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. 2021 Apr 7;9(4):397. doi: 10.3390/biomedicines9040397

Mesothelin Expression in Human Tumors: A Tissue Microarray Study on 12,679 Tumors

Sören Weidemann 1, Pauline Gagelmann 1, Natalia Gorbokon 1, Maximilian Lennartz 1, Anne Menz 1, Andreas M Luebke 1, Martina Kluth 1, Claudia Hube-Magg 1, Niclas C Blessin 1, Christoph Fraune 1, Katharina Möller 1, Christian Bernreuther 1, Patrick Lebok 1, Till S Clauditz 1, Frank Jacobsen 1, Jakob R Izbicki 2, Kristina Jansen 2, Guido Sauter 1, Ria Uhlig 1, Waldemar Wilczak 1, Stefan Steurer 1, Sarah Minner 1, Eike Burandt 1, Rainer H Krech 3, David Dum 1, Till Krech 1,3, Andreas H Marx 1,4, Ronald Simon 1,*
Editor: Paola Maroni
PMCID: PMC8067734  PMID: 33917081

Abstract

Mesothelin (MSLN) represents an attractive molecule for targeted cancer therapies. To identify tumors that might benefit from such therapies, tissue microarrays including 15,050 tumors from 122 different tumor types and 76 healthy organs were analyzed for MSLN expression by immunohistochemistry. Sixty-six (54%) tumor types showed at least occasional weak staining, including 50 (41%) tumor types with at least one strongly positive sample. Highest prevalence of MSLN positivity had ovarian carcinomas (serous 97%, clear cell 83%, endometrioid 77%, mucinous 71%, carcinosarcoma 65%), pancreatic adenocarcinoma (ductal 75%, ampullary 81%), endometrial carcinomas (clear cell 71%, serous 57%, carcinosarcoma 50%, endometrioid 45%), malignant mesothelioma (69%), and adenocarcinoma of the lung (55%). MSLN was rare in cancers of the breast (7% of 1138), kidney (7% of 807), thyroid gland (1% of 638), soft tissues (0.3% of 931), and prostate (0 of 481). High expression was linked to advanced pathological tumor (pT) stage (p < 0.0001) and metastasis (p < 0.0001) in 1619 colorectal adenocarcinomas, but unrelated to parameters of malignancy in 1072 breast-, 386 ovarian-, 174 lung-, 757 kidney-, 171 endometrial-, 373 gastric-, and 925 bladder carcinomas. In summary, numerous important cancer types with high-level MSLN expression might benefit from future anti-MSLN therapies, but MSLN’s prognostic relevance appears to be limited.

Keywords: mesothelin, multi-tumor tissue micro array, immunohistochemistry

1. Introduction

The mesothelin (MSLN) gene, located at chromosome 16p13.3, encodes for a membranous precursor glycoprotein that is subsequently cleaved into the soluble 31kD protein megakaryocyte potentiating factor (MPF) and the 40kD membrane-bound protein MSLN [1,2,3]. MSLN was first described as a membrane protein expressed in normal and neoplastic mesothelial cells, but subsequent studies demonstrated a broader expression pattern [1,4,5,6,7,8,9]. The function of MSLN is not fully understood. In normal cells, MSLN does not seem to be essential as a homozygous MSLN mutant mouse lacking MSLN protein developed and reproduced normally [10]. However, MSLN has been identified as a specific binding protein of cancer antigen (CA125) that mediates cell adhesion [11,12]. This interaction was suggested to play a role in the development of peritoneal metastasis [11,13]. In cell line and animal experiments, MSLN overexpression was shown to activate the PI3K/AkT, NFκB, and MAPK/ERK pathways, to hinder apoptosis and to promote cell proliferation, migration, and metastasis [14,15,16,17,18,19,20,21].

MSLN is expressed in only few normal tissues but has been found to be overexpressed in various tumor types at a relevant frequency [4,5,6,7,8,9,22]. Therefore, and due to its membranous location, MSLN represents an attractive molecule for target-specific cancer therapies. Targeted therapies use drugs to inhibit specific genes and proteins that are involved in tumor cell growth. Several therapeutic approaches, including adaptive immunotherapy (CAR-T cells, TC-210 T cells), monoclonal antibodies (Amatuximab/MORAb-009), recombinant immunotoxins (SS1P, LMB-100/RG7787), antibody-drug conjugates (Anetumab Ravtansine/BAY94-9343, DMOT4039A, BAY2287411, BMS-986148, h7D9.v3), listeria monocytogene induced anti-tumor immune response (CRS-207, JNJ-64041757), and immunocytokines (IL12-SS1) have provided encouraging data in animal models and/or clinical phase I and II trials [23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Which tumor entities might benefit most from anti-MSLN therapies is difficult to predict since the literature on MSLN expression is controversial for many tumor entities. For example, MSLN positivity has been described in 38% to 69% of lung adenocarcinomas [37,38,39], 17% to 100% of pancreatic adenocarcinomas [40,41], 2% to 68% of colorectal carcinomas [5,9,42], 55% to 100% of serous carcinomas of the ovary [43,44], 21% to 78% of gastric adenocarcinomas [5,9,45], and 3% to 36% of breast carcinomas [9,46,47]. These conflicting data are likely to be caused by the use of different antibodies, immunostaining protocols, and criteria to categorize MSLN immunostaining in these studies.

