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. 2022 Aug 11;481(6):945–961. doi: 10.1007/s00428-022-03394-5

FABP1 expression in human tumors: a tissue microarray study on 17,071 tumors

David Dum 1, Ana Ocokoljic 1, Maximilian Lennartz 1, Claudia Hube-Magg 1, Viktor Reiswich 1, Doris Höflmayer 1, Frank Jacobsen 1, Christian Bernreuther 1, Patrick Lebok 1,2, Guido Sauter 1, Andreas M Luebke 1, Eike Burandt 1, Andreas H Marx 1,3, Ronald Simon 1,✉, Till S Clauditz 1, Sarah Minner 1, Anne Menz 1, Franziska Büscheck 1, Natalia Gorbokon 1, Stefan Steurer 1, Niclas C Blessin 1, Till Krech 1,2
PMCID: PMC9734244  PMID: 35951102

Abstract 

Fatty acid–binding proteins (FABPs) play a pivotal role in the metabolism of fatty acids and are expressed in a tissue-specific manner. FABP1 is most abundantly expressed in the liver where it accounts for about 10% of the total cytosolic protein and is thought to have diagnostic utility. To comprehensively determine FABP1 expression in normal and neoplastic tissues, a tissue microarray containing 17,071 samples from 150 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types was analyzed by immunohistochemistry. Among normal tissues, a strong FABP1 immunostaining was observed in hepatocytes, proximal tubuli of the kidney and epithelium of small intestine, appendix, and the colorectum. FABP1 positivity was found in 24 of 150 tumor categories, including 17 tumor categories with at least 1 strongly positive case. The highest FABP1 positivity rates were seen in colorectal adenomas (86%), in colorectal adenocarcinomas (71.1%), and in hepatocellular carcinomas (65.3%), followed by mucinous carcinoma of the ovary (34.6%), cholangiocarcinoma (21.6%), and various adenocarcinomas from the digestive tract (10–23%). Eleven additional entities had positivity rates between 0.2 and 6.5%. FABP1 staining was not seen in 169 primary adenocarcinomas of the lung. In colorectal cancer, reduced FABP1 expression was linked to poor-grade, right-sided tumor location, microsatellite instability (p < 0.0001 each), and absence of BRAF V600E mutations (p = 0.001), but unrelated to pT and pN status. FABP1 expression has considerably high tumor specificity. As FABP1 expression was virtually absent in adenocarcinomas of the lung, FABP1 immunohistochemistry might be particularly helpful to assist in the identification of metastatic colorectal or gastrointestinal adenocarcinoma to the lung.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00428-022-03394-5.

Keywords: FABP1, Tissue microarray, Immunohistochemistry, Diagnostic, Human cancer

Introduction 

Fatty acid–binding proteins (FABPs) constitute a family of at least 9 proteins, which play a pivotal role in the metabolism of fatty acids and related molecules. All FABPs are expressed in a tissue-specific manner, and their levels of expression are considered to be proportional to the rate of fatty acid metabolism [1–4]. Fatty acid–binding protein 1, also termed liver FABP (L-FABP), is expressed from the FABP1 gene located at human chromosome 2p11.2 [5]. The 14-kilodalton protein is most abundantly expressed in the liver where it accounts for about 10% of the total cytosolic protein [6, 7]. FABP1 is involved in the binding, transport, and metabolism of long-chain fatty acids in the liver [6, 7]. Unlike other members of the FABP family, the large hydrophobic binding pocket located in the FABP1 structure is capable of binding to a particularly broad spectrum of hydrophobic ligands and to simultaneously attach multiple ligands [8]. FABP1 ligands include bilirubin, bile acids, or monoglycerides but also benzodiazepines, fibrates, β-blockers, and non-steroidal anti-inflammatory drugs [9, 10]. FABP1 plays a significant role in preventing cytotoxicity/activity of these molecules [9]. Several mutations of the FABP1 gene have been linked to specific metabolic conditions including obesity, cardiovascular disease, and diabetes [8, 11].

Because of its high tissue specificity, FABP1 expression analysis by immunohistochemistry might have diagnostic utility. Studies using FABP1 immunohistochemistry have so far described FABP1 positivity in 47–100% of hepatocellular carcinomas [12, 13], 47.4–83.3% of various subtypes of lung cancer [14], 30–81.5% of colorectal carcinomas [15, 16], 38.6% of gastric adenocarcinomas [17], 27–36.4% of various kidney cancer subtypes [18], and in 12.1% of pancreatic carcinomas [19]. Many other tumor entities have so far not been systematically analyzed.

