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. 2024 Dec 3;16(23):4052. doi: 10.3390/cancers16234052

Carcinoembryonic Antigen Expression in Human Tumors: A Tissue Microarray Study on 13,725 Tumors

Kristina Jansen 1, Lara Kornfeld 2, Maximilian Lennartz 2, Sebastian Dwertmann Rico 2, Simon Kind 2, Viktor Reiswich 2, Florian Viehweger 2, Ahmed Abdulwahab Bawahab 3, Christoph Fraune 2, Natalia Gorbokon 2, Andreas M Luebke 2, Claudia Hube-Magg 2, Anne Menz 2, Ria Uhlig 2, Till Krech 2,4, Andrea Hinsch 2, Frank Jacobsen 2, Eike Burandt 2, Guido Sauter 2, Ronald Simon 2,*, Martina Kluth 2, Stefan Steurer 2, Andreas H Marx 2,5, Till S Clauditz 2, David Dum 2, Patrick Lebok 2,4, Sarah Minner 2, Christian Bernreuther 2
Editor: Giuseppe Palmieri
PMCID: PMC11640007  PMID: 39682238

Simple Summary

Carcinoembryonic antigen is a cell-surface glycoprotein and target for anti-cancer drugs. In this study, more than 15,000 samples from 120 different tumor types were analyzed by immunohistochemistry. CEA expression was found at least occasionally in 65 tumor types, most frequently in colorectal cancers and other gastrointestinal tumors, thyroid gland cancers, and pulmonary adenocarcinomas. Reduced CEA expression was linked to colon cancer aggressiveness. In contrast, aggressiveness cancers of the urinary bladder and breast cancers were characterized by CEA overexpression. We present a comprehensive catalog of tumor types that might benefit from anti-CEA therapies.

Keywords: CEA, diagnostic marker, tissue microarray, immunohistochemistry, human tumors

Abstract

Background/Objectives: Carcinoembryonic antigen (CEA) is a cell-surface glycoprotein serving as a drug target, diagnostic marker, and serum marker for cancer monitoring. However, prevalence data on CEA expression in cancer tissues vary considerably. This study was designed to determine CEA expression in normal and neoplastic tissues. Methods: A tissue microarray containing 13,725 samples from 120 different tumor types, as well as 76 different normal tissue types, was analyzed by immunohistochemistry (IHC). Results: CEA was detectable in 65 (54.2%) of 120 tumor categories, including 49 (40.8%) tumor types with at least one strongly positive case. CEA positivity was most common in colorectal adenomas (100%) and carcinomas (98.7%), other gastrointestinal adenocarcinomas (61.1–80.3%), medullary carcinomas of the thyroid (96.3%), pulmonary adenocarcinoma (73.7%), mucinous carcinomas of the ovary (79.8%) and the breast (43.2%), small-cell carcinomas of the lung (64.3%), and urinary bladder (38.9%). CEA overexpression was linked to high tumor grade and invasive growth (p < 0.0001 each) in urinary bladder cancer, and estrogen and HER2 receptor positivity (p ≤ 0.0158) in invasive breast cancer of no special type. In colorectal adenocarcinomas, reduced CEA expression was associated with mismatch repair deficiency (p < 0.0001). Conclusions: The comprehensive list of CEA-positive human tumor types demonstrates that CEA is expressed in a broad range of epithelial neoplasms, many of which might benefit from CEA serum monitoring and anti-CEA therapies.

1. Introduction

Carcinoembryonic antigen (CEA; CEACAM5) is a cell-surface glycoprotein with a role in cell adhesion [1]. CEA is extensively produced in many tissues during fetal development, but even before birth, its expression becomes limited to a limited number of different normal cell types [2]. CEA is overexpressed in various cancers (summarized in [3,4,5,6]). Because CEA is also shed into the blood stream, CEA measurement in the serum is used as a tool for early detection and recurrence monitoring of cancer [7,8]. There are several therapeutic approaches targeting CEA. For example, an ongoing phase I study is investigating the CEA-CD3 bispecific antibody cibisatamab on metastatic CEA-positive colorectal carcinomas. In all, 11% (4/36) of patients treated with cibisatamab monotherapy and 50% (5/10) of patients receiving cibisatamab in combination with a PD-L1-inhibitor showed radiological shrinkage, reflecting its antitumor activity [9,10]. Labetuzumab govitecan, an SN-38 CEA-antibody–drug conjugate, resulted in stable disease in 49% (42/86) of patients with metastatic colorectal cancer in a phase I/II study [11]. A phase I pretargeted radioimmunotherapy trial using anti-CEA-HSG-TF2 showed promising dose optimization for the treatment of CEA-positive metastasized lung carcinomas [12]. Three phase I studies showed that CEA is an auto-antigen that can be safely targeted by CAR T cells, resulting in stable disease in 7/10 patients with metastatic colorectal carcinomas (NCT02349724), 7/14 patients with metastatic gastrointestinal carcinomas (NCT01212887), and 1/6 patients with liver metastases of different adenocarcinomas (NCT01373047) [13]. In addition, vaccination with Ad5 [E1-, E2b-]-CEA(6D)—encoding CEA—induced CEA-specific cell-mediated immune response with antitumor activity in a phase I/II colorectal cancer study [14].