To better understand the prevalence and significance of MSLN expression in cancer, a comprehensive study analyzing a large number of neoplastic and non-neoplastic tissues under highly standardized conditions is needed. Therefore, MSLN expression was analyzed in more than 15,000 tumor tissue samples from 122 different tumor types and subtypes, as well as 76 non-neoplastic tissue categories, by immunohistochemistry (IHC) in a tissue microarray (TMA) format in this study.

2. Material 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 15,050 primary tumors from 122 tumor types and subtypes. Detailed histopathological data on grade, pathological tumor stage (pT), or pathological lymph node status (pN) were available from 7625 tumors (cancers of the colon, bladder, ovarian, endometrium, lung, stomach, breast, and kidney tumors). Clinical follow-up data were available from 1178 breast cancer, 865 kidney cancer, and 254 bladder cancer patients with a median follow-up time of 49/39/14 months (range 1–88/1–250/1–77). No data on previous therapies were available. The composition of both normal and cancer TMAs is described in detail in the results section. All samples were from the archives of the Institutes of Pathology, University Hospital of Hamburg, Germany, the Institute of Pathology, Clinical Center Osnabrueck, Germany, and 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 [48,49]. In brief, one tissue spot (diameter: 0.6 mm) was transmitted from a cancer containing donor block (≥70% cancer cells) 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 analysis, has been approved by local laws (HmbKHG, §12) and by the local ethics committee (Ethics commission Hamburg, WF-049/09, 25 January 2010). 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 DakoTarget Retrieval SolutionTM (Agilent, Santa Clara, CA, USA; #S2367). Endogenous peroxidase activity was blocked with Dako Peroxidase Blocking SolutionTM (Agilent, CA, USA; #52023) for 10 min. Primary antibody specific against MSLN protein (mouse monoclonal, MSVA-235, MS Validated Antibodies, Hamburg, Germany) was applied at 37 °C for 60 min at a dilution of 1:150. Bound antibody was then visualized using the EnVision KitTM (Agilent, CA, USA; #K5007) according to the manufacturer’s directions. The sections were counterstained with hemalaun. A trained pathologist scored all tissue spots and marked tissue spots with questionable findings for revision by a second pathologist. For normal tissues, the staining intensity of positive cells was semi-quantitively recorded (+, ++, +++). For tumor tissues, the percentage of MSLN 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, 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 14 software (SAS Institute Inc., Cary, NC, USA). Contingency tables and the chi²-test were performed to search for associations between MSLN and tumor phenotype. 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 defined as significant.

3. Results

3.1. Technical Issues

A total of 12,679 (84.2%) of 15,050 tumor samples were interpretable in the TMA analysis. The remaining 2371 (15.8%) samples were not analyzable due to the lack of unequivocal tumor cells or loss of the tissue spot during the technical procedures. On the normal tissue TMA, a sufficient number of samples was always interpretable per tissue to determine MSLN expression.

3.2. MSLN Immunostaining in Normal Tissues

In normal tissues, the strongest MSLN expression was observed in the squamous epithelium of tonsil crypts (Figure 1A), where a fraction of cells (intermediate to superficial cell layers) showed strong (+++) MSLN staining. Strong MSLN immunostaining was also seen in some cells and cell groups of the rectal mucosa (+++), the anal transitional epithelium (+++) (Figure 1B) where staining was often particularly prominent in superficial mucinous cells, amnion cells (+++) (Figure 1C) and some chorion cells (++) of the mature placenta, and some elements of corpuscles of Hassall’s of the thymus (++). A somewhat weaker MSLN staining was seen in scattered cells and groups of cells of endocervical mucosa (++) and endometrium (++), epithelial cells of fallopian tube (apical cell border and cilia; ++) (Figure 1D), some intermediate (neck) cells of the stomach antrum (+), some scattered glands in sublingual (Figure 1E) and Brunner glands, few cells of respiratory epithelium (goblet cells;++), some cells or groups of cells in bronchial glands (++), seminal vesicle (+; not in all samples), and in the cytoplasm of few cells of the adenohypophysis (+). MSLN immunostaining was absent in endothelium and media of the aorta, heart muscle, striated muscle, tongue muscle, myometrium of the uterus, muscular wall of the appendix, esophagus, ileum, kidney pelvis, and urinary bladder, corpus spongiosum of the penis, ovarian stroma, fat, skin, hair follicles and sebaceous glands of the skin, non-keratinizing squamous epithelium from the lip, oral cavity, ectocervix, and the esophagus, urothelium of the kidney pelvis and urinary bladder, spleen, antrum and corpus of the stomach, gallbladder epithelium, liver, kidney (Figure 1F), epididymis, testis, lung, decidua cells, cerebellum, cerebrum, salivary glands, prostate, breast, adrenal gland, and lymphatic tissue.

Figure 1.

