Anatomic Pathology / SIGNET-RING CELL CARCINOMAS OF THE STOMACH, BREAST, AND COLON

Immunohistochemical Characterization of Signet-Ring Cell Carcinomas of the Stomach, Breast, and Colon Peiguo G. Chu, MD, PhD, and Lawrence M. Weiss, MD Key Words: Signet-ring cell carcinoma; Hepatocyte paraffin 1; Intestinal metaplasia; Immunohistochemistry DOI: 10.1309/A09ERYMFR64NERDW

We studied the immunophenotype of signet-ring cell carcinoma (SRCC) of the stomach (30 cases), breast (21 cases), and colon (9 cases) with the following expression patterns: (1) breast: consistent, MUC1 (21 [100%]), cytokeratin (CK) 7 (20 [95%]), estrogen receptor (ER; 17 [81%]); infrequent, E-cadherin (6 [29%]), MUC2, MUC5AC, CK20 (1 [5%] each); negative, CDX2 and hepatocyte paraffin 1 (Hep Par 1; 0 [0%] each); (2) gastric: frequent, CDX2 (27 [90%]) and Hep Par 1 (25 [83%]); variable, E-cadherin and CK20 (17 [57%] each), MUC2 and MUC5AC (15 [50%] each), MUC1 (5 [17%]); negative, ER (0 [0%]); and (3) colon: frequent, MUC2 (9 [100%]), CDX2 and MUC5AC (8 [89%] each); infrequent or negative, MUC1 (3 [33%]), Hep Par 1 (2 [22%]), ER (0 [0%]). Immunohistochemical staining distinguished breast from gastric SRCC (ER, MUC1, Hep Par 1, CDX2) and colon SRCC (ER, CDX2, MUC2, and MUC5AC). Gastric and colon SRCCs showed a similar staining pattern for antibodies tested except for Hep Par 1 and CDX2 (gastric, 83% Hep Par 1 positivity and heterogeneous, weak, patchy CDX2 nuclear staining; colon, 22% Hep Par 1 positivity and homogeneous, strong, diffuse CDX2 nuclear staining). About half of the cases of gastric SRCC expressed MUC2 and MUC5AC, whereas virtually all cases of colon SRCC expressed them.

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Signet-ring cell carcinoma (SRCC), a unique subtype of mucin-producing adenocarcinoma, can arise from virtually all organs. However, more than 90% of cases of human SRCCs arise from the stomach, breast, and colon.1-3 In the breast, most cases of SRCC are infiltrating lobular carcinoma, and a minority of cases are infiltrating ductal carcinoma.4 Breast SRCC shows a distinctive systemic metastatic pattern. A statistically significant greater frequency of metastatic breast SRCC can be found in the peritoneum, gastrointestinal tract, lung, and gynecologic organs than other cases of breast carcinoma.5,6 Intra-abdominal metastases tend to involve the serosal surface, retroperitoneum, gastric mucosa, and ovaries.7,8 Gastric SRCC preferentially involves lymph nodes and peritoneal surfaces.9 Colon SRCC is notorious for its diffuse intramural infiltration, with lymph node involvement and peritoneal surface metastasis. Because SRCCs from other peritoneal organs (such as bladder, ovary, uterus, and prostate) are uncommon, most cases of intraabdominal and intralymphatic SRCC are metastases from the stomach, breast, or colon.10 Non-SRCC adenocarcinomas from the breast, stomach, and colon express characteristic patterns of keratins, which commonly are used in the differential diagnosis of metastatic adenocarcinomas from these sites.11,12 Mucin production is the biologic hallmark of SRCC. Of 12 human mucins characterized so far, MUC1, MUC2, MUC5AC have been used widely in the differential diagnosis of various types of adenocarcinomas.13,14 Loss of immunoreactivity for E-cadherin has been reported in more than three fourths of cases of breast lobular carcinoma 15,16 and one third of cases of gastric SRCC. Decreased expression of E-cadherin in these 2 types of SRCC has been used to confirm the diagnosis. CDX2 is a © American Society for Clinical Pathology