More than 700 studies analyzed the expression of CEA in cancer by immunohistochemistry (IHC) and described CEA positivity in at least 62 different tumor types and subtypes. CEA is considered to occur at a particularly high frequency in colorectal cancers, other gastrointestinal carcinomas, and in pulmonary adenocarcinomas (summarized in [3,4,5,6]). Because CEA expression is rare in hepatocellular carcinoma and in malignant mesothelioma, CEA IHC has been suggested as a tool to distinguish mesothelioma from pulmonary adenocarcinoma and hepatocellular carcinoma from liver metastasis [15,16]. However, the results of previous studies on CEA expression in cancer vary considerably for many tumor types. For example, reported CEA positivity rates ranged from 17% to 100% of pulmonary adenocarcinoma [17,18], 0% to 54% of malignant mesothelioma [15,19], 0% to 100% of hepatocellular carcinoma [20,21], 29% to 100% of colorectal adenocarcinoma [22,23], 25% to 100% of different subtypes of gastric adenocarcinoma [24,25,26,27,28,29], 0% to 100% of cholangiocarcinoma [20,30], 0% to 71% of endometrioid endometrial carcinoma [31,32], 9% to 58% of small-cell carcinoma of the lung [33,34], 0% to 100% of mucinous carcinoma of the ovary [35,36], and 14% to 94% of invasive breast carcinoma of no special type [37,38]. Technical factors, including staining protocols and antibodies used and differences in the definition of thresholds determining positivity, as well as possible selection bias with respect to the analyzed tumors, may have caused these discrepancies. A comprehensive study analyzing as many tumor types as possible under standardized experimental conditions and analysis criteria is, therefore, highly warranted.

Using IHC in a tissue microarray (TMA) format, more than 15,000 tissue samples from 120 different tumor types and subtypes, and 76 non-neoplastic tissues were analyzed, allowing us to better understand the relative importance of CEA expression in various cancers and normal tissues.

2. Materials and Methods

2.1. Tissue Microarrays (TMAs)

The normal tissue TMA was composed of 8 samples from 8 different donors for each of 76 different normal tissue types (608 samples on one slide). The cancer TMAs contained a total of 15,413 primary tumors from 120 tumor types and subtypes. Detailed histopathological and molecular data on grade, pathological tumor stage (pT), pathological lymph node status (pN), HER2, estrogen receptor (ER),progesterone receptor (PR) status, and mismatch repair protein status were available from subsets of adenocarcinomas of the colon (n = 2351), the pancreas (n = 598), and the stomach (n = 327); invasive breast carcinomas of no special type (n = 1208); urothelial bladder carcinomas (n = 1663); endometrioid endometrial carcinomas (n = 182); and endometrioid (n = 40) and serous carcinoma of the ovary (n = 369). Clinical follow-up data (overall survival) were available from 877 breast cancer patients, with a median follow-up time of 49 months (range 1–88 months). The composition of both normal and cancer TMAs is described in detail in the Section 3. All samples were from the archives of the Institutes of Pathology, University Hospital of Hamburg, Germany; the Institute of Pathology, Clinical Center Osnabrueck, Germany; or the Department of Pathology, Academic Hospital, Fuerth, Germany. Tissues were fixed in 4% buffered formalin and then embedded in paraffin. The TMA manufacturing process was described earlier in detail [39,40]. In brief, one tissue spot (diameter: 0.6 mm) was transmitted from a cancer-containing donor block in an empty recipient paraffin block. The use of archived remnants of diagnostic tissues for manufacturing of TMAs, and their analysis for research purposes, as well as patient data analyses, have been approved by local laws (HmbKHG, §12) and by the local ethics committee (Ethics commission Hamburg, WF-049/09). All work has been carried out in compliance with the Helsinki Declaration.

2.2. Immunohistochemistry (IHC)

Freshly prepared TMA sections were immunostained on one day in one experiment. Slides were deparaffinized with xylol, rehydrated through a graded alcohol series and exposed to heat-induced antigen retrieval for 5 min in an autoclave at 121 °C in pH 9.0 DakoTarget Retrieval SolutionTM (Agilent, Santa Clara, CA, USA; #S2367). Endogenous peroxidase activity was blocked with Dako Peroxidase Blocking SolutionTM (Agilent #52023) for 10 min. Primary antibody specific against CEA protein (rabbit recombinant, MSVA-465R, MS Validated Antibodies, Hamburg, Germany; #2563-465R) was applied at 37 °C for 60 min at a dilution of 1:150. Bound antibody was visualized using the EnVision KitTM (Agilent #K5007) according to the manufacturer’s directions. For the purpose of antibody validation, the normal tissue TMA was also analyzed by an additional CEA antibody (monoclonal mouse, II-7, Agilent #M7072) on a Agilent DAKO autostainer Link48 according to a protocol suggested by Agilent DAKO. The sections were counterstained with hemalaun. For tumor tissues, the percentage of CEA-positive tumor cells was estimated and the staining intensity was semi-quantitatively recorded (0, 1+, 2+, 3+). For statistical analyses, the staining results were categorized into four groups as follows: negative, no staining at all; weak staining, staining intensity of 1+ in ≤70% or staining intensity of 2+ in ≤30% of tumor cells; moderate staining, staining intensity of 1+ in >70%, staining intensity of 2+ in >30% but in ≤70%, or staining intensity of 3+ in ≤30% of tumor cells; and strong staining: staining intensity of 2+ in >70% or staining intensity of 3+ in >30% of tumor cells.

2.3. Statistics

Statistical calculations were performed with JMP 16 software (SAS Institute Inc., Cary, NC, USA). Contingency tables and the chi2 test were performed to search for associations between CEA immunostaining and tumor phenotype. Overall survival curves were calculated according to Kaplan–Meier. The Log-Rank test was applied to detect significant differences between groups. A p-value of ≤0.05 was considered to be statistically significant.

3. Results

3.1. Technical Issues

In our TMA analysis, a total of 13,725 (89.0%) of 15,413 tumor samples and over three samples for each normal tissue category were analyzable. Non-analyzable samples showed absence of tissue or lack of indisputable tumor cells in their respective TMA spots.