Figure 1

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Mesothelin (MSLN) immunostaining in normal tissues. Among normal tissues, MSLN immunostaining is particularly strong in a fraction of squamous epithelial cells in tonsil crypts (A), the anal transitional epithelium (B) and amnion cells (C). A somewhat weaker MSLN staining is seen at the apical cell border and in cilia of fallopian tube epithelium (D) and in a fraction mucinous cells (often grouped together) in sublingual glands (E). MSLN immunostaining was consistently lacking in the kidney (F).

3.3. MSLN Immunostaining in Neoplastic Tissues

A significant MSLN immunostaining was observed in 2413 (19.0%) of 12,679 analyzable tumors, including 8.0% with weak, 3.4% with moderate, and 7.6% with strong staining intensity. The staining pattern was variable. Most positive tumors showed a predominantly apical membranous MSLN staining, often accompanied by a less intense cytoplasmic coloration. Other tumors showed a pure membranous staining or a predominantly cytoplasmic positivity. Representative images are shown in Figure 2. At least an occasional weak MSLN positivity was detected in 66 of 122 (54.1%) different tumor types and tumor subtypes and 50 (41.0%) tumor types and subtypes had at least one tumor sample exhibiting strong positivity. The highest frequencies of MSLN positivity were seen in different subtypes of ovarian (65% to 97%) and endometrium (45% to 71%) carcinomas, pancreatic adenocarcinoma (75% and 81%), malignant mesothelioma (69%), and adenocarcinoma of the lung (55%). Rare or absent MSLN positivity was observed in different subtypes of breast tumors (0% in 50 phyllodes, 0.9% in 294 lobular, 5.3% in 27 tubular, 6.6% in 1391 invasive no special type, and 10.9% in 58 mucinous subtypes), renal cell (0% in 177 oncocytomas, 1.6% in 131 chromophobe, 6.6% in 858 clear cell, and 8.7% in 255 papillary subtypes), and thyroid carcinomas (0% to 1.4%), as well as soft tissue tumors (0.3%), and adenocarcinomas of the prostate (0%). A detailed description of the immunostaining results is given in Table 1 and Figure 3.

Figure 2.

Figure 2

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Pattern of MSLN immunostaining in cancer. MSLN immunostaining was found to be strong and predominantly membranous (A) or predominantly situated at the apical/luminal cell border (B) in two serous high-grade ovarian cancers, variable but predominantly apical in a cholangiocellular carcinoma (C), strong and predominantly cytoplasmic in a diffuse type adenocarcinoma of the stomach (D), strong and predominantly membranous in a malignant (epitheloid) mesothelioma (E), and weak to moderate, cytoplasmic and membranous in a colorectal adenocarcinoma (F).

Table 1.

MSLN immunostaining in human tumors.