In order to comprehensively assess the potential diagnostic utility of FABP1 expression in cancer, a preexisting set of tissue microarrays containing more than 17,000 tumor tissue samples from 150 different tumor types and subtypes as well as 76 non-neoplastic tissue categories was analyzed by immunohistochemistry (IHC) in this study.

Material and methods

Tissue microarrays (TMAs)

The normal 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 17,071 primary tumors from 150 tumor types and subtypes. Detailed histopathological data on tumor phenotype and molecular data on microsatellite instability, RAS mutations, and BRAF V600E mutations were available from the majority of 2351 colorectal adenocarcinomas. The composition of both normal and cancer TMAs is described in detail in the “Results” section. All samples were from the archives of the Institute of Pathology, University Hospital of Hamburg, Germany; the Institute of Pathology, Clinical Center Osnabrück, Germany; and 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 [20, 21]. 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 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.

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 7,8 Dako target Retrieval Solution™ (Agilent, CA, USA; #S2367). Endogenous peroxidase activity was blocked with Dako Peroxidase Blocking Solution™ (Agilent, CA, USA; #52,023) for 10 min. Primary antibody specific against FABP1 protein (mouse monoclonal, MSVA-501 M, #3737-501 M, MS Validated Antibodies, Hamburg, Germany) was applied at 37 °C for 60 min at a dilution of 1:150. Bound antibody was visualized using the EnVision Kit™ (Agilent, CA, USA; #K5007) according to the manufacturer’s directions. The sections were counterstained with haemalaun. For tumor tissues, the percentage of FABP1-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 described before [22]: 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%, or 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. Examples of tumors with different scores are shown in Suppl. Figure 1.

Statistics

Statistical calculations were performed with JMP 14 software (SAS Institute Inc., NC, USA). Contingency tables and the chi2 test were performed to search for associations between FABP1 immunostaining and tumor phenotype. A p value of ≤ 0.05 was defined as significant. Cox proportional hazard regression analysis was performed to test the statistical independence of associations between pathological and molecular variables.

Results

FABP1 in normal tissues

A strong FABP1 immunostaining was observed in hepatocytes of the liver, in proximal tubular cells of the kidney, and in epithelial cells of the small intestine, appendix, and the colorectum. In the entire intestine, the staining was strongest in the surface epithelium and sometimes low or even inexistent in the crypt bases. In the stomach epithelium, FABP1 staining was usually absent. Focal positivity was seen, however, in case of intestinal metaplasia. In case of very strong staining of intestinal or liver cells, adjacent structures often also showed FABP1 immunostaining. This is considered a contamination artifact due to diffusion of the antigen. Representative images of FABP1-positive normal tissues are shown in Fig. 1.

Fig. 1.

Fig. 1

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FABP1 immunostaining in normal tissues. The panels show a strong (3 +) cytoplasmic FABP1 staining of hepatocytes in the liver (A), surface epithelium of the appendix (B), and the ileum (C) as well as in proximal tubular cells of the kidney (D). FABP1 expression can be so strong in these tissues that considerable contamination artifacts occur in adjacent cells/tissues (A–C). FABP1 staining is lacking in the renal medulla (E) and in the stomach epithelium (F)

FABP1 in cancer

A positive FABP1 immunostaining was detectable in 1980 (14%) of the 14,597 analyzable tumors, including 470 (3.2%) with weak, 563 (3.9%) with moderate, and 947 (6.5%) with strong immunostaining. Overall, 24 (16%) of 150 tumor categories showed detectable FABP1 expression with 17 (11%) tumor categories including at least one case with strong positivity (Table 1). Representative images of FABP1-positive tumors are shown in Fig. 2. By far the highest positivity rates were seen in colorectal adenomas (44–88%), in colorectal adenocarcinomas (71%), and in hepatocellular carcinomas (65%), followed by mucinous carcinoma of the ovary (35%), cholangiocarcinoma (22%), and various adenocarcinomas from the digestive tract (10–23%). Of note, none of our FABP1-positive cholangiocarcinomas qualified for a diagnosis of combined HCC-cholangiocarcinoma as all of these tumors showed a predominantly small-glandular growth pattern and did not show any HepPar1 or arginase1 immunostaining (data not shown). Eleven further tumor entities had positivity rates between 0.2 and 6.5%. A graphical representation of a ranking order of tumor entities according to their rate of FABP1-positive and strongly positive cases is given in Fig. 3. FABP1 expression was not found in any of 252 arrayed lung cancers, including 169 adenocarcinomas of the lung. FABP1 was also negative in all 85 pulmonary adenocarcinomas for which data were available from previous studies on CK20 [23], villin [24], and SATB2 [25]. Evidence for a possible enteric/intestinal differentiation had been found in 20 (24%) of these tumors because of a positive staining for at least one of these intestinal markers (Supplementary Table 1). The relationship between FABP1 immunostaining and histopathological and molecular features of colorectal adenocarcinomas and hepatocellular carcinomas are shown in Table 2. In colorectal cancer, reduced FABP1 expression was strikingly linked to histologic grade, microsatellite instability (MSI), and tumor location in the right side of the colon (p < 0.0001 each), and absence of BRAF V600E mutations (p = 0.001) but was unrelated to pT and pN status or RAS mutation status. A multivariate analysis including MSI, pT, pN, and histologic grade showed that associations between these parameters and reduced FABP1 expression was driven by the histologic grade and stage (p ≤ 0.05; Supplementary Table 2). Within 84 MSI tumors, reduced FABP1 expression was weakly associated with L0 status (p = 0.0203) and tumor location in the right colon (p = 0.0023). Within 1067 MSS tumors, reduced FABP1 expression was weakly associated with right-sided tumor location (p = 0.0372). In hepatocellular carcinomas, reduced FABP1 expression was linked to advanced stage (p = 0.0002), presence of lymph node metastasis (p = 0.0042), and female gender (p = 0.0002).