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Abstract

Anatomic Pathology / ORIGINAL ARTICLE

Materials and Methods Cases We selected 30 cases of gastric SRCC, 21 of breast SRCC, and 9 of colon SRCC from the surgical pathology files of the City of Hope National Medical Center, Duarte, CA. Of 30 cases of gastric SRCC, 7 were metastatic ❚Table 1❚. Of 21 cases of lobular breast carcinoma with signet-ring cells, 3 were metastatic (Table 1). Of 9 cases of colon SRCC, 3 were metastatic (Table 1). The tissue samples had been fixed routinely in 10% neutral formalin and embedded in paraffin. One paraffin tissue block was selected from each case. To qualify as SRCC, more than 90% of tumor cells had to be signet-ring cells. Immunohistochemical Analysis Commercially available monoclonal antibodies to Hep Par 1 (dilution 1:100, DAKO, Carpinteria, CA), CK7 (dilution 1:2,000, DAKO), CK20 (1:40, American Research Products, Belmont, CA), E-cadherin (dilution 1:200, Novocastra, Newcastle upon Tyne, England), MUC1 (1:100, Novocastra), MUC2 (dilution 1:100, Novocastra), MUC5AC (dilution 1:150, Novocastra), CDX2 (dilution 1:50, BioGenex, San Ramon CA), and ER (dilution 1:400, Immunotech, Marseille, France) were used. The sections were deparaffinized and rehydrated in graded alcohol. For heat-induced epitope retrieval, the sections stained for Hep Par 1, CDX2, and E-cadherin were subjected to a 1.0mmol/L concentration of EDTA buffer (pH 8.0); the sections stained for MUC1, MUC2, and MUC5AC were subjected to a 1.0-mmol/L concentration of citrate buffer

(pH 6.0) in a steamer (Black & Decker, Shelton, CT) at 100°C for 20 minutes; and the sections stained for CK7 and CK20 were digested with Proteinase K for 5 minutes. The sections then were brought to an automated stainer (DAKO), following the vendor’s protocol. EnVision Plus (DAKO) detection methods were used. Cytoplasmic immunoreactivity for Hep Par 1, CK7, CK20, MUC1, MUC2, and MUC5AC and nuclear immunoreactivity for ER and CDX2 were assessed. Cases with more than 5% positive cells were considered positive.

Results Staining Patterns of Gastric SRCC Results are detailed in Table 1 and summarized in ❚Table 2❚. Staining results are shown in ❚Image 1❚. The vast majority of cases of gastric SRCC expressed CDX2 (Image 1B) and Hep Par 1 (Image 1D). The CDX2 staining in gastric SRCC varied in the intensity and percentage of positive tumor cells. The positive Hep Par 1 staining was cytoplasmic and granular and usually patchy. Approximately one half to two thirds of the cases of gastric SRCC expressed MUC2, MUC5AC, CK20, E-cadherin, and CK7. Only 5 of 30 cases expressed MUC1, and none expressed ER. The metastatic gastric SRCCs showed an immunohistochemical profile similar to that of the primary cases. Staining Patterns of Breast SRCC Detailed results are given in Table 1 and summarized in Table 2. Staining results are shown in ❚Image 2❚. As expected, the majority of cases of breast SRCC were positive for ER (Image 2E) and negative for E-cadherin. All cases expressed MUC1 (Image 2C), and all but 1 case expressed CK7. The positive MUC1 staining was cytoplasmic and diffuse. All cases were negative for Hep Par 1 and CDX2, and all cases except 1 were negative for MUC2, MUC5AC, and CK20. The immunohistochemical profile for the metastatic cases was similar to that of the primary cases. Staining Patterns of Colon SRCC Detailed results are given in Table 1 and summarized in Table 2. Staining results are shown in ❚Image 3❚. All 9 cases of colon SRCC expressed MUC2 (Image 3F), and all cases except 1 expressed CDX2 (Image 3B) and MUC5AC. Unlike the heterogeneous staining seen in gastric SRCC (Image 1B), the nuclear CDX2 staining in colon SRCC was homogeneous and strong, and virtually all tumor cell nuclei were positive. The colon SRCC rarely expressed Hep Par 1 and MUC1 and did not express ER. Am J Clin Pathol 2004;121:884-892

