (clone 1D5; Nichirei, Tokyo, Japan); and (5) anti-progesterone receptor (clone 1A6; Nichirei). For immunohistochemistry, the streptavidin–biotin–peroxidase method was performed using a Histofine kit (Nichirei). Periodic acid–Schiff (PAS) staining was also performed.
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CASE REPORT |
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TOPABSTRACTINTRODUCTIONIMMUNOHISTOCHEMICAL STAININGCASE REPORTDISCUSSIONREFERENCES |
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A 55-year-old woman presented with unexpected obstructive jaundice in February 2000. In July 1991 she had undergone a modified radical mastectomy for cancer of the left breast diagnosed as invasive ductal carcinoma. Carcinoembryonic antigen (CEA) and CA15-3 levels were within the normal range before the treatment. The clinical tumor size was 30 x 24 mm. Two metastatic lymph nodes were involved in the right axilla. Lymphatic invasion by the tumor cells was not observed in the breast tissue. The nuclear/histological grade of the primary tumor following the modified Bloom–Richardson histological grading was as follows: tubule formation, score 3; nuclear size, score 3; mitotic count, score 1; and the overall histological grade was intermediate (grade II). The patient received adjuvant radiotherapy (total dose 50 Gy) for the parasternal, supraclavicular and infraclavicular lymph nodes and she also underwent adjuvant chemotherapy with fluorouracil (150 mg) and endocrine therapy with tamoxifen citrate (20 mg) daily for 3 years. Left supraclavicular lymph node metastases were revealed in April 1994. She received radiotherapy at 60 Gy on the supraclavicular area and three courses of chemotherapy using fluorouracil (750 mg), pirarubicin hydrochloride (50 mg) and cyclophosphamide (200 mg), intravenously. Tegafur uracil (1.5 g) and tamoxifen citrate (20 mg) were administered orally daily for 1.5 years. A right 8th rib metastasis was revealed in November 1995. She received radiotherapy 39 Gy on the right 8th rib and the same regime of intravenous chemotherapy as above and then doxifluridine (300 mg), cyclophosphamide (200 mg) and toremifene citrate (120 mg) were administered orally daily for 1 year. Lumbar vertebral metastases were revealed in September 1996 and were treated with local radiotherapy at 50 Gy. The CEA and CA15-3 levels were still within the normal range even under the condition of multiple lymph node involvement and bone metastases. Cerebellar metastasis was observed in September 1999. The CEA and CA15-3 levels increased to 20.6 ng/ml and 420 U/ml, respectively. After docetaxel hydrate (total dosages 220 mg) had been administered, the CEA and CA15-3 levels decreased to 11.7 ng/ml and 95 U/ml, respectively.
In February 2000, jaundice appeared rapidly, with elevation of the total and direct bilirubin levels to 7.4 and 4.4 mg/dl, respectively. Computed tomography demonstrated that the tumor was located at the head of the pancreas (Fig. 1), that the common bile duct and intrahepatic bile ducts were dilated and that no metastatic tumor was found in the liver. The CEA and CA15-3 levels increased again to 14.0 ng/ml and 170 U/ml, respectively. We diagnosed obstructive jaundice due to the tumor of the pancreas head and then performed percutaneous transhepatic cholangio-drainage (PTCD) (Fig. 2). After having PTCD, the patient gradually recovered from the jaundice. Although the patient was scheduled to undergo insertion of a percutaneous transhepatic biliary endo-prosthesis using an expandable metallic stent, she unfortunately contracted aspiration pneumonia and failed to recover from it. She died of exacerbation of the pneumonia 18 days after undergoing PTCD. At autopsy, whitish tumor tissue was diffusely found in the whole of the pancreas. The tumor compressed the common bile duct. Other small tumors were found in the stomach, liver, thyroid, bone marrow, uterus and bilateral adrenal glands. Microscopically, severe lymphatic involvements were observed in these organs. Three tumors of the stomach were located in the cardia and the antrum of the stomach with atypical trabecular and papillo-tubular structures seen histologically. These stomach tumors existed predominantly in the submucosa and were exposed focally to the mucosal surface. The pancreatic tumor also revealed papillo-tubular structures, which were similar to the histological characters of the initial breast cancer operated on in 1991 (Fig. 3). This pancreatic tumor was, therefore, suspected as a metastasis from the breast cancer. However, because pancreatic head tumors metastasizing from breast cancer are uncommon, immunohistochemical staining was performed to confirm whether the pancreatic tumor was a primary tumor or metastatic from the primary breast cancer. HMFG1, HMFG2 and GCDFP-15 were expressed both in the primary breast tumor and the pancreatic tumor (Fig. 4). Both breast and pancreatic tumors were negative for PAS staining, whereas primary pancreatic cancers are often positive for PAS staining. These findings demonstrated that the pancreatic tumor in this patient’s case was a metastasis from the breast cancer. Both anti-estrogen receptor and anti-progesterone receptor antibodies stained positively in the primary breast cancer; however, neither of them was positive in the metastatic pancreatic tumor.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONIMMUNOHISTOCHEMICAL STAININGCASE REPORTDISCUSSIONREFERENCES |