MSLN Immunostaining
Tumor Entity on TMA (n) Analyzable (n) Negative (%) Weak (%) Moderate (%) Strong (%) Positive (%)
Tumors of the skin Pilomatrixoma 35 31 100.0 0.0 0.0 0.0 0.0
Basal cell carcinoma 88 83 98.8 1.2 0.0 0.0 1.2
Benign nevus 29 26 100.0 0.0 0.0 0.0 0.0
Squamous cell carcinoma of the skin 90 84 95.2 4.8 0.0 0.0 4.8
Malignant melanoma 48 44 100.0 0.0 0.0 0.0 0.0
Merkel cell carcinoma 46 44 100.0 0.0 0.0 0.0 0.0
Tumors of the head and neck Squamous cell carcinoma of the larynx 110 105 80.0 11.4 3.8 4.8 20.0
Squamous cell carcinoma of the pharynx 60 57 80.7 5.3 8.8 5.3 19.3
Oral squamous cell carcinoma (floor of the mouth) 130 121 83.5 9.1 5.0 2.5 16.5
Pleomorphic adenoma of the parotid gland 50 35 57.1 20.0 5.7 17.1 42.9
Warthin tumor of the parotid gland 49 45 46.7 31.1 11.1 11.1 53.3
Basal cell adenoma of the salivary gland 15 15 66.7 33.3 0.0 0.0 33.3
Tumors of the lung, pleura, and thymus Squamous cell carcinoma of the lung 127 71 74.6 18.3 5.6 1.4 25.4
Adenocarcinoma of the lung 250 174 44.8 19.0 13.8 22.4 55.2
Small cell carcinoma of the lung 20 16 93.8 0.0 6.3 0.0 6.3
Mesothelioma, epitheloid 39 25 36.0 12.0 4.0 48.0 64.0
Mesothelioma, other types 76 65 29.2 10.8 4.6 55.4 70.8
Thymoma 29 28 96.4 0.0 0.0 3.6 3.6
Tumors of the female genital tract Squamous cell carcinoma of the vagina 78 75 88.0 4.0 2.7 5.3 12.0
Squamous cell carcinoma of the vulva 130 123 89.4 7.3 0.8 2.4 10.6
Squamous cell carcinoma of the cervix 130 125 57.6 21.6 8.0 12.8 42.4
Endometrioid endometrial carcinoma 236 220 54.5 22.3 11.8 11.4 45.5
Endometrial serous carcinoma 82 69 43.5 17.4 10.1 29.0 56.5
Carcinosarcoma of the uterus 48 46 50.0 21.7 10.9 17.4 50.0
Endometrial carcinoma, high grade, G3 13 13 61.5 23.1 0.0 15.4 38.5
Endometrial clear cell carcinoma 8 7 28.6 28.6 14.3 28.6 71.4
Endometrioid carcinoma of the ovary 115 100 23.0 28.0 19.0 30.0 77.0
Serous carcinoma of the ovary 567 511 2.7 5.1 8.4 83.8 97.3
Mucinous carcinoma of the ovary 97 80 28.8 37.5 18.8 15.0 71.3
Clear cell carcinoma of the ovary 54 42 16.7 33.3 19.0 31.0 83.3
Carcinosarcoma of the ovary 47 43 34.9 16.3 11.6 37.2 65.1
Brenner tumor 9 9 55.6 11.1 0.0 33.3 44.4
Tumors of the breast Invasive breast carcinoma of no special type 1391 1138 93.4 2.8 0.8 3.0 6.6
Lobular carcinoma of the breast 294 215 99.1 0.0 0.9 0.0 0.9
Medullary carcinoma of the breast 26 26 76.9 11.5 7.7 3.8 23.1
Tubular carcinoma of the breast 27 19 94.7 0.0 0.0 5.3 5.3
Mucinous carcinoma of the breast 58 46 89.1 4.3 0.0 6.5 10.9
Phyllodes tumor of the breast 50 36 100.0 0.0 0.0 0.0 0.0
Tumors of the digestive system Adenomatous polyp, low-grade dysplasia 50 48 72.9 16.7 8.3 2.1 27.1
Adenomatous polyp, high-grade dysplasia 50 46 56.5 30.4 8.7 4.3 43.5
Adenocarcinoma of the colon 1882 1186 58.6 29.0 6.9 5.5 41.4
Adenocarcinoma of the small intestine 10 6 0.0 50.0 16.7 33.3 100.0
Gastric adenocarcinoma, diffuse type 176 164 51.2 14.6 11.6 22.6 48.8
Gastric adenocarcinoma, intestinal type 174 170 60.6 18.8 11.2 9.4 39.4
Gastric adenocarcinoma, mixed type 62 59 50.8 25.4 10.2 13.6 49.2
Adenocarcinoma of the esophagus 133 75 58.7 14.7 18.7 8.0 41.3
Squamous cell carcinoma of the esophagus 124 71 78.9 14.1 4.2 2.8 21.1
Squamous cell carcinoma of the anal canal 91 86 75.6 14.0 2.3 8.1 24.4
Cholangiocarcinoma 114 105 78.1 4.8 4.8 12.4 21.9
Hepatocellular carcinoma 50 50 100.0 0.0 0.0 0.0 0.0
Ductal adenocarcinoma of the pancreas 130 64 25.0 12.5 21.9 40.6 75.0
Pancreatic/Ampullary adenocarcinoma 58 26 19.2 19.2 23.1 38.5 80.8
Acinar cell carcinoma of the pancreas 7 6 100.0 0.0 0.0 0.0 0.0
Gastrointestinal stromal tumor (GIST) 50 43 100.0 0.0 0.0 0.0 0.0
Tumors of the urinary system Non-invasive papillary urothelial carcinoma, pTa G2 low grade 177 154 96.1 3.2 0.0 0.6 3.9
Non-invasive papillary urothelial carcinoma, pTa G2 high grade 141 125 96.8 3.2 0.0 0.0 3.2
