Case Report
Metastatic signet-ring cell carcinoma of unknown primary origin C. Gregoire1,2, G. Muller3, J.-P. Machiels1, J.-C. Goeminne2 1
Service d’oncologie me´dicale, Cliniques universitaires Saint-Luc, Universite´ catholique de Louvain, Brussels, Belgium, 2Service d’oncologie me´dicale, Clinique St-Elisabeth, Namur, Belgium, 3Institut de Pathologie et de Ge´ne´tique, Gosselies, Belgium About 3–5% of metastatic cancers originate from an unknown primary origin. Some have a signet-ring cell (SRC) component. We report the medical history of three patients with SRC carcinoma expressing both the oestrogen (ER) and progesterone receptors (PR). Although no primary breast cancer could be identified, we considered these three patients as having metastatic breast cancer. All of them were therefore treated with standard breast anti-hormonal therapies and all demonstrated benefit. The pitfalls of clinical presentation, diagnostic work-up, and treatment are discussed. Keywords: Signet-ring cell, Unknown origin, E-cadherin, CDH1 gene
Introduction In cancer, about 3–5% of metastatic diseases originate from an unknown primary origin. The most commonly suspected origins include the lung, breast, ovary, digestive tract (colon, pancreas, stomach, and biliary duct), and gynaecological sites (ovary, endometrium, or cervix). Adenocarcinoma (60%) is the most frequent histology1 and some will have a signetring cell (SRC) component. Knowledge of the primary tumour is important for appropriate patient management, and prognosis. However, identifying the primary is a challenging task as there is no single immunohistochemical marker able to discriminate one origin from another. Furthermore, the initial diagnosis is often complicated by atypical localisation of metastases. The first presentation of metastatic SRC breast cancer can be peritoneal, pleural, or gastric (such as a linitis plastica). Unusual presentations, such as gastric cancer with mammary metastases, have also been described.2 In this review, we present three patients with SRC carcinoma (SRCC) of unknown primary origin. Although no breast lesions were diagnosed despite careful breast work-up, all patients were successfully treated for metastatic breast cancer based on the immunohistochemical findings.
Case Reports A 66-year-old woman presented to the emergency room with ongoing abdominal pain. A bowel Correspondence to: J-C Goeminne, Clinique St-Elisabeth, Pl louise Godin 15, 5000 Namur, Belgium. Email: [email protected]
ß Acta Clinica Belgica 2014 DOI 10.1179/0001551213Z.0000000002
obstruction was initially suspected given her diffuse abdominal pain and lack of bowel sounds on clinical examination. The patients’ non-oncological medical history was limited to arterial hypertension. She had lost 30 kg over the previous 6 months. There was no history of cancer. On admission, the patient had a distended painful abdomen but no sign of peritoneal inflammation. Computed tomography scan showed parietal thickening of the stomach and transverse colon with diffuse peritoneal carcinomatosis and bone metastases. Gastroscopy revealed a linitis plastica. Her serum CEA was 145 ng/ml (normal value ,3.5 ng/ml). Gastric biopsies showed infiltration by a diffuse SRC adenocarcinoma, supporting the diagnosis of metastatic SRC adenocarcinoma of the stomach. Chemotherapy with ECF (epirubicin, cisplatin, and 5-fluorouracil) was not well tolerated and required dose reductions. The disease remained stable. After 3 months of treatment, medroxyprogesterone (500 mg per day) was added to increase her appetite. After the start of hormonal treatment, a rapid improvement in the patient’s general status and a decrease in CEA were recorded. Puzzled by this unexpected evolution, we asked our pathologist to review the tumour biopsies. There was a positive immunostaining for the oestrogen (ER) and progesterone (PR) receptors. Her2neu testing was not performed. Immunostaining for E-cadherin was negative. The diagnosis was revised to possible metastatic lobular carcinoma of the breast, despite the fact that both mammography and magnetic resonance imaging (MRI) of the breasts did not