3.2. CEA in Normal Tissues

For MSVA-465R, a moderate-to-strong CEA immunostaining was seen, particularly in the upper layers of the non-keratinizing (but not keratinizing) squamous epithelium, irrespective of the location. In the skin, eccrine glands showed a luminal membrane staining. Strong CEA staining occurred in the transitional epithelium of the anal canal and in most cells of Hassall’s corpuscles in the thymus. The strongest CEA staining in the gastrointestinal tract was seen in the colorectal mucosa, where the staining was strongest in the surface cells and the upper half of crypts. Stomach mucosa surface cell layers showed a moderate-to-strong CEA positivity, while glands were either negative or much less stained. Duodenum and small intestine showed a moderate staining of a subset of goblet cells, primarily at the surface epithelium, while deeper glands were mostly negative. A weak-to-moderate staining occurred at the apical membranes of a fraction of (mainly) mucinous cells in salivary glands. A variable CEA staining occurred in respiratory epithelium, primarily in goblet cells. A significant fraction of pneumocytes also showed an apical membrane positivity. Urothelium was usually CEA-negative but occasionally showed a variable weak staining of umbrella cells. Representative images are shown in Figure 1. All of these cell types were also found to be CEA-positive by using the monoclonal mouse antibody IL-7 (Supplementary Figure S1). CEA staining was absent in mesenchymal, lymphatic, and hematopoietic cells; skin; liver; adrenal gland; kidney; gall bladder epithelium; Brunner glands; prostate; seminal vesicle; epididymis; testis; breast; placenta; endocervix; endometrium; ovary with corpus luteum and follicular cysts; thyroid; hypophysis; cerebrum; and in the cerebellum (Supplementary Table S1).

Figure 1.

Figure 1

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CEA immunostaining of normal tissues. A membranous and cytoplasmic CEA staining of variable intensity is seen in surface epithelial cells of the stomach (A), epithelial cells (predominantly at the surface) of the colon (B), goblet cells of the small intestine (C), respiratory epithelial cells (D), Hassal’s corpuscles of the thymus (E), and in superficial cell layers of the squamous epithelium of the cervix uteri (F). CEA staining is absent in tissues from the epidermis of the skin (G) and in the pancreas (H). Original magnifications 10×, spot size 600 μm.

3.3. CEA in Cancer

All cancers were analyzed with MSVA-465R. CEA immunostaining was detectable in 4323 (31.5%) of the 13,725 analyzable tumors. Weak CEA immunostaining was seen in 1076 tumors (7.8%), moderate in 425 (3.1%), and strong in 2822 (20.6%). Of the 120 tumor categories included, CEA positivity was found in 65 (54.2%) while 49 (40.8%) tumor categories showed at least one case of strong positivity (Table 1).

Table 1.

CEA immunostaining in human tumors. Abbreviations: int. = number of interpretable samples, neg. = negative, mod. = moderate, str. = strong.