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homeobox gene that is expressed exclusively in normal intestinal epithelium and its neoplasms.17 More than two thirds of cases of gastric adenocarcinomas also express CDX2.18 Hepatocyte paraffin 1 (Hep Par 1) antibody recognizes a cytoplasmic antigen in normal hepatocytes, superficial small intestinal absorptive cells, and hepatocellular carcinoma.19,20 Its expression also has been found in a high percentage of gastric SRCCs.21 A variety of markers have been studied to attempt to distinguish SRCCs arising from various organs. We studied the expression of cytokeratin (CK) 7, CK20, MUC1, MUC2, MUC5AC, estrogen receptor (ER), Hep Par 1, CDX2, and Ecadherin in breast, gastric, and colon SRCCs. We found that MUC1 and ER might aid in the diagnosis of breast SRCC, and MUC2, MUC5AC and CDX2 might aid in the diagnosis of colon SRCC. Unlike colon and breast SRCCs, more than 80% of cases of gastric SRCC express Hep Par 1, which might aid in the diagnosis of gastric SRCC.

Chu and Weiss / SIGNET-RING CELL CARCINOMAS OF THE STOMACH, BREAST, AND COLON

❚Table 1❚ Hep Par 1, CK7, CK20, E-Cadherin, MUC1, MUC2, MUC5AC, CDX2, and ER Expression in Signet-Ring Cell Carcinoma Case No. Hep Par 1

CK7

CK20

E-Cadherin

+ + + + + + + + + + + + + + + + + + + – – – – + + – + + + +

+ – + + + + + + + + + + + + + + + + + + + + – + + + + + – +

+ – + + + + – – + + – + + – – – + – + + + + + + – + + – + +

– – – + + – + + – – + – + + + + + + + – – + – + + – + – + –

+ – + + – + – + – + – + – – + + + + + – + – – + + – – + – +

– – – – – – – – – – – – – – – – – – – – –

– – – – – – – – – – – – – – – – – – – – –

+ + + + + + + + + + + + + + – + + + + + +

– – – – – – – + – – – – – – – – – – – – –

– – – – + – – – +

– + + + + + + + +

+ + + + – – – – –

+ – – + + + + + +

MUC2

MUC5AC

MUC1

ER

Tumor Site

– – – + + + + + – – – + + + + + + + + – – – – – + – + – – –

+ – + + + + + – – – – + – – + – – – – – + + + + – + – + + –

– – – – – – – – – – – + + – – – – – – – – – + – + – – – – +

– – – – – – – – – – – – – – – – – – – – – – – – – – – – – –

Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Stomach Ovary Small bowel Abdominal wall Omentum Small bowel Small bowel Breast

+ + – – – – – – – – – + + – – + + – – – –

+ – – – – – – – – – – – – – – – – – – – –

+ – – – – – – – – – – – – – – – – – – – –

+ + + + + + + + + + + + + + + + + + + + +

+ + + + + + + + + + + + + + – – – – + + +

Breast Breast Breast Breast Breast Breast Breast Breast Breast Breast Breast Breast Breast Breast Breast Breast Breast Breast Stomach Ovary Lung

+ – – – + + + + –

+ + + + + + + + +

+ + + + + – + + +

– – – + – + + – –

– – – – – – – – –

Colon Colon Colon Small bowel Colon Rectum Lymph node Mesentery Ovary

CK, cytokeratin; ER, estrogen receptor; Hep Par 1, hepatocyte paraffin 1.