Non-invasive papillary urothelial carcinoma, pTa G3 187 130 96.9 2.3 0.0 0.8 3.1
Urothelial carcinoma, pT2-4 G3 940 838 87.5 8.0 2.5 2.0 12.5
Small cell neuroendocrine carcinoma of the bladder 18 18 100.0 0.0 0.0 0.0 0.0
Sarcomatoid urothelial carcinoma 25 22 90.9 9.1 0.0 0.0 9.1
Clear cell renal cell carcinoma 858 807 93.4 3.7 1.6 1.2 6.6
Papillary renal cell carcinoma 255 242 91.3 5.4 1.7 1.7 8.7
Clear cell (tubulo) papillary renal cell carcinoma 21 21 81.0 19.0 0.0 0.0 19.0
Chromophobe renal cell carcinoma 131 124 98.4 0.8 0.8 0.0 1.6
Oncocytoma 177 170 100.0 0.0 0.0 0.0 0.0
Tumors of the male genital organs Adenocarcinoma of the prostate, Gleason 3 + 3 83 80 100.0 0.0 0.0 0.0 0.0
Adenocarcinoma of the prostate, Gleason 4 + 4 80 76 100.0 0.0 0.0 0.0 0.0
Adenocarcinoma of the prostate, Gleason 5 + 5 85 84 100.0 0.0 0.0 0.0 0.0
Adenocarcinoma of the prostate (recurrence) 330 241 100.0 0.0 0.0 0.0 0.0
Small cell neuroendocrine carcinoma of the prostate 17 17 100.0 0.0 0.0 0.0 0.0
Seminoma 624 613 99.7 0.0 0.0 0.3 0.3
Embryonal carcinoma of the testis 50 44 100.0 0.0 0.0 0.0 0.0
Yolk sack tumor 50 37 100.0 0.0 0.0 0.0 0.0
Teratoma 50 43 83.7 11.6 4.7 0.0 16.3
Squamous cell carcinoma of the penis 80 76 93.4 5.3 0.0 1.3 6.6
Tumors of endocrine organs Adenoma of the thyroid gland 114 104 100.0 0.0 0.0 0.0 0.0
Papillary thyroid carcinoma 392 358 99.2 0.8 0.0 0.0 0.8
Follicular thyroid carcinoma 158 146 98.6 1.4 0.0 0.0 1.4
Medullary thyroid carcinoma 107 91 100.0 0.0 0.0 0.0 0.0
Anaplastic thyroid carcinoma 45 43 100.0 0.0 0.0 0.0 0.0
Adrenal cortical adenoma 50 49 100.0 0.0 0.0 0.0 0.0
Adrenal cortical carcinoma 26 25 100.0 0.0 0.0 0.0 0.0
Phaeochromocytoma 50 49 100.0 0.0 0.0 0.0 0.0
Appendix, neuroendocrine tumor (NET) 22 14 92.9 0.0 7.1 0.0 7.1
Colorectal, neuroendocrine tumor (NET) 10 10 70.0 30.0 0.0 0.0 30.0
Ileum, neuroendocrine tumor (NET) 49 47 87.2 8.5 0.0 4.3 12.8
Lung, neuroendocrine tumor (NET) 19 17 94.1 5.9 0.0 0.0 5.9
Pancreas, neuroendocrine tumor (NET) 102 95 98.9 0.0 0.0 1.1 1.1
Colorectal, neuroendocrine carcinoma (NEC) 11 9 100.0 0.0 0.0 0.0 0.0
Gallbladder, neuroendocrine carcinoma (NEC) 4 4 100.0 0.0 0.0 0.0 0.0
Pancreas, neuroendocrine carcinoma (NEC) 13 12 100.0 0.0 0.0 0.0 0.0
Tumors of hematopoietic and lymphoid tissues Hodgkin Lymphoma 103 101 100.0 0.0 0.0 0.0 0.0
Non-Hodgkin Lymphoma 62 14 100.0 0.0 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 0.0
Diffuse large B cell lymphoma (DLBCL) 114 114 100.0 0.0 0.0 0.0 0.0
Follicular lymphoma 88 87 100.0 0.0 0.0 0.0 0.0
T-cell Non Hodgkin lymphoma 24 24 100.0 0.0 0.0 0.0 0.0
Mantle cell lymphoma 18 18 100.0 0.0 0.0 0.0 0.0
Marginal zone lymphoma 16 16 100.0 0.0 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 0.0
Burkitt lymphoma 5 2 100.0 0.0 0.0 0.0 0.0
Tumors of soft tissue and bone Tenosynovial giant cell tumor 45 43 100.0 0.0 0.0 0.0 0.0
Granular cell tumor 53 47 100.0 0.0 0.0 0.0 0.0
Leiomyoma 50 43 100.0 0.0 0.0 0.0 0.0
Angiomyolipoma 91 84 100.0 0.0 0.0 0.0 0.0
Angiosarcoma 73 66 100.0 0.0 0.0 0.0 0.0
Dermatofibrosarcoma protuberans 21 16 100.0 0.0 0.0 0.0 0.0
Ganglioneuroma 14 14 100.0 0.0 0.0 0.0 0.0
Kaposi sarcoma 8 6 100.0 0.0 0.0 0.0 0.0
Leiomyosarcoma 87 84 100.0 0.0 0.0 0.0 0.0
Liposarcoma 132 116 100.0 0.0 0.0 0.0 0.0
Malignant peripheral nerve sheath tumor (MPNST) 13 12 100.0 0.0 0.0 0.0 0.0
Myofibrosarcoma 26 26 100.0 0.0 0.0 0.0 0.0
Neurofibroma 117 113 100.0 0.0 0.0 0.0 0.0
Sarcoma, not otherwise specified (NOS) 75 73 100.0 0.0 0.0 0.0 0.0
Paraganglioma 41 40 100.0 0.0 0.0 0.0 0.0
Primitive neuroectodermal tumor (PNET) 23 19 100.0 0.0 0.0 0.0 0.0
Rhabdomyosarcoma 7 7 100.0 0.0 0.0 0.0 0.0
Schwannoma 121 111 100.0 0.0 0.0 0.0 0.0
Synovial sarcoma 12 11 72.7 27.3 0.0 0.0 27.3
Osteosarcoma 43 36 100.0 0.0 0.0 0.0 0.0
Chondrosarcoma 39 18 100.0 0.0 0.0 0.0 0.0
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Figure 3.