Table 1.

FABP1 immunostaining in human tumors

FABP1 immunostaining result
Tumor entity On TMA (n) Analyzable (n) Negative (%) Weak (%) Moderate (%) Strong (%)
Tumors of the skin Pilomatrixoma 35 27 100.0 0.0 0.0 0.0
Basal cell carcinoma 88 78 100.0 0.0 0.0 0.0
Benign nevus 29 26 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the skin 90 89 100.0 0.0 0.0 0.0
Malignant melanoma 46 44 100.0 0.0 0.0 0.0
Malignant melanoma Lymph node metastasis 86 85 100.0 0.0 0.0 0.0
Merkel cell carcinoma 46 35 100.0 0.0 0.0 0.0
Tumors of the head and neck Squamous cell carcinoma of the larynx 110 80 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the pharynx 60 59 100.0 0.0 0.0 0.0
Oral squamous cell carcinoma (floor of the mouth) 130 112 100.0 0.0 0.0 0.0
Pleomorphic adenoma of the parotid gland 50 31 100.0 0.0 0.0 0.0
Warthin tumor of the parotid gland 104 81 100.0 0.0 0.0 0.0
Adenocarcinoma, NOS (Papillary Cystadenocarcinoma) 14 12 100.0 0.0 0.0 0.0
Salivary duct carcinoma 15 10 100.0 0.0 0.0 0.0
Acinic cell carcinoma of the salivary gland 181 129 100.0 0.0 0.0 0.0
Adenocarcinoma NOS of the salivary gland 109 68 98.5 0.0 0.0 1.5
Adenoid cystic carcinoma of the salivary gland 180 85 100.0 0.0 0.0 0.0
Basal cell adenocarcinoma of the salivary gland 25 19 100.0 0.0 0.0 0.0
Basal cell adenoma of the salivary gland 101 77 100.0 0.0 0.0 0.0
Epithelial-myoepithelial carcinoma of the salivary gland 53 50 100.0 0.0 0.0 0.0
Mucoepidermoid carcinoma of the salivary gland 343 243 100.0 0.0 0.0 0.0
Myoepithelial carcinoma of the salivary gland 21 18 100.0 0.0 0.0 0.0
Myoepithelioma of the salivary gland 11 10 100.0 0.0 0.0 0.0
Oncocytic carcinoma of the salivary gland 12 8 100.0 0.0 0.0 0.0
Polymorphous adenocarcinoma, low grade, of the salivary gland 41 32 100.0 0.0 0.0 0.0
Pleomorphic adenoma of the salivary gland 53 40 100.0 0.0 0.0 0.0
Tumors of the lung, pleura, and thymus Adenocarcinoma of the lung 196 169 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the lung 80 71 100.0 0.0 0.0 0.0
Small cell carcinoma of the lung 16 12 100.0 0.0 0.0 0.0
Mesothelioma, epithelioid 39 29 100.0 0.0 0.0 0.0
Mesothelioma, other types 76 51 100.0 0.0 0.0 0.0
Thymoma 29 24 100.0 0.0 0.0 0.0
Tumors of the female genital tract Squamous cell carcinoma of the vagina 78 46 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the vulva 130 109 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the cervix 129 109 100.0 0.0 0.0 0.0
Adenocarcinoma of the cervix 21 21 100.0 0.0 0.0 0.0
Endometrioid endometrial carcinoma 236 207 100.0 0.0 0.0 0.0
Endometrial serous carcinoma 82 56 100.0 0.0 0.0 0.0
Carcinosarcoma of the uterus 48 42 100.0 0.0 0.0 0.0
Endometrial carcinoma, high grade, G3 13 12 100.0 0.0 0.0 0.0