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Gastric G1 G2 G3 G4 G5 G6 G7 G8 G9 G10 G11 G12 G13 G14 G15 G16 G17 G18 G19 G20 G21 G22 G23 G24 G25 G26 G27 G28 G29 G30 Breast B1 B2 B3 B4 B5 B6 B7 B8 B9 B10 B11 B12 B13 B14 B15 B16 B17 B18 B19 B20 B21 Colonic C1 C2 C3 C4 C5 C6 C7 C8 C9

CDX2

Anatomic Pathology / ORIGINAL ARTICLE

B

C

D

E

F

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A

❚Image 1❚ (Case G24) Gastric signet-ring cell carcinoma metastasized to the ovary (A, H&E, ×400; B, CDX2, ×400; C, MUC1, ×400; D, Hep Par 1, ×400; E, estrogen receptor, ×400; F, MUC2, ×400). Note the heterogeneous (variable positive cells and staining intensity) CDX2 staining (B) and focal granular cytoplasmic Hep Par 1 staining (D).

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B

C

D

E

F

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A

❚Image 2❚ (Case B19) Breast signet-ring cell carcinoma metastasized to the ovary (A, H&E, ×400; B, CDX2, ×400; C, MUC1, ×400; D, Hep Par 1, ×400; E, estrogen receptor, ×400; F, MUC2, ×400). Note the strong cytoplasmic MUC1 staining (C) and strong nuclear estrogen receptor staining (E) 888 888

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B

C

D

E

F

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A

❚Image 3❚ (Case C9) A case of colon signet-ring cell carcinoma metastasized to the ovary (A, H&E, ×400; B, CDX2, ×400; C, MUC1, ×400; D, Hep Par 1, ×400; E, estrogen receptor, ×400; F, MUC2, ×400). Note the strong homogeneous CDX2 staining (B) and strong cytoplasmic MUC2 staining (F). Am J Clin Pathol 2004;121:884-892

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❚Table 2❚ Summary of Positive Expression of Hep Par 1, CK7, CK20, E-Cadherin, MUC1, MUC2, MUC5AC, CDX2, and ER in Gastric, Breast, and Colon SRCC* Antibody

Gastric SRCC (n = 30)

Breast SRCC (n = 21)

Colon SRCC (n = 9)

27 (90)† 25 (83) 20 (67) 17 (57) 17 (57) 15 (50) 15 (50) 5 (17) 0 (0)

0 (0) 0 (0) 21 (100) 1 (5) 6 (29) 1 (5) 1 (5) 21 (100) 17 (81)

8 (89)‡ 2 (22) 4 (44) 7 (78) 5 (56) 9 (100) 8 (89) 2 (22) 0 (0)

CDX2 Hep Par 1 CK7 CK20 E-Cadherin MUC2 MUC5AC MUC1 ER

Discussion More than 95% cases of human SRCC arise from the stomach, breast, colon, lung, and prostate. Regardless of the tissue origin, SRCCs frequently metastasize to regional lymph nodes, peritoneal surfaces, the ovaries, and lung. Breast SRCCs might show some morphologic differences from gastric and colon SRCCs in that breast SRCC might contain intracytoplasmic lumina containing sialomucin, whereas other SRCCs usually have the extended, globoid, and optically clear cytoplasmic acid mucin that pushes nuclei against the cell membrane; however, these differences might be difficult to detect in individual cases. Owing to the morphologic similarity of various SRCCs on H&E-stained sections, immunohistochemical analysis might have a key role in the determination of the tissue origins of metastatic SRCCs. Because most cases of SRCC arising from the lung and prostate are positive for thyroid transcription factor122,23 and prostate-specific antigen,24 respectively, they can be separated easily from SRCCs from the breast, stomach, and colon. A variety of immunologic markers have been applied to distinguish SRCCs from the breast, stomach, and colon. Lobular breast carcinoma with signet-ring cells and gastric SRCCs share similar decreased E-cadherin immunoreactivity. Approximately 85% of lobular breast carcinomas and 50% of gastric SRCCs have decreased E-cadherin immunoreactivity.25-28 Other SRCCs also might be negative for E-cadherin; in the present study, we demonstrated that 4 of 9 cases of colon SRCC were negative for Ecadherin. Thus, E-cadherin is not a sensitive marker for breast or gastric SRCC. Although ER is expressed exclusively in breast carcinoma, approximately 20% of breast SRCCs can be negative for ER,29 whereas some studies 890 890