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reveal any detectable breast cancer. Chemotherapy was stopped. Afterwards, the disease was well controlled for 2 years with hormonal therapy (tamoxifen, followed by letrozole). The second patient was a 70-year-old woman with a history of rapid onset dyspnoea. Bilateral pleural effusions were diagnosed. The analysis of the liquid showed a transudate with no evidence of neoplasia. After 6 months of follow-up requiring repetitive pleural drainages, a pleuroscopy was finally performed. Pleural biopsies showed an infiltration with adenocarcinoma cells with a SRC component. Tumour cells had a strong immunostaining for ER and PR receptors. The tumour was also positive for cytokeratin (CK)-7, but negative by FISH for HER2. Immunostaining for E-cadherin was weak and therefore considered to be negative. Mammography and breast MRI were both negative for a primary breast lesion. CA 15.3 was elevated to 209 U/ml (normal ,30 U/ml). Treatment with tamoxifen was initiated. Three months later, the patient developed a bilateral uretero-hydronephrosis due to retroperitoneal carcinomatosis. Renal function recovered after the placement of ureteral stents. At the same time, several asymptomatic bone metastases were diagnosed. Treatment was switched to letrozole and the disease remained stable for a further 12 months (Fig. 1). Later, still on treatment with letrozole, the patient developed cardiac failure on tumoural pericarditis. Afterwards, the disease had a good response on chemotherapy and hormonal treatment with fulfestrant was reintroduced that maintained a stable disease for several months (Fig. 2). The third case was a woman who presented to our clinic with lower abdominal pain. Computed tomography scan showed peritoneal carcinomatosis and diffuse bone metastasis. Abdominal laparoscopy confirmed the diagnosis of peritoneal carcinomatosis. Upper and lower bowel endoscopy showed no intestinal tumoural lesions. The pathological analysis
Figure 1 Pleural and pericardial carcinomatosis in patient 2, October 2009.
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Figure 2 August 2010 on hormonal treatment with fulvestrant.
of the peritoneal metastases showed a SRC adenocarcinoma. Immunohistochemistry tests were positive for ER, PR, and CK-7, but negative for CK-20, Ecadherin, and HER-2. CA 15.3 was slightly elevated at 51 UI/ml (normal ,35 UI/ml). Mammary clinical examination and breast MRI were normal. The patient started treatment with tamoxifen and zoledronic acid. After 16 months, there was a relapse of bowel discomfort and tumour marker elevation. Tamoxifen was replaced by second line hormonal treatment letrozole for 12 months, followed by a third-line hormonal treatment with exemestane and everolimus. In September 2013, 37 months after the diagnosis of peritoneal carcinomatosis, the patient is still on hormonal treatment and has a good tumour control.
Discussion We observed three patients with SRC carcinoma with ER and PR expression. Although no primary breast cancer could be diagnosed, these patients benefitted from treatment with classical breast anti-hormonal therapy. The first patient was initially diagnosed with locally advanced gastric cancer and was treated with chemotherapy for several months. The second patient underwent several pleural evacuations for ‘inflammatory’ pleural disease before hormone-sensitive pleural tumoural infiltration was diagnosed. The third patient was considered to have a primary peritoneal carcinomatosis by her surgeon. In each of these three cases, the initial diagnosis was delayed due to atypical clinical features. All three patients were finally considered to have a metastatic mammary lobular hormone-sensitive adenocarcinoma, even though the primary breast lesion was undetectable. The prognosis of the SRC tumours seems to be worse than tumours without a SRC component.3,4 SRC subgroups have a higher risk of distant metastasis and a lower overall survival. For this reason, some authors suggest to start a more aggressive therapy for this kind of tumours. To note, in the review of Orvieto et al.,3 the SRCC subgroup
Gregoire et al.