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The pancreas is not a common site for metastatic deposits. Metastatic deposits in the pancreas were found at an incidence of 3% in a series of 1000 autopsies performed for malignant diseases (1,2). The incidence of pancreatic metastases from breast cancer has been reported to range from 5 to 13% in some autopsy series of breast cancer patients (1,4–6). Because most metastatic pancreatic tumors are found incidentally during autopsy, the clinical sign of obstructive jaundice due to a metastatic pancreatic tumor is rarely evident (2). In the present case, the patient presented with obstructive jaundice caused by the metastatic tumor of the head of the pancreas 9 years after undergoing a modified radical mastectomy for cancer of the left breast. The obstructive jaundice was seen to improve after performing the PTCD; however, the patient most unfortunately died of worsening pneumonia without lung metastasis. It has been reported that choledochoduodenostomy (2) and pancreatoduodenostomy (7) have been effective for prolonging the outcome of patients with pancreas head tumors metastatic from breast cancer. The expanding metallic stent has been reported to be effective for obstructive jaundice due to metastatic pancreatic tumors (4,8). Although several recurrences were clinically revealed in the lymph nodes, bone and cerebellum in the present case, all of them had grown slowly and none of them were fatal at that time. The findings at autopsy of this case revealed that there were metastatic tumors in the stomach, liver, thyroid, bone marrow, uterus and bilateral adrenal glands; however, none of them was the direct cause of her death. Tumors in breast cancer are relatively slow growing. Among 707 autopsies of breast cancer patients, it was demonstrated that only 10% of patients with a previous history of breast cancer were free from metastases at the time of death (2,5). However, the median survival rates of patients with breast cancer after diagnosis of bone metastasis alone, bone metastasis concomitant with lung metastasis and bone metastasis concomitant with liver metastasis are 21.4, 17.9 and 17.1 months, respectively (3,4). Breast cancer patients even with various metastatic tumors may have relatively longer survival than other cancer patients with metastatic tumors (9–14). These facts may justify an aggressive palliative treatment in patients with metastatic tumors from breast cancer. Unless diffusely metastatic tumors of the liver cause obstructive jaundice, aggressive palliative treatments of PTCD following insertion of an expanding metallic stent or endoscopic stent tube should be seriously considered to improve the quality of life of these patients with obstructive jaundice. In recent years, various kinds of adjuvant therapies (e.g. chemotherapy, radiation therapy, hormone therapy or any combination of them) for breast cancer patients have greatly improved and prolonged survival rates and times and thus uncommon metastatic tumors as in the present case may increase henceforth. The indication and choice of treatments for these metastatic tumors may become more important to improve the patient’s quality of life.
The question as to how the breast carcinoma in our patient unusually metastasized to the pancreas and grew there should be addressed. Systemic metastasis is likely to occur from breast carcinomas (15). Metastatic tumor cells can be spread via the lymphatics as well as by hematogenous dissemination, since breast carcinoma with lymph node metastases can more often metastasize systemically than that without lymph node metastases (16). In an autopsy series it has been reported that malignant lymphoma and intra-abdominal malignancies in the stomach, gall bladder, kidney, adrenal gland and bile duct, all of which are located close to the pancreas, have a much higher percentage metastasizing to the pancreas than any other malignancies, suggesting that metastatic pancreatic tumors may result from subsequently being spread through the lymphatics via the lymph node metastases around the pancreas (17). Indeed, in the present case, breast carcinoma with lymph node metastases metastasized to the stomach and bilateral adrenal glands. Severe lymphatic involvement was observed in these metastatic organs. Metastatic stomach tumors were located in the antrum. Adenocarcinoma occurring in the antrum of the stomach can easily spread to the lymph nodes around the head of the pancreas (18). This lymphatic dissemination of the tumor may have caused obstruction of the lymphatic flow and brought about retrograde involvement of the head of the pancreas in the present case.
It is difficult to determine whether adenocarcinoma of the pancreas is primary or not and it is even more difficult when the metastatic site is unusual for the tumor. To make sure of the fact that our reported pancreatic tumor was a metastasis from the previous breast cancer, we used an immunohistochemical staining technique using various kinds of antibodies related to mammary gland tissues. Both HMFG1 and HMFG2 expressions are detectable in a large mucin-like molecule normally produced by the lactating human mammary epithelial cells, in tumors of the breast and ovary, but not mesenchymal tissue tumors (19). GCDFP-15 expression, which is found in the cysts lining the apocrine epithelium, is a major protein constituent of breast cysts and breast cancer and of other non-mammary tissues such as skin, salivary gland, bronchial gland, prostate and seminal vesicle (20,21). In the present case, HMFG1, HMFG2 and GCDFP-15 expression were observed in both the primary breast cancer tissue and pancreatic tumor tissue. Moreover, it has not been shown, to the best of our knowledge, that tumors derived from the stomach, liver, thyroid, bone marrow, adrenal gland and pancreas, as observed in this case, express HMFG1, HMFG2 or GCDFP-15. The pancreatic tumor was, therefore, confirmed as having metastasized from the primary breast cancer. Immunohistochemical staining using these antibodies targeted to mammary gland tissue may be helpful for the diagnosis of metastatic tumors from breast cancer. In contrast, the primary breast tumor had positive staining for anti-estrogen receptor and anti-progesterone receptor antibodies; however, the metastatic pancreatic tumor stained negatively for both of them. Although this patient had been treated with tamoxifen for 3.5 years and with toremifene for 1 year, both of which could cause false-negative expression of hormone receptors within 2 months of stopping anti-hormone treatment (22), she had finished taking them 3 years before she died. Whether this result represents a loss of hormone receptors in the metastatic cells due to the treatment of tamoxifen and toremifene (22,23) or the heterogeneity of the cancer cells (24,25) concerning their metastatic ability or their affinity to the pancreas tissue requires further study.
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FOOTNOTES |
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+ For reprints and all correspondence: Naomi Kitamura, Department of Surgery, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan. E-mail: k-naomi@nagoya.tokushukai.or.jp
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Received September 20, 2002; accepted November 19, 2002
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