Figure 3

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Ranking order of MSLN immunostaining in cancers. Both the frequency of positive cases (blue dots) and the frequency of strongly positive cases (orange dots) are shown. Fifty-six additional tumor entities without any MSLN positive cases are not shown due to space restrictions.

3.4. MSLN Immunostaining, Tumor Phenotype, and Prognosis

A comparison of MSLN immunostaining with pT, pN, and histological grade in 1619 colorectal adenocarcinomas, 1072 invasive breast carcinomas of no special type, 386 serous carcinomas of the ovary, 174 lung adenocarcinomas, 757 clear cell renal cell carcinomas, and 171 endometrioid endometrial, in 373 gastric, and in 925 bladder carcinomas revealed only a statistically significant association between MSLN immunostaining and pT stage, as well as pN status in colorectal cancer (p < 0.0001 each, Table 2). MSLN immunostaining was unrelated to overall survival in 227 bladder carcinomas (p = 0.3302; only pT ≥ 2), 593 invasive breast carcinomas of no special types (p = 0.0976), and 502 clear cell renal cell carcinomas (p = 0.3144, Figure 4). A significant association was found between positive MSLN immunostaining and RAS mutations in colorectal carcinomas (p = 0.0010), and triple negative invasive breast carcinomas of no special type (p < 0.0001, Table 2). There was also a strong tendency towards higher MSLN expression in HPV positive than in HPV negative squamous cell carcinomas (p = 0.0098, Table 3).

Table 2.

MSLN immunostaining and tumor phenotype.

MSLN Immunostaining p Value
Analyzable (n) Negative (%) Weak (%) Moderate (%) Strong (%)
endometrioid endometrial carcinoma all cancers 171 55.0 20.5 12.9 11.7
pT1 108 55.6 17.6 14.8 12.0 0.5077
pT2 24 58.3 25.0 4.2 12.5
pT3-4 35 51.4 28.6 14.3 5.7
pN0 50 42.0 24.0 22.0 12.0 0.6098
pN+ 30 56.7 20.0 13.3 10.0
serous high grade ovarian carcinoma all cancers 386 3.1 5.2 8.8 82.9
pT1 32 0.0 12.5 9.4 78.1 0.3821
pT2 42 2.4 7.1 4.8 85.7
pT3 259 2.7 3.9 9.3 84.2
pN0 81 1.2 3.7 9.9 85.2 0.0621
pN1 166 1.8 6.6 10.8 80.7
Invasive breast carcinoma of no special type all cancers 1072 93.7 2.7 0.8 2.8
pT1 545 95.0 1.8 1.1 2.0 0.0262
pT2 406 93.8 2.5 0.5 3.2
pT3-4 79 86.1 8.9 0.0 5.1
G1 150 98.0 1.3 0.0 0.7 <0.0001
G2 540 97.6 0.7 0.4 1.3
G3 381 86.4 6.0 1.8 5.8
pN0 544 92.5 2.5 1.8 3.3 0.0390
pN+ 398 95.4 1.7 0.2 2.8
non triple negative 737 98.2 0.9 0.1 0.7 <0.0001
Triple negative 133 67.7 14.3 6.0 12.0
Urinary bladder carcinoma all cancers 925 90.7 5.8 1.8 1.6
pTa G2 low 154 96.1 3.2 0.0 0.6 <0.0001
pTa G2 high 125 96.8 3.2 0.0 0.0
pTaG3 130 96.9 2.3 0.0 0.8
pT ≥2 G3 792 87.8 8.1 2.3 1.9
pN0 312 87.2 7.4 2.9 2.6 0.7125
pN+ 170 83.7 9.0 4.5 2.8
Clear cell renal cell carcinoma all cancers 757 93.4 4.0 1.6 1.1
pT1 450 93.3 4.0 1.3 1.3 0.8197
pT2 82 95.1 2.4 1.2 1.2
pT3-4 219 92.7 4.6 2.3 0.5
ISUP 1 241 92.9 3.7 2.5 0.8 0.6913
ISUP 2 250 92.0 4.8 1.2 2.0
ISUP 3 211 95.3 3.3 0.9 0.5
ISUP 4 45 93.3 4.4 2.2 0.0
pN0 127 93.7 3.1 2.4 0.8 0.5127
pN+ 19 100.0 0.0 0.0 0.0
Gastric carcinoma all cancers 373 55.0 19.0 10.2 15.8
pT1-2 63 57.1 17.5 12.7 12.7 0.2490
pT3 122 60.7 18.9 9.0 11.5
pT4 122 45.9 22.1 10.7 21.3
pN0 83 65.1 13.3 8.4 13.3 0.0697
pN+ 222 48.7 23.0 11.3 17.1
Colorectal adenocarcinoma all cancers 1619 58.8 28.9 6.5 5.8
pT1 68 66.2 30.9 1.5 1.5 <0.0001
pT2 323 68.4 22.9 5.9 2.8
pT3 894 55.8 31.4 7.4 5.4
pT4 322 56.5 27.3 5.3 10.9
pN0 839 64.2 25.4 5.7 4.6 <0.0001
pN+ 752 52.5 33.0 7.3 7.2
MMR proficient 1114 58.6 29.0 6.9 5.5 0.7017
MMR deficient 82 62.2 25.6 4.9 7.3
RAS wildtype 441 62.4 28.1 5.4 4.1 0.0010
RAS mutation 345 49.0 34.5 9.0 7.5
BRAF wildtype 122 60.7 27.9 8.2 3.3 0.1063
BRAF V600E mutation 21 47.6 19.0 19.0 14.3
adenocarcinoma of the lung all cancers 174 44.8 19.0 13.8 22.4
pT1 83 45.8 19.3 14.5 20.5 0.8172
pT2 52 46.2 21.2 7.7 25.0
pT3 28 42.9 17.9 17.9 21.4
pT4 9 44.4 11.1 33.3 11.1
pN0 95 51.6 14.7 14.7 18.9 0.1194
pN1 57 36.8 28.1 10.5 24.6
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Abbreviation: pT: pathological tumor stage, pN: pathological lymph node status, G: grade, ISUP: International Society of Urological Pathology, MMR: mismatch repair.