included also other breast tumour histologies (for example: apocrine, pleiomorphic carcinomas) that could worsen the prognosis. While 90% of SRC tumours originate from the stomach, breast, or colon, almost every organ is a potential primary site.5 A greater accuracy of the primary origin of the SRCC may offer targeted treatment options and improve the patient’s outcome. Pathologists have to consider patients’ clinical presentation when selecting immunohistochemical markers to look for the origin of the SRC metastases. Usually, positive immunostaining for ER and PR is considered indicative of breast cancer. Although hormone receptors are usually not expressed in gastric cancers,5,6 some authors report ER expression in up to 20% of gastric cancers.6 In a pooled literature review, Wei et al. showed that ER and/or PR is expressed in up to 3% of adenocarcinomas.7 In contrast, 20% of SRC breast cancers are negative for ER.5,6 For these reasons, the finding of positive hormone receptors in SRC adenocarcinomas does not necessarily predict that the primary tumour will be of breast origin. Androgen receptor (AR) staining can be useful, however, to distinguish gastric from breast SRC carcinoma, as ARs are found positive in 25% of metastatic breast cancers. Shidman et al. found no expression of AR in gastric cancer.8 Other immunohistochemical features can be useful to distinguish breast and gastric SRC cancers. The overexpression of the HER-2 protein is of high therapeutic value in both gastric and breast carcinoma, although lobular breast cancer rarely shows HER-2 overexpression. A CK 7z/CK 202 pattern favours breast cancer whereas CK20z staining favours gastric or colon cancer.5,6 Many other markers are used to distinguish breast from gastric cancer metastases, but none have been shown to be highly specific.5,6 E-cadherin is often non-expressed in SRC breast and gastric cancers.5 E-cadherin is a homophilic cellto-cell adhesion glycoprotein that is expressed ubiquitously at the adherent junction of epithelial tissue and acts as a bridge between the cytoskeleton of adjacent cells. Abrogation of E-cadherin expression leads to a loss of apical-basal cell polarity and, as a consequence, a disruption of some fundamental processes that require spatial asymmetry. This loss seems to promote metastases by decreasing the strength of cellular adhesion within a tissue. Cellular motility is therefore increased and may allow the cancer cells to pass through the basement membrane.9 E-cadherin is thus often described as an inhibitor of invasion and migration. More studies are necessary to understand the molecular mechanism by which the loss of E-cadherin, as found in our three patients, may correlate with the carcinogenesis
Metastatic signet-ring cell carcinoma (SRCC): review
of SRC carcinoma. Diffuse metastatic SRC carcinoma is a classical presentation of hereditary diffuse gastric cancer (HDGC), with a typical loss of Ecadherin. HDGC is a cancer syndrome caused by germline mutations in the gene for the E-cadherin protein (CDH1). In HDGC, germline mutations in CDH1 confer an 80% lifetime risk of developing diffuse gastric cancer. Female CDH1 mutation carriers have a 39–52% lifetime risk of developing lobular breast cancer (LBC).10 As there is an increased risk of LBC in families with HDGC, a group of investigators attempted to assess the prevalence of CDH1 mutations in women with early-onset LBC or with a family history of breast cancer.10 In a group of 318 women, they found that the prevalence of CDH1 variants was low when there were no cases of diffuse gastric cancer in the family. They concluded that the CDH1 mutation associated with LBC without gastric cancer is very rare. The authors also outlined the importance to look for a family history of HDGC when LBC occurs, particularly in the younger patient. In the same way, family members of patients with known HDGC syndrome should be offered regular followup with breast examinations and gastroscopy.
Conclusions The primary origin of a cancer can be difficult to identify in the presence of metastatic SRC carcinoma. The most frequent cancers are the breast, colon, and stomach. The localisation of metastases can be misleading. The history of our three patients demonstrates that it is of interest to look for ER and PR expression in metastatic SRC carcinoma of unknown primary origin and that ER/PRpositive SRC carcinoma can be successfully treated with anti-hormonal agents.
Acknowledgements The authors wish to thank Aileen Eiszele for editing this manuscript.