CEA Immunostaining Result
Tumor Entity On TMA (n) Int. (n) Neg.
(%)		 Weak (%) Mod. (%) Str. (%)
Tumors of the skin Pilomatricoma 35 23 100.0 0.0 0.0 0.0
Basal cell carcinoma of the skin 88 80 96.3 3.8 0.0 0.0
Benign nevus 29 29 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the skin 90 90 65.6 31.1 2.2 1.1
Malignant melanoma 46 43 86.0 9.3 4.7 0.0
Merkel cell carcinoma 46 42 100.0 0.0 0.0 0.0
Tumors of the head and neck Squamous cell carcinoma of the larynx 109 103 46.6 30.1 7.8 15.5
Squamous cell carcinoma of the pharynx 60 58 60.3 22.4 5.2 12.1
Oral squamous cell carcinoma (floor of the mouth) 130 126 69.8 17.5 7.1 5.6
Pleomorphic adenoma of the parotid gland 50 39 82.1 15.4 2.6 0.0
Warthin tumor of the parotid gland 49 49 91.8 8.2 0.0 0.0
Basal cell adenoma of the salivary gland 15 15 93.3 6.7 0.0 0.0
Tumors of the lung, pleura, and thymus Adenocarcinoma of the lung 196 179 26.3 19.6 8.9 45.3
Squamous cell carcinoma of the lung 80 71 46.5 28.2 5.6 19.7
Small-cell carcinoma of the lung 16 14 35.7 0.0 7.1 57.1
Mesothelioma, epithelioid 39 28 100.0 0.0 0.0 0.0
Mesothelioma, biphasic 76 62 100.0 0.0 0.0 0.0
Thymoma 29 28 100.0 0.0 0.0 0.0
Lung, neuroendocrine tumor (NET) 19 18 100.0 0.0 0.0 0.0
Tumors of the female genital tract Squamous cell carcinoma of the vagina 78 71 57.7 25.4 9.9 7.0
Squamous cell carcinoma of the vulva 130 119 60.5 30.3 2.5 6.7
Squamous cell carcinoma of the cervix 129 123 30.9 23.6 13.8 31.7
Endometrioid endometrial carcinoma 236 227 80.6 18.1 0.4 0.9
Endometrial serous carcinoma 82 68 82.4 17.6 0.0 0.0
Carcinosarcoma of the uterus 48 46 91.3 4.3 2.2 2.2
Endometrial carcinoma, high grade, G3 13 13 92.3 7.7 0.0 0.0
Endometrial clear cell carcinoma 8 8 87.5 12.5 0.0 0.0
Endometrioid carcinoma of the ovary 110 95 76.8 15.8 2.1 5.3
Serous carcinoma of the ovary 559 499 98.0 1.8 0.2 0.0
Mucinous carcinoma of the ovary 96 84 20.2 28.6 17.9 33.3
Clear cell carcinoma of the ovary 50 43 93.0 4.7 0.0 2.3
Carcinosarcoma of the ovary 47 44 95.5 4.5 0.0 0.0
Brenner tumor 9 9 100.0 0.0 0.0 0.0
Tumors of the breast Invasive breast carcinoma of no special type 1345 1042 72.2 13.1 5.4 9.4
Lobular carcinoma of the breast 293 193 79.3 8.8 5.7 6.2
Medullary carcinoma of the breast 26 19 94.7 5.3 0.0 0.0
Tubular carcinoma of the breast 27 19 89.5 0.0 0.0 10.5
Mucinous carcinoma of the breast 58 44 56.8 11.4 6.8 25.0
Phyllodes tumor of the breast 50 43 100.0 0.0 0.0 0.0
Tumors of the digestive system Adenomatous polyp, low-grade dysplasia 50 50 0.0 0.0 8.0 92.0
Adenomatous polyp, high-grade dysplasia 50 47 0.0 0.0 8.5 91.5
Adenocarcinoma of the colon 1882 1773 1.3 2.1 3.3 93.3
Gastric adenocarcinoma, diffuse type 176 149 32.2 12.1 8.1 47.7
Gastric adenocarcinoma, intestinal type 174 161 25.5 15.5 14.9 44.1
Gastric adenocarcinoma, mixed type 62 54 38.9 13.0 9.3 38.9
Adenocarcinoma of the esophagus 83 79 29.1 16.5 6.3 48.1
Squamous cell carcinoma of the esophagus 76 69 65.2 14.5 10.1 10.1
Squamous cell carcinoma of the anal canal 89 80 52.5 23.8 3.8 20.0
Cholangiocarcinoma 113 107 72.9 12.1 6.5 8.4
Hepatocellular carcinoma 50 50 100.0 0.0 0.0 0.0
Ductal adenocarcinoma of the pancreas 612 553 19.7 20.3 10.8 49.2
Pancreatic/Ampullary adenocarcinoma 89 81 22.2 18.5 11.1 48.1
Acinar cell carcinoma of the pancreas 16 15 80.0 6.7 6.7 6.7
Gastrointestinal stromal tumor (GIST) 50 46 100.0 0.0 0.0 0.0
Appendix, neuroendocrine tumor (NET) 22 15 80.0 6.7 0.0 13.3
Colorectal, neuroendocrine tumor (NET) 12 12 100.0 0.0 0.0 0.0
Ileum, neuroendocrine tumor (NET) 49 45 97.8 2.2 0.0 0.0
Pancreas, neuroendocrine tumor (NET) 97 89 91.0 2.2 2.2 4.5
Colorectal, neuroendocrine carcinoma (NEC) 12 10 70.0 10.0 0.0 20.0
Gallbladder, neuroendocrine carcinoma (NEC) 4 4 100.0 0.0 0.0 0.0
Pancreas, neuroendocrine carcinoma (NEC) 14 14 92.9 0.0 0.0 7.1
Tumors of the urinary system Non-invasive papillary urothelial ca., pTa G2 low grade 177 141 94.3 5.0 0.0 0.7
Non-invasive papillary urothelial ca., pTa G2 high grade 141 116 75.0 20.7 0.9 3.4
Non-invasive papillary urothelial carcinoma, pTa G3 187 116 66.4 26.7 3.4 3.4
Urothelial carcinoma, pT2-4 G3 1206 835 70.1 19.2 4.7 6.1
Small-cell neuroendocrine carcinoma of the bladder 20 18 61.1 16.7 5.6 16.7
Sarcomatoid urothelial carcinoma 25 21 85.7 9.5 0.0 4.8
Clear cell renal cell carcinoma 857 835 100.0 0.0 0.0 0.0
Papillary renal cell carcinoma 255 242 100.0 0.0 0.0 0.0
Clear cell (tubulo) papillary renal cell carcinoma 21 21 100.0 0.0 0.0 0.0
Chromophobe renal cell carcinoma 131 127 100.0 0.0 0.0 0.0