Figure 4.

Figure 4

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MSLN immunostaining and patient prognosis. All bladder cancer patients had at least pT2 cancers and were treated by cystectomy.

Table 3.

MSLN immunostaining and HPV status.

MSLN Immunostaining n HPV Status
Negative (%) Positive (%)
All cancers negative 427 56.7 43.3 0.0098
positive 93 41.9 58.1
Oral squamous cell carcinoma negative 60 85.0 15.0 0.3061
positive 15 73.3 26.7
Squamous cell carcinoma of the pharynx negative 43 44.2 55.8 0.0996
positive 3 18.2 81.8
Squamous cell carcinoma of the larynx negative 47 83.0 17.0 0.4281
positive 12 91.7 8.3
Squamous cell carcinoma of the cervix negative 48 10.4 89.6 0.6182
positive 28 14.3 85.7
Squamous cell carcinoma of the vagina negative 26 50.0 50.0 1.0000
positive 4 50.0 50.0
Squamous cell carcinoma of the vulva negative 71 70.4 29.6 0.0698
positive 8 20.0 80.0
Squamous cell carcinoma of the penis negative 68 38.2 61.8 0.3435
positive 5 60.0 40.0
Squamous cell carcinoma of the skin negative 37 97.3 2.7 0.8161
positive 1 100.0 0.0
Squamous cell carcinoma of the anal canal negative 27 11.1 88.9 0.4237
positive 9 22.2 77.8
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4. Discussion

The result of our normal tissue analysis for MSLN expression is consistent with a high potential of this protein as a therapeutic target. It is obvious that the risk for potential side effects of targeted therapies is connected to the target protein’s site and level of expression in normal tissues. MSLN expression was mostly seen in organs that are not vital for adult or old-aged people, such as tonsil, thymus, gallbladder, seminal vesicle, fallopian tube, uterus, and placenta. In the stomach, duodenum, rectum, and the anal canal, the fraction of MSLN expressing cells was so low that critical side effects might not occur, even if these rare cells were disturbed by drug effects. Our normal tissue results are largely consistent with RNA expression data derived from the FANTOM5 project [50,51] and the Genotype-Tissue Expression (GTEx) project [52] which are all summarized in the protein atlas (https://www.proteinatlas.org/ENSG00000102854-MSLN/tissue, accessed on 6 January 2021). These RNA data would suggest the lung as the organ, which might be most endangered by side effects of anti-MSLN therapies. A high MSLN RNA expression in the lung could be explained by strong MSLN immunostaining in goblet cells of respiratory epithelium and occasional positivity of bronchial glands. As the alveolar system did not show any MSLN expression, we would expect that possible lung side effects derived from therapeutic anti-MSLN antibodies would rather affect the bronchial system than the alveolar space.

The successful analysis of more than 12,000 tumors identified various cancer types that might be particularly well suited for anti-MSLN drugs. Although the usage of tissue microarrays has disadvantages connected to the small size of the analyzed tissue spots (0.6 mm in diameter), including the risk of missing “relevant” tumor components in heterogenous tumors, or the impossibility to capture different tumor compartments (such as invasion front and tumor center) within one tissue spot, it allows for an unprecedented degree of experimental standardization across the analyzed tumors. Although different staining conditions may alter the absolute numbers of positive cancers, the relative ranking order of positive tumor types will remain unchanged. The cancer entities with highest prevalence and also highest levels of MSLN expression included all types of ovarian and endometrium carcinomas, pancreatic adenocarcinoma, malignant mesothelioma, and adenocarcinomas of the lung, stomach, esophagus, and the colorectum. High rates of MSLN expression have already been described for these tumor entities, although the results varied between studies. Previously described high MSLN positivity rates range from 55% to 100% in ovarian cancer [35,43,44,53], 59% to 76% in endometrium cancer [5,8], 57% to 100% in pancreatic adenocarcinoma [43,47,54], 45% to 100% in malignant mesothelioma [33,43,55,56], 38% to 69% of lung adenocarcinomas [37,38,39], 45% to 78% in stomach cancer [5,45,57,58], 29% to 46% in esophageal adenocarcinoma [6,59], and 30% to 68% of colorectal adenocarcinoma [5,8]. These cancers with a positivity rate of 40% or higher in our study appear to be the best candidates for targeted anti-MSLN therapy. Squamous cell carcinomas of various different sites of origin represent the next group of cancers that show MSLN expression at a relatively high frequency (10–40%). Clinical studies using adaptive immunotherapy (CAR-T cells), monoclonal antibodies (Amatuximab/MORAb-009), recombinant immunotoxins (SS1P, LMB-100/RG7787), antibody-drug conjugates (Anetumab, DMOT4039A), or listeria monocytogene induced anti-tumor immune response (CRS-207) therapies have so far focused on malignant mesothelioma, pancreatic adenocarcinoma, and carcinomas of the ovarian, lung, and breast [24,25,26,27,28,35,60,61,62,63].