References 1 DeVita V, Hellman S, Rosenberg S, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia (PA): LippincottRaven; 1997. p. 2423–26. 2 Boutis AL, Andreadis C, Patakiouta F, Mouratidou D. Gastric signet-ring adenocarcinoma presenting with breast metastasis. World J Gastr. 2006;12(18):2958–61. 3 Orvieto E, Maiorano E, Bottiglieri L, Maisonneuve P, Rotmensz N, Galimberti V, et al. Clinicopathologic characteristics of invasive lobular carcinoma of the breast. Cancer. 2008;113(7):1511–20. 4 Makino T, Tsujinaka T, Mishima H, Ikenaga M, Sawamura T, Nakamori S, et al. Primary signet-ring cell carcinoma of the colon and rectum: report of eight cases and review of 154 Japanese cases. Hepatogastroenterology 2006;53(72):845–9. 5 Chu PG, Weiss L. Immunohistochemical characterization of signet-ring cell carcinomas of the stomach, breast and colon. Am J Clin Pathol. 2004;121:884–92. 6 O’Connell FP, Wang HH, Odze RD. Utility of immunohistochemistry in distinguishing primary adenocarcinoma from metastatic breast carcinomas in the gastrointestinal tract. Arch Pathol Lab Med. 2005;129:338–47.
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7 Wei S, Said-Al-Naief N, Hameed O. Estrogen and progesterone receptor expression is not always specific for mammary and gynecologic carcinomas: a tissue microarray and pooled literature review study. Appl Immunohistochem Mol Morphol. 2009;17:393–402. 8 Shidham V, Komorowski R, Machhi J. Androgen receptor expression in metastatic adenocarcinoma in females favors a breast primary. Diag Pathol. 2006;1:34.
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9 Mimata A, Fukamachi H, Eishi Y, Yuasa Y. Loss of Ecadherin in mouse gastric epithelial cells induces signet-ring-like cells, a possible precursor lesion of diffuse gastric cancer. Cancer Sci. 2011;102:942–50. 10 Schrader KA, Masciari S, Boyd N, Salamanca C, Senz J, Saunders DN, et al. Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. J Med Genet. 2011;48:64–8.
Metastatic signet-ring cell carcinoma of unknown primary origin C. Gregoire1,2, G. Muller3, J.-P. Machiels1, J.-C. Goeminne2 1
Service d’oncologie me´dicale, Cliniques universitaires Saint-Luc, Universite´ catholique de Louvain, Brussels, Belgium, 2Service d’oncologie me´dicale, Clinique St-Elisabeth, Namur, Belgium, 3Institut de Pathologie et de Ge´ne´tique, Gosselies, Belgium About 3–5% of metastatic cancers originate from an unknown primary origin. Some have a signet-ring cell (SRC) component. We report the medical history of three patients with SRC carcinoma expressing both the oestrogen (ER) and progesterone receptors (PR). Although no primary breast cancer could be identified, we considered these three patients as having metastatic breast cancer. All of them were therefore treated with standard breast anti-hormonal therapies and all demonstrated benefit. The pitfalls of clinical presentation, diagnostic work-up, and treatment are discussed. Keywords: Signet-ring cell, Unknown origin, E-cadherin, CDH1 gene
Introduction In cancer, about 3–5% of metastatic diseases originate from an unknown primary origin. The most commonly suspected origins include the lung, breast, ovary, digestive tract (colon, pancreas, stomach, and biliary duct), and gynaecological sites (ovary, endometrium, or cervix). Adenocarcinoma (60%) is the most frequent histology1 and some will have a signetring cell (SRC) component. Knowledge of the primary tumour is important for appropriate patient management, and prognosis. However, identifying the primary is a challenging task as there is no single immunohistochemical marker able to discriminate one origin from another. Furthermore, the initial diagnosis is often complicated by atypical localisation of metastases. The first presentation of metastatic SRC breast cancer can be peritoneal, pleural, or gastric (such as a linitis plastica). Unusual presentations, such as gastric cancer with mammary metastases, have also been described.2 In this review, we present three patients with SRC carcinoma (SRCC) of unknown primary origin. Although no breast lesions were diagnosed despite careful breast work-up, all patients were successfully treated for metastatic breast cancer based on the immunohistochemical findings.