Oncocytoma of the kidney 177 165 100.0 0.0 0.0 0.0
Tumors of the male genital organs Adenocarcinoma of the prostate, Gleason 3 + 3 83 83 100.0 0.0 0.0 0.0
Adenocarcinoma of the prostate, Gleason 4 + 4 80 78 91.0 7.7 0.0 1.3
Adenocarcinoma of the prostate, Gleason 5 + 5 85 85 98.8 1.2 0.0 0.0
Adenocarcinoma of the prostate (recurrence) 258 248 87.9 10.1 0.8 1.2
Small-cell neuroendocrine carcinoma of the prostate 19 16 50.0 18.8 6.3 25.0
Seminoma 621 613 100.0 0.0 0.0 0.0
Embryonal carcinoma of the testis 50 44 100.0 0.0 0.0 0.0
Yolk sac tumor 50 37 94.6 5.4 0.0 0.0
Teratoma 50 45 88.9 4.4 4.4 2.2
Squamous cell carcinoma of the penis 80 76 67.1 19.7 7.9 5.3
Tumors of endocrine organs Adenoma of the thyroid gland 113 107 100.0 0.0 0.0 0.0
Papillary thyroid carcinoma 391 384 99.7 0.3 0.0 0.0
Follicular thyroid carcinoma 154 152 98.0 0.0 0.0 2.0
Medullary thyroid carcinoma 111 107 3.7 0.9 3.7 91.6
Anaplastic thyroid carcinoma 45 42 100.0 0.0 0.0 0.0
Adrenal cortical adenoma 50 45 100.0 0.0 0.0 0.0
Adrenal cortical carcinoma 26 25 96.0 0.0 4.0 0.0
Pheochromocytoma 50 49 100.0 0.0 0.0 0.0
Tumors of hematopoetic and lymphoid tissues Hodgkin lymphoma 103 98 100.0 0.0 0.0 0.0
Small lymphocytic lymphoma, B-cell type (B-SLL/B-CLL) 50 50 100.0 0.0 0.0 0.0
Diffuse large B cell lymphoma (DLBCL) 113 113 100.0 0.0 0.0 0.0
Follicular lymphoma 88 88 100.0 0.0 0.0 0.0
T-cell non-Hodgkin lymphoma 25 25 100.0 0.0 0.0 0.0
Mantle cell lymphoma 18 18 100.0 0.0 0.0 0.0
Marginal zone lymphoma 16 16 100.0 0.0 0.0 0.0
Diffuse large B-cell lymphoma (DLBCL) in the testis 16 16 100.0 0.0 0.0 0.0
Burkitt lymphoma 5 3 100.0 0.0 0.0 0.0
Tumors of soft tissue and bone Tenosynovial giant cell tumor 45 44 100.0 0.0 0.0 0.0
Granular cell tumor 53 45 100.0 0.0 0.0 0.0
Leiomyoma 50 49 100.0 0.0 0.0 0.0
Leiomyosarcoma 87 87 100.0 0.0 0.0 0.0
Liposarcoma 132 123 100.0 0.0 0.0 0.0
Malignant peripheral nerve sheath tumor (MPNST) 13 13 100.0 0.0 0.0 0.0
Myofibrosarcoma 26 26 100.0 0.0 0.0 0.0
Angiosarcoma 73 68 100.0 0.0 0.0 0.0
Angiomyolipoma 91 89 100.0 0.0 0.0 0.0
Dermatofibrosarcoma protuberans 21 18 100.0 0.0 0.0 0.0
Ganglioneuroma 14 14 100.0 0.0 0.0 0.0
Kaposi sarcoma 8 5 100.0 0.0 0.0 0.0
Neurofibroma 117 114 100.0 0.0 0.0 0.0
Sarcoma, not otherwise specified (NOS) 74 71 100.0 0.0 0.0 0.0
Paraganglioma 41 41 100.0 0.0 0.0 0.0
Ewing sarcoma 23 16 100.0 0.0 0.0 0.0
Rhabdomyosarcoma 6 6 100.0 0.0 0.0 0.0
Schwannoma 121 118 100.0 0.0 0.0 0.0
Synovial sarcoma 12 11 100.0 0.0 0.0 0.0
Osteosarcoma 43 37 100.0 0.0 0.0 0.0
Chondrosarcoma 38 21 100.0 0.0 0.0 0.0
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Examples for particularly high positivity rates and high levels of expression were colorectal adenomas (100% positive) and adenocarcinomas (98.7%), other gastrointestinal adenocarcinomas (61.1–80.3%), medullary thyroid carcinomas (96.3%), adenocarcinoma of the lung (73.7%), mucinous carcinomas of the ovary (79.8%) and the breast (43.2%), squamous cell carcinomas of different sites of origin (30.2–69.1%) as well as small-cell carcinomas of the lung (64.3%), the prostate (50.0%), and the urinary bladder (38.9%). In many of these tumor types, CEA expression was often stronger than in the corresponding normal tissues. Figure 2 shows representative images. Figure 3 gives a graphical representation of the ranking order of CEA-positive and strongly positive tumors. Associations between CEA immunostaining and histopathological features are shown in Table 2. High CEA expression was associated with advanced pT stage (p < 0.0001) and muscle-invasive growth (p < 0.0001) in urinary bladder cancer. In invasive breast carcinomas of no special type, high CEA expression was linked to ER positivity (p = 0.0005) and HER2 positivity (p < 0.0001) but was unrelated to grade, pT, pN, and overall survival (p = 0.2520, Figure 4). Reduced CEA expression was associated with defective mismatch repair status (dMMR; p < 0.0001), BRAF V600E mutations (p = 0.0498), and tumor localization in the right colon (p = 0.0024) in colorectal adenocarcinoma. There was no association of the CEA expression level to histopathological, molecular, or clinical tumor characteristics in pancreatic and gastric adenocarcinomas, or endometroid endometrium carcinoma. A combined analysis of 524 squamous cell carcinomas from nine different sites showed a link between HPV infection and CEA positivity (p = 0.0281; Supplementary Table S2) but subgroup analysis by organs of origins did not show significant associations between HPV status and CEA expression levels.