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CK, cytokeratin; ER, estrogen receptor; Hep Par 1, hepatocyte paraffin 1; SRCC, signet-ring cell carcinoma. * Data are given as number (percentage). † Heterogeneous CDX2 positivity. ‡ Homogeneous CDX2 positivity.

have found that up to 30% of gastrointestinal adenocarcinomas were positive for ER.30,31 Thus, it is possible that immunohistochemical analysis for ER alone might not distinguish breast SRCC from gastric or colon SRCC. Although the human gross cystic disease fluid protein 15 (GCDFP-15) is a relatively sensitive marker for breast carcinoma, it has a sensitivity for breast carcinoma similar to that of ER.32 Adenocarcinomas of the breast, stomach, and colon show different CK7 and CK20 expression patterns.11,12,29 Goldstein et al33 had statistically significant results when they used CK7 and CK20 expression patterns to distinguish gastric and colon SRCCs. Tot29 found that in combination with ER staining, CK7 and CK20 expression patterns can be used to distinguish gastrointestinal SRCCs from breast SRCCs. In recent years, new antibodies have been found useful in the differential diagnosis of adenocarcinomas from the stomach, breast, and colon, and adenocarcinomas from the stomach, breast, and colon have been reported to express different types of mucins. Nonmucinous breast adenocarcinomas usually express MUC1 but not MUC2 and MUC5AC,34-37 whereas gastrointestinal adenocarcinomas frequently express MUC2 and MUC5AC but less frequently express MUC1.38 CDX2 antigen is expressed in epithelial cells throughout the intestine. CDX2 has been demonstrated in all cases of colorectal adenocarcinoma and almost 50% of gastric adenocarcinomas.18 In contrast, only rare cases of adenocarcinomas of the genitourinary and gynecologic tracts (with 1 exception of ovarian mucinous adenocarcinoma, which commonly expresses CDX2), breast, lung, and head and neck show significant levels of CDX2 expression.18 The expression pattern of CDX2 in gastrointestinal SRCC has not been studied. Although villin has sensitivity and specificity for colorectal adenocarcinoma similar to that of CDX2, CDX2 is an easier marker to evaluate, given the focal nature of villin expression, with the positive staining restricted to the apical surface, compared with a nuclear pattern of positivity with CDX2. 18 We observed that a significantly high percentage of gastric SRCC expressed Hep Par 1 antigen.21 However, whether these antibodies are useful in the differential diagnosis of SRCCs from these organs has not been well studied. Before performing immunohistochemical staining, obtaining a complete clinical history is the first step in the evaluation of a metastatic SRCC. In the present study, we studied the expression patterns of immunohistochemical markers in SRCCs arising from the breast, stomach, and colon. We found that use of a combination of immunomarkers can substantially increase the sensitivity and specificity for diagnosing SRCCs from these organs. Breast SRCC can be distinguished from gastrointestinal SRCC if ER and

Anatomic Pathology / ORIGINAL ARTICLE

MUC1 are used as markers for breast SRCC, and MUC2 and CDX2 can be used as markers for gastric and colon SRCCs. To distinguish SRCCs of gastric vs colonic origin, Hep Par 1 positivity and heterogeneous CDX2 staining strongly favor a gastric primary site, whereas Hep Par 1 negativity along with diffuse and homogeneous CDX2 nuclear positivity and diffuse cytoplasmic MUC2 and MUC5AC positivity strongly favor a colonic primary site. CK7, CK20, and E-cadherin are less useful and lack sensitivity. From the Division of Pathology, City of Hope National Medical Center, Duarte, CA. Address reprint requests to Dr Chu: Division of Pathology, City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA 91010.

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