Case Reports A 66-year-old woman presented to the emergency room with ongoing abdominal pain. A bowel Correspondence to: J-C Goeminne, Clinique St-Elisabeth, Pl louise Godin 15, 5000 Namur, Belgium. Email: [email protected]
ß Acta Clinica Belgica 2014 DOI 10.1179/0001551213Z.0000000002
obstruction was initially suspected given her diffuse abdominal pain and lack of bowel sounds on clinical examination. The patients’ non-oncological medical history was limited to arterial hypertension. She had lost 30 kg over the previous 6 months. There was no history of cancer. On admission, the patient had a distended painful abdomen but no sign of peritoneal inflammation. Computed tomography scan showed parietal thickening of the stomach and transverse colon with diffuse peritoneal carcinomatosis and bone metastases. Gastroscopy revealed a linitis plastica. Her serum CEA was 145 ng/ml (normal value ,3.5 ng/ml). Gastric biopsies showed infiltration by a diffuse SRC adenocarcinoma, supporting the diagnosis of metastatic SRC adenocarcinoma of the stomach. Chemotherapy with ECF (epirubicin, cisplatin, and 5-fluorouracil) was not well tolerated and required dose reductions. The disease remained stable. After 3 months of treatment, medroxyprogesterone (500 mg per day) was added to increase her appetite. After the start of hormonal treatment, a rapid improvement in the patient’s general status and a decrease in CEA were recorded. Puzzled by this unexpected evolution, we asked our pathologist to review the tumour biopsies. There was a positive immunostaining for the oestrogen (ER) and progesterone (PR) receptors. Her2neu testing was not performed. Immunostaining for E-cadherin was negative. The diagnosis was revised to possible metastatic lobular carcinoma of the breast, despite the fact that both mammography and magnetic resonance imaging (MRI) of the breasts did not
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Metastatic signet-ring cell carcinoma (SRCC): review
reveal any detectable breast cancer. Chemotherapy was stopped. Afterwards, the disease was well controlled for 2 years with hormonal therapy (tamoxifen, followed by letrozole). The second patient was a 70-year-old woman with a history of rapid onset dyspnoea. Bilateral pleural effusions were diagnosed. The analysis of the liquid showed a transudate with no evidence of neoplasia. After 6 months of follow-up requiring repetitive pleural drainages, a pleuroscopy was finally performed. Pleural biopsies showed an infiltration with adenocarcinoma cells with a SRC component. Tumour cells had a strong immunostaining for ER and PR receptors. The tumour was also positive for cytokeratin (CK)-7, but negative by FISH for HER2. Immunostaining for E-cadherin was weak and therefore considered to be negative. Mammography and breast MRI were both negative for a primary breast lesion. CA 15.3 was elevated to 209 U/ml (normal ,30 U/ml). Treatment with tamoxifen was initiated. Three months later, the patient developed a bilateral uretero-hydronephrosis due to retroperitoneal carcinomatosis. Renal function recovered after the placement of ureteral stents. At the same time, several asymptomatic bone metastases were diagnosed. Treatment was switched to letrozole and the disease remained stable for a further 12 months (Fig. 1). Later, still on treatment with letrozole, the patient developed cardiac failure on tumoural pericarditis. Afterwards, the disease had a good response on chemotherapy and hormonal treatment with fulfestrant was reintroduced that maintained a stable disease for several months (Fig. 2). The third case was a woman who presented to our clinic with lower abdominal pain. Computed tomography scan showed peritoneal carcinomatosis and diffuse bone metastasis. Abdominal laparoscopy confirmed the diagnosis of peritoneal carcinomatosis. Upper and lower bowel endoscopy showed no intestinal tumoural lesions. The pathological analysis
Figure 1 Pleural and pericardial carcinomatosis in patient 2, October 2009.