Figure 2.

Figure 2

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CEA immunostaining in cancer. The panels show a strong CEA staining in an adenocarcinoma of the colon (A), an adenocarcinoma of the esophagus (B), a ductal adenocarcinoma of the pancreas (C), a cholangiocellular carcinoma of the liver (D), a small-cell neuroendocrine carcinoma of the lung (E), and an adenocarcinoma of the lung (F). CEA staining is lacking in a malignant mesothelioma of the pleura (H) and a hepatocellular carcinoma in the liver (G). Original magnifications 10×, spot size 600 μm.

Figure 3.

Figure 3

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Ranking order of CEA immunostaining in cancers. Both the percentage of positive cases (blue dots) and the percentage of strongly positive cases (orange dots) are shown.

Table 2.

CEA immunostaining and cancer phenotype.

CEA Immunostaining Result
n Negative (%) Weak (%) Moderate (%) Strong (%) p
Invasive breast carcinoma of no special type pT1 491 75.2 12.0 5.3 7.5 0.5044
pT2 369 70.5 13.6 5.1 10.8
pT3–4 80 68.8 15.0 3.8 12.5
G1 153 78.4 10.5 5.2 5.9 0.1972
G2 472 69.9 14.0 6.6 9.5
G3 345 74.2 12.5 3.5 9.9
pN0 269 71.4 18.2 5.6 4.8 0.6430
pN+ 171 66.7 20.5 8.2 4.7
pM0 137 70.1 16.8 5.1 8.0 0.8864
pM1 93 66.7 17.2 7.5 8.6
HER2 negative 771 74.2 11.9 5.1 8.8 0.0158
HER2 positive 113 62.8 23.0 3.5 10.6
ER negative 184 83.7 8.7 2.2 5.4 0.0005
ER positive 662 68.9 15.4 6.0 9.7
PR negative 351 74.6 12.8 4.0 8.5 0.6741
PR positive 527 71.5 13.7 5.5 9.3
Non-triple negative 701 68.9 15.4 5.6 10.1 <0.0001
Triple negative 123 91.1 4.1 2.4 2.4
Urothelial bladder carcinoma pTa G2 low 143 93.0 5.6 0.0 1.4 <0.0001
pTa G2 high 116 75.0 20.7 0.9 3.4
pTa G3 116 66.4 26.7 3.4 3.4
pT2 136 69.1 20.6 2.9 7.4 0.0167
pT3 216 69.0 16.2 10.6 4.2
pT4 97 76.3 17.5 2.1 4.1
G2 22 68.2 22.7 4.5 4.5 0.9255 *
G3 427 70.7 17.6 6.6 5.2
pN0 253 72.7 17.0 5.5 4.7 0.4985 *
pN+ 170 66.5 20.6 8.2 4.7
Adenocarcinoma of the pancreas pT1 14 21.4 14.3 7.1 57.1 0.4277
pT2 70 10.0 27.1 11.4 51.4
pT3 373 20.6 19.0 10.7 49.6
pT4 29 17.2 27.6 17.2 37.9
G1 16 18.8 18.8 12.5 50.0 0.9969
G2 344 18.9 19.5 11.3 50.3
G3 104 19.2 22.1 9.6 49.0
pN0 106 19.8 17.9 13.2 49.1 0.7820
pN+ 379 18.5 21.4 10.6 49.6
R0 249 18.5 20.9 11.6 49.0 0.8254
R1 198 18.2 20.7 9.1 52.0
MMR proficient 440 19.3 20.7 11.8 48.2 0.2974
MMR deficient 4 0.0 50.0 25.0 25.0
Adenocarcinoma of the stomach pT1–2 57 31.6 8.8 10.5 49.1 0.6383
pT3 110 33.6 11.8 9.1 45.5
pT4 106 24.5 16.0 13.2 46.2
pN0 68 27.9 8.8 19.1 44.1 0.1081
pN+ 204 30.9 13.7 8.3 47.1
MMR proficient 232 30.6 13.8 9.9 45.7 0.0899
MMR deficient 37 18.9 16.2 24.3 40.5
Endometrioid endometrial carcinoma pT1 115 79.1 20.0 0.0 0.9 0.3498
pT2 24 83.3 12.5 4.2 0.0
pT3–4 35 88.6 11.4 0.0 0.0
pN0 50 80.0 20.0 0.0 0.0 0.7254
pN+ 30 76.7 23.3 0.0 0.0
Endometrioid carcinoma of the ovary pT1 23 82.6 17.4 0.0 0.0 0.2037
pT2 5 60.0 20.0 0.0 20.0
pT3 6 50.0 33.3 0.0 16.7
pN0 21 71.4 28.6 0.0 0.0 0.0516
pN1 8 62.5 12.5 0.0 25.0
Serous carcinoma of the ovary pT1 32 100.0 0.0 0.0 0.0 0.2000
pT2 44 95.5 4.5 0.0 0.0
pT3 255 99.2 0.8 0.0 0.0
pN0 83 100.0 0.0 0.0 0.0 0.1147
pN1 163 98.2 1.8 0.0 0.0
Adenocarcinoma of the colon pT1 66 3.0 0.0 3.0 93.9 0.5369
pT2 336 1.2 2.4 2.7 93.8
pT3 936 1.3 1.7 3.4 93.6
pT4 345 1.2 3.5 2.9 92.5
pN0 877 1.0 1.5 3.2 94.3 0.1474
pN+ 790 1.6 2.9 3.0 92.4
V0 1225 1.1 2.2 3.1 93.6 0.6785
V1 432 1.9 2.1 3.2 92.8
L0 629 1.1 1.3 2.7 94.9 0.1296
L1 1013 1.5 2.8 3.5 92.3
Right side 454 2.4 3.3 4.6 89.6 0.0024
Left side 1237 0.8 1.8 2.6 94.8
MMR proficient 1162 0.6 1.3 2.0 96.1 <0.0001
MMR deficient 88 5.7 11.4 13.6 69.3
RAS wildtype 468 0.9 2.8 3.0 93.4 0.7409
RAS mutation 355 1.1 2.3 2.0 94.6
BRAF wildtype 124 0.8 3.2 1.6 94.4 0.0498
BRAF V600E mutation 21 0.0 9.5 14.3 76.2
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* only in pT2–4 urothelial bladder carcinomas. Abbreviations: pT, pathological tumor stage; G, Grade; pN, pathological lymph node status; pM, pathological status of distant metastasis; R, resection margin status; V, venous invasion; L, lymphatic invasion; PR, progesterone receptor; ER, estrogen receptor; MMR, mismatch repair.

Figure 4.

Figure 4

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CEA immunostaining and patient prognosis in invasive breast carcinoma of no special type.

4. Discussion

The importance of CEA as a cancer-related protein is reflected by more than 3000 Medline articles meeting the search terms “CEA + immunohistochemistry + cancer” (pubmed_January 2023). The articles generally agree on colorectal adenocarcinoma being the cancer entity most commonly CEA-positive, but data on the prevalence of CEA expression vary considerably in other tumor types. Based on our highly standardized analysis of 120 tumor types and subtypes, we were able to create a ranking order of human tumors according to the prevalence of CEA expression (Figure 3), which allows for a direct comparison of CEA positivity obtained under identical experimental conditions. A collection of data from the literature (Figure 5, Supplementary Table S3) demonstrates that such information could not easily be retrieved from the literature.