It is of note that MSLN was initially suggested to represent a diagnostic marker for identification of tumors derived from the mesothelium [1]. Subsequent studies have however identified numerous other tumor entities with MSLN expression [5,6,7,8,9,22,33,35,36,37,38,39,40,41,42,43,44,45,46,47,53,54,55,56,57,58,59,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104]. That 66 of our 122 analyzed tumor entities contained MSLN positive cases demonstrates that a positive MSLN expression cannot be viewed as an argument for a specific tumor entity. However, a positive MSLN immunostaining might be considered an argument against a tumor origin from organs that never or very rarely gave rise to MSLN positive cancer cells, such as the prostate, thyroid, kidney, germ cell tumors, adrenal tumors, melanoma, many soft tissue tumor types, and hematologic neoplasms.

Our analysis of 1619 colorectal carcinomas identified significant associations with advanced pT stage and lymph node metastases. This is in line with data from 4 earlier studies all describing associations between high MSLN expression and parameters for cancer aggressiveness or poor patient prognosis [42,99,100,104]. However, the absence of statistical associations between MSLN expression and tumor phenotype and/or prognosis in carcinomas of the bladder, breast, ovary, endometrium, kidney, lung, and stomach argues against a major prognostic role of MSLN expression levels. In principle, this notion is consistent with the existing literature. Only 9 previous studies have earlier described associations between high MSLN expression and poor prognosis and/or unfavorable tumor phenotype in these tumor types [43,45,46,57,74,96,105,106,107], while there were 7 other studies which could not find associations with clinico-pathological parameters [5,44,47,58,64,65,92]. The concept of MSLN expression not representing a universal parameter of malignancy is also supported by the frequent MSLN expression in various benign tumors, including Brenner tumors of the ovary, as well as Warthin tumors, pleomorphic adenomas, and basal cell adenomas of the salivary glands. It is of note that high MSLN expression was linked to several key molecular features in the cancer types analyzed, such as triple negative breast cancer and RAS (KRAS or NRAS) mutations. This observation fits with known interactions of MSLN with relevant molecular pathways interacting with these molecular features, such as the MAPK/ERK pathway (interacting with MMP-7, MUC16, and ERK) [15,16,108], deregulation of HER2 expression [109], and the PI3K/AkT pathway (interacting with PI3K and MUC6) [16,108,110]. Importantly, all prevalences described in this study are specific to the reagents and the protocol used in our laboratory. It is almost certain that the use of different antibodies, protocols, and interpretation criteria have jointly caused highly diverse literature data on MSLN expression in cancer (summarized in Figure 5). It is well known that different antibodies designed for the same target protein can vary to a large extent in their binding properties and that protocol modifications greatly impact the rate of immunostained cases [111].

Figure 5.

Figure 5

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Graphical comparison of MSLN data from this study (×) in comparison with the previous literature. Yellow dots are used for studies involving 1–50 cases, and black dots are used for studies involving more than 50 cases. Red dots are used for studies without subtype analyses. All studies are quoted in the list of references.

5. Conclusions

Our analysis of 12,679 cancers generated a ranking order of cancers according to their frequency of MSLN expression. Top ranked tumor entities, such as ovarian carcinomas, endometrium carcinomas, pancreatic adenocarcinomas, and malignant mesothelioma, thus, may be the best candidates for therapy with drugs targeting MSLN. Despite a link between MSLN positivity and aggressive colon cancer phenotype, the prognostic impact of MSLN expression appears to be low in many other tumor types. This section is not mandatory but can be added to the manuscript if the discussion is unusually long or complex.

Acknowledgments

We are grateful to Melanie Witt, Inge Brandt, Maren Eisenberg, and Sünje Seekamp for excellent technical assistance.

Author Contributions

S.W., T.K., A.H.M., R.S., and G.S. designed the study. P.G., N.G., M.L., A.M., A.M.L., C.F., K.M., C.B., P.L., T.S.C., F.J., J.R.I., K.J., R.U., W.W., S.S., S.M., E.B., R.H.K., and D.D. performed the immunohistochemical analyses and/or contributed to the pathological validation of the tumors, the tissue microarray construction, and data collection. M.K., N.C.B., C.H.-M., and R.S. carried out the data analyses. G.S., R.S., S.W., T.K., A.H.M., and M.K. wrote the first draft of the manuscript. All authors contributed toward data analysis, drafting and critically revising the paper, gave final approval of the version to the published, and agree to be accountable for all aspects of the work. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The use of archived remnants of diagnostic tissues for manufacturing of TMAs and their analysis for research purposes, as well as patient data analysis, has 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.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study (HmbKHG, §12).

Data Availability Statement

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

Conflicts of Interest

The mesothelin (MSLN) antibody clone MSVA-235 was provided from MS Validated Antibodies GmbH (owned by a family member of GS).

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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