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Figure 2 August 2010 on hormonal treatment with fulvestrant.
of the peritoneal metastases showed a SRC adenocarcinoma. Immunohistochemistry tests were positive for ER, PR, and CK-7, but negative for CK-20, Ecadherin, and HER-2. CA 15.3 was slightly elevated at 51 UI/ml (normal ,35 UI/ml). Mammary clinical examination and breast MRI were normal. The patient started treatment with tamoxifen and zoledronic acid. After 16 months, there was a relapse of bowel discomfort and tumour marker elevation. Tamoxifen was replaced by second line hormonal treatment letrozole for 12 months, followed by a third-line hormonal treatment with exemestane and everolimus. In September 2013, 37 months after the diagnosis of peritoneal carcinomatosis, the patient is still on hormonal treatment and has a good tumour control.
Discussion We observed three patients with SRC carcinoma with ER and PR expression. Although no primary breast cancer could be diagnosed, these patients benefitted from treatment with classical breast anti-hormonal therapy. The first patient was initially diagnosed with locally advanced gastric cancer and was treated with chemotherapy for several months. The second patient underwent several pleural evacuations for ‘inflammatory’ pleural disease before hormone-sensitive pleural tumoural infiltration was diagnosed. The third patient was considered to have a primary peritoneal carcinomatosis by her surgeon. In each of these three cases, the initial diagnosis was delayed due to atypical clinical features. All three patients were finally considered to have a metastatic mammary lobular hormone-sensitive adenocarcinoma, even though the primary breast lesion was undetectable. The prognosis of the SRC tumours seems to be worse than tumours without a SRC component.3,4 SRC subgroups have a higher risk of distant metastasis and a lower overall survival. For this reason, some authors suggest to start a more aggressive therapy for this kind of tumours. To note, in the review of Orvieto et al.,3 the SRCC subgroup
Gregoire et al.
included also other breast tumour histologies (for example: apocrine, pleiomorphic carcinomas) that could worsen the prognosis. While 90% of SRC tumours originate from the stomach, breast, or colon, almost every organ is a potential primary site.5 A greater accuracy of the primary origin of the SRCC may offer targeted treatment options and improve the patient’s outcome. Pathologists have to consider patients’ clinical presentation when selecting immunohistochemical markers to look for the origin of the SRC metastases. Usually, positive immunostaining for ER and PR is considered indicative of breast cancer. Although hormone receptors are usually not expressed in gastric cancers,5,6 some authors report ER expression in up to 20% of gastric cancers.6 In a pooled literature review, Wei et al. showed that ER and/or PR is expressed in up to 3% of adenocarcinomas.7 In contrast, 20% of SRC breast cancers are negative for ER.5,6 For these reasons, the finding of positive hormone receptors in SRC adenocarcinomas does not necessarily predict that the primary tumour will be of breast origin. Androgen receptor (AR) staining can be useful, however, to distinguish gastric from breast SRC carcinoma, as ARs are found positive in 25% of metastatic breast cancers. Shidman et al. found no expression of AR in gastric cancer.8 Other immunohistochemical features can be useful to distinguish breast and gastric SRC cancers. The overexpression of the HER-2 protein is of high therapeutic value in both gastric and breast carcinoma, although lobular breast cancer rarely shows HER-2 overexpression. A CK 7z/CK 202 pattern favours breast cancer whereas CK20z staining favours gastric or colon cancer.5,6 Many other markers are used to distinguish breast from gastric cancer metastases, but none have been shown to be highly specific.5,6 E-cadherin is often non-expressed in SRC breast and gastric cancers.5 E-cadherin is a homophilic cellto-cell adhesion glycoprotein that is expressed ubiquitously at the adherent junction of epithelial tissue and acts as a bridge between the cytoskeleton of adjacent cells. Abrogation of E-cadherin expression leads to a loss of apical-basal cell polarity and, as a consequence, a disruption of some fundamental processes that require spatial asymmetry. This loss seems to promote metastases by decreasing the strength of cellular adhesion within a tissue. Cellular motility is therefore increased and may allow the cancer cells to pass through the basement membrane.9 E-cadherin is thus often described as an inhibitor of invasion and migration. More studies are necessary to understand the molecular mechanism by which the loss of E-cadherin, as found in our three patients, may correlate with the carcinogenesis