Figure 5.

Figure 5

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Comparison of CEA expression with previous works in the literature. An “X” represents the proportion of CEA-positive cancers in the present study, dots indicate the frequencies reported in the literature for comparison: studies with ≤10 tumors analyzed are marked with red dots, studies with 11 to 25 tumors analyzed are marked with yellow dots, and green dots mark studies with >25 tumors analyzed.

Although—in line with our data—multiple studies showed high rates of CEA positivity in tumor types arising from epithelial tissues, including gastrointestinal adenocarcinomas, medullary carcinomas of the thyroid, adenocarcinomas of the lung, and squamous cell carcinomas of various origins, as well as in small-cell carcinomas, there were also numerous studies suggesting much lower positivity rates in these tumor types. Moreover, our data identified low CEA positivity rates in several tumor entities for which high CEA expression levels were suggested in multiple earlier studies, such as, for example, in high-grade serous carcinomas of the ovary [41], or prostatic adenocarcinomas [42]. That high levels of CEA expression can be observed in many different tumor entities is consistent with data summarized in The Cancer Genome Atlas (TCGA) database (www.cancer.gov, data available from https://www.proteinatlas.org/ENSG00000105388-CEACAM5/summary/rna, accessed on 21 November 2024).

Considering the high expression levels of CEA in various tumor entities and the relatively low CEA levels in normal tissues, CEA represents an attractive therapeutic target. However, previous attempts at targeting CEA by using humanized anti-CEA antibodies showed disappointing results. It is assumed that in cancers with high serum CEA levels, the therapeutic antibodies are prevented from reaching the tumor cells, as they bind to circulating CEA (summarized in [43]). Promising recent approaches include developing a vaccination (summarized in [44]) and the generation of CAR-T cells (summarized in [45]) targeting CEA. CEA-targeting drugs are currently studied in more than 200 phase I and II clinical trials. Included in these studies are colorectal, breast, esophageal, stomach, lung, gastric, and pancreatic carcinomas as well as CEA-positive tumors regardless of their sites of origin (www.clinicaltrials.gov). If one of these treatment approaches should become clinically available, our ranking order of tumors based on their CEA positivity rates could help to determine the tumor entities for which such approaches would be most beneficial.

Our data support two important diagnostic applications of CEA IHC. The complete CEA-negativity of all our 90 malignant mesotheliomas while 74% of the 179 pulmonary adenocarcinomas were CEA-positive supports the use of CEA IHC for the distinction of malignant mesothelioma from pulmonary adenocarcinoma. Panels that have been proposed for this application also include calretinin, D2-40, WT1, cytokeratin 5/6, D2-40, EpCAM, TTF-1, Ber-EP4/MOC31, and Napsin A [46]. Total absence of CEA staining in all 50 hepatocellular carcinomas analyzed in this study supports the concept of using CEA as a marker for the distinction of primary tumors from metastases in the liver [16]. This is all the more useful, as carcinomas from the entire gastrointestinal tract—the most common source of liver metastases—were often CEA-positive. The high rate of CEA-positive hepatocellular carcinomas described in several previous studies is likely due to the use of less specific and/or polyclonal CEA antibodies, which leads to positivity rates between 15–100% [30,47,48,49]. Previous studies with monoclonal CEA antibodies identified a CEA positivity in 0–55% of hepatocellular carcinomas [35,48,49,50].

For several of our tumor categories, the large number of tumors analyzed allowed an analysis of the potential clinical significance of CEA expression. The strong link between a reduced CEA expression and dMMR in colorectal cancer, in which 96% of mismatch repair-proficient (pMMR) but only 69% of dMMR cancers showed strong CEA staining is in agreement with data from Schiemann et al. [51] finding lower CEA serum levels in colorectal cancer patients with hereditary non-polyposis colorectal carcinomas than found in those with sporadic carcinomas. However, another study showed only a marginal difference between dMMR (67% negative) and pMMR (58%) colorectal carcinomas [52] while three further studies found no difference in CEA immunostaining between dMMR and pMMR carcinomas [53,54,55]. Given the abundance of DNA mutations in microsatellite instable/dMMR cancers, it appears possible that functionally relevant DNA alterations of genes that directly or indirectly regulate CEA expression may cause the reduced CEA expression in a subset of dMMR cancers. The absence of clear-cut associations with histopathological parameters of tumor aggressiveness in several tumor entities and the lack of a prognostic significance in invasive breast cancers of no special type strongly argues against a strong and clinically relevant prognostic role of CEA expression in cancer and suggests that CEA upregulation may parallel tumor development in various cancer types. This interpretation is supported by controversial results of previous studies. Although there were more than 18 studies suggesting an unfavorable tumor phenotype or poor prognosis for tumors with high CEA expression, there were at least 24 studies denying such a role of CEA expression (Supplementary Table S4). Similarly controversial data were seen for specific tumor entities. For example, in colorectal adenocarcinomas, eight studies linked high CEA expression to unfavorable tumor features and/or prognosis while six studies found no association between CEA immunostaining and tumor phenotype and/or prognosis (Supplementary Table S4).