Metastatic signet-ring cell carcinoma (SRCC): review
of SRC carcinoma. Diffuse metastatic SRC carcinoma is a classical presentation of hereditary diffuse gastric cancer (HDGC), with a typical loss of Ecadherin. HDGC is a cancer syndrome caused by germline mutations in the gene for the E-cadherin protein (CDH1). In HDGC, germline mutations in CDH1 confer an 80% lifetime risk of developing diffuse gastric cancer. Female CDH1 mutation carriers have a 39–52% lifetime risk of developing lobular breast cancer (LBC).10 As there is an increased risk of LBC in families with HDGC, a group of investigators attempted to assess the prevalence of CDH1 mutations in women with early-onset LBC or with a family history of breast cancer.10 In a group of 318 women, they found that the prevalence of CDH1 variants was low when there were no cases of diffuse gastric cancer in the family. They concluded that the CDH1 mutation associated with LBC without gastric cancer is very rare. The authors also outlined the importance to look for a family history of HDGC when LBC occurs, particularly in the younger patient. In the same way, family members of patients with known HDGC syndrome should be offered regular followup with breast examinations and gastroscopy.
Conclusions The primary origin of a cancer can be difficult to identify in the presence of metastatic SRC carcinoma. The most frequent cancers are the breast, colon, and stomach. The localisation of metastases can be misleading. The history of our three patients demonstrates that it is of interest to look for ER and PR expression in metastatic SRC carcinoma of unknown primary origin and that ER/PRpositive SRC carcinoma can be successfully treated with anti-hormonal agents.
Acknowledgements The authors wish to thank Aileen Eiszele for editing this manuscript.
References 1 DeVita V, Hellman S, Rosenberg S, editors. Cancer: principles and practice of oncology. 5th ed. Philadelphia (PA): LippincottRaven; 1997. p. 2423–26. 2 Boutis AL, Andreadis C, Patakiouta F, Mouratidou D. Gastric signet-ring adenocarcinoma presenting with breast metastasis. World J Gastr. 2006;12(18):2958–61. 3 Orvieto E, Maiorano E, Bottiglieri L, Maisonneuve P, Rotmensz N, Galimberti V, et al. Clinicopathologic characteristics of invasive lobular carcinoma of the breast. Cancer. 2008;113(7):1511–20. 4 Makino T, Tsujinaka T, Mishima H, Ikenaga M, Sawamura T, Nakamori S, et al. Primary signet-ring cell carcinoma of the colon and rectum: report of eight cases and review of 154 Japanese cases. Hepatogastroenterology 2006;53(72):845–9. 5 Chu PG, Weiss L. Immunohistochemical characterization of signet-ring cell carcinomas of the stomach, breast and colon. Am J Clin Pathol. 2004;121:884–92. 6 O’Connell FP, Wang HH, Odze RD. Utility of immunohistochemistry in distinguishing primary adenocarcinoma from metastatic breast carcinomas in the gastrointestinal tract. Arch Pathol Lab Med. 2005;129:338–47.
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7 Wei S, Said-Al-Naief N, Hameed O. Estrogen and progesterone receptor expression is not always specific for mammary and gynecologic carcinomas: a tissue microarray and pooled literature review study. Appl Immunohistochem Mol Morphol. 2009;17:393–402. 8 Shidham V, Komorowski R, Machhi J. Androgen receptor expression in metastatic adenocarcinoma in females favors a breast primary. Diag Pathol. 2006;1:34.
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9 Mimata A, Fukamachi H, Eishi Y, Yuasa Y. Loss of Ecadherin in mouse gastric epithelial cells induces signet-ring-like cells, a possible precursor lesion of diffuse gastric cancer. Cancer Sci. 2011;102:942–50. 10 Schrader KA, Masciari S, Boyd N, Salamanca C, Senz J, Saunders DN, et al. Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. J Med Genet. 2011;48:64–8.