CEA mainly functions as a serum marker for colorectal cancer. Serial CEA serum measurements were recommended in a 2014 update of the European group on tumor marker guidelines for postoperative surveillance of UICC stage II and III patients considered for surgical resection or systemic therapy in case of distant metastasis and for monitoring response to treatment in advanced disease [56]. High preoperative [57] and postoperative [58] serum CEA levels have also been suggested as a prognostic tool in colorectal cancer. Given the abundant and homogeneous expression of CEA in most colorectal cancers, this is likely due to a link between CEA serum levels, tumor burden, and residual disease. Our findings demonstrate that similarly high levels of tumoral CEA expression can occur in many other tumor types, at least in a significant fraction of cases. Given the close to 100% prevalence of CEA expression in colorectal cancer, serological CEA monitoring obviously does not require CEA analysis in tumor tissue. It appears possible, however, that an immunohistochemical tumor tissue analysis documenting high-level CEA expression in a non-colorectal cancer could identify individual patients for whom CEA serum levels would also be suited for monitoring response to therapy and early detection of tumor relapse. Various studies suggested a clinical utility of CEA serum assessment in gastric [59], pancreatic [60], non-small-cell lung [61], and breast cancer [62], although the majority of these studies did not improve patient selection by immunohistochemical CEA analysis of the tumor tissue.

Regarding the large scale of our study, a particular emphasis was placed on the validation of our staining procedure, which was conducted according to the methods proposed by the International Working Group for Antibody Validation (IWGAV). In these guidelines, a comparison with expression data obtained by an additional independent method or a second independent antibody are suggested [63]. Both methods were applied in this study. CEA IHC in 76 different normal tissues was first compared with RNA expression data compiled from the Human Protein Atlas RNA-seq tissue dataset [64], the Functional Annotation of the Mammalian Genome (FANTOM5) project [65,66], and the Genotype-Tissue Expression (GTEx) project [67]. Our normal tissue analysis revealed CEA immunostaining in 10 of 12 organs for which RNA expression had been described (rectum, colon, appendix, small intestine, duodenum, stomach, salivary gland, tonsil, cervix, and lung). Only two organs with documented RNA expression did not show CEA immunostaining (esophagus, smooth muscle). As esophagus and smooth muscle can both be adjacent to CEA-expressing epithelium, these RNA findings may reflect contaminations. In the—CEA RNA negative—thymus and the skin, CEA immunostaining was limited to very small subpopulations that might have been missed in RNA analyses of entire organs. For two other CEA IHC positive tissues (bronchus, anal canal), RNA data were unavailable. The comparison with an independent second antibody (IL-7) confirmed CEA protein expression in bronchus, anal canal, thymus, and the skin, as well as in all other cell types identified as CEA-positive by MSVA-465R.

5. Conclusions

The comprehensive list of CEA positivity across human tumor types shows that CEA is abundantly expressed in a broad range of epithelial neoplasms and serves as a basis for potential future research. Our data identify these tumor entities where most CEA-positive cancers might benefit from CEA serum monitoring and anti-CEA therapies. However, the level of CEA expression does not appear to be largely related to cancer aggressiveness.

Acknowledgments

We are grateful to Melanie Steurer, Laura Behm, Inge Brandt, and Sünje Seekamp for excellent technical assistance.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers16234052/s1. Supplementary Figure S1: IHC validation by comparison of antibodies. The panels show a concordance of immunostaining results obtained by two independent CEA antibodies. Using MSVA-465R, a cytoplasmic or membranous CEA positivity was seen in a fraction of squamous epithelial cells (A), a fraction of cells in Hassal’s corpuscles (black arrow) of the thymus (B), superficial epithelial cells of the colon (C), respiratory epithelial cells (D), a fraction of alveolar cells in the lung (E), eccrine glands of the skin (F), a fraction of glandular cells in the submandibular gland (G), and some goblet cells of the small intestine (H). Using II-7, a comparable staining was seen in squamous epithelium (I), Hassal’s corpuscles (K), colon (L), respiratory epithelium (M), the lung (N), eccrine glands (O), the submandibular gland (P), and the small intestine (Q). The images A–H and I–Q are from consecutive tissue sections. Supplementary Table S1: CEA immunostaining in normal tissue. Supplementary Table S2: CEA immunostaining and HPV status in squamous cell carcinomas of different sites of origin. Supplementary Table S3: Summary of previous CEA immunostaining studies in tumors. Supplementary Table S4: Summary of previous CEA prognosis studies in tumors.

cancers-16-04052-s001.zip (665.7KB, zip)

Author Contributions

K.J., L.K., M.K., R.S., G.S. and C.B.: contributed to conception, design, data collection, data analysis, and manuscript writing. M.L., S.D.R., S.K., V.R., F.V., A.A.B., C.F., N.G., A.M.L., A.M., R.U., T.K., A.H., F.J., E.B., S.S., A.H.M., T.S.C., D.D., P.L. and S.M.: participated in pathology data analysis, data interpretation, and collection of samples. R.S., M.K. and C.H.-M.: data analysis. C.B., R.S. and G.S.: study supervision. All authors agree to be accountable for the content of the work. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

The usage of archived diagnostic leftover tissues for manufacturing of TMAs and their analysis for research purposes, as well as patient data analyses, have been approved by local laws (HmbKHG, §12,1) and by the local ethics committee (Ethics commission Hamburg, WF-049/09). All work has been carried out in compliance with the Helsinki Declaration.

Informed Consent Statement

Patient consent was waived due to local laws (HmbKHG, §12.1) that permit research with anonymized diagnostic leftover tissue samples.

Data Availability Statement

All data generated or analyzed during this study are included in this published article.

Conflicts of Interest

The rabbit recombinant antibody, clone MSVA-465R was provided from MS Validated Antibodies GmbH (owned by a family member of GS). All other authors declare no conflicts of interest.

Funding Statement

This research received no external funding.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

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Associated Data

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Supplementary Materials

cancers-16-04052-s001.zip (665.7KB, zip)

Data Availability Statement

All data generated or analyzed during this study are included in this published article.

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