Endometrial clear cell carcinoma 8 7 100.0 0.0 0.0 0.0
Endometrioid carcinoma of the ovary 110 93 93.5 1.1 1.1 4.3
Serous carcinoma of the ovary 559 510 100.0 0.0 0.0 0.0
Mucinous carcinoma of the ovary 96 81 65.4 8.6 11.1 14.8
Clear cell carcinoma of the ovary 50 47 100.0 0.0 0.0 0.0
Carcinosarcoma of the ovary 47 39 100.0 0.0 0.0 0.0
Granulosa cell tumor of the ovary 37 35 100.0 0.0 0.0 0.0
Leydig cell tumor of the ovary 4 4 100.0 0.0 0.0 0.0
Sertoli cell tumor of the ovary 1 1 100.0 0.0 0.0 0.0
Sertoli-Leydig cell tumor of the ovary 3 3 100.0 0.0 0.0 0.0
Steroid cell tumor of the ovary 3 3 100.0 0.0 0.0 0.0
Brenner tumor 41 39 100.0 0.0 0.0 0.0
Tumors of the breast Invasive breast carcinoma of no special type 499 485 100.0 0.0 0.0 0.0
Lobular carcinoma of the breast 192 171 100.0 0.0 0.0 0.0
Medullary carcinoma of the breast 23 22 100.0 0.0 0.0 0.0
Tubular carcinoma of the breast 20 11 100.0 0.0 0.0 0.0
Mucinous carcinoma of the breast 29 24 100.0 0.0 0.0 0.0
Phyllodes tumor of the breast 50 47 100.0 0.0 0.0 0.0
Tumors of the digestive system Adenomatous polyp, low-grade dysplasia 50 33 12.1 15.2 24.2 48.5
Adenomatous polyp, high-grade dysplasia 50 45 15.6 20.0 24.4 40.0
Adenocarcinoma of the colon 2482 2147 28.9 16.6 22.2 32.4
Gastric adenocarcinoma, diffuse type 176 150 88.0 6.0 2.0 4.0
Gastric adenocarcinoma, intestinal type 174 160 79.4 8.1 5.6 6.9
Gastric adenocarcinoma, mixed type 62 55 85.5 1.8 10.9 1.8
Adenocarcinoma of the esophagus 83 77 89.6 3.9 5.2 1.3
Squamous cell carcinoma of the esophagus 75 66 100.0 0.0 0.0 0.0
Squamous cell carcinoma of the anal canal 89 68 100.0 0.0 0.0 0.0
Cholangiocarcinoma 50 37 78.4 5.4 5.4 10.8
Gallbladder adenocarcinoma 31 29 82.8 10.3 0.0 6.9
Gallbladder Klatskin tumor 41 38 86.8 5.3 5.3 2.6
Hepatocellular carcinoma 300 285 34.7 3.9 4.2 57.2
Ductal adenocarcinoma of the pancreas 612 380 98.2 0.5 1.3 0.0
Pancreatic/ampullary adenocarcinoma 89 61 77.0 1.6 4.9 16.4
Acinar cell carcinoma of the pancreas 16 15 100.0 0.0 0.0 0.0
Gastrointestinal stromal tumor (GIST) 50 45 100.0 0.0 0.0 0.0
Tumors of the urinary system Non-invasive papillary urothelial carcinoma, pTa G2 low grade 177 122 100.0 0.0 0.0 0.0
Non-invasive papillary urothelial carcinoma, pTa G2 high grade 141 98 100.0 0.0 0.0 0.0
Non-invasive papillary urothelial carcinoma, pTa G3 219 157 99.4 0.0 0.6 0.0
Urothelial carcinoma, pT2-4 G3 735 564 99.8 0.0 0.2 0.0
Squamous cell carcinoma of the bladder 22 21 100.0 0.0 0.0 0.0
Small cell neuroendocrine carcinoma of the bladder 23 21 100.0 0.0 0.0 0.0
Sarcomatoid urothelial carcinoma 25 21 100.0 0.0 0.0 0.0
Urothelial carcinoma of the kidney pelvis 62 60 100.0 0.0 0.0 0.0
Clear cell renal cell carcinoma 1287 1178 95.8 3.3 0.8 0.0
Papillary renal cell carcinoma 368 335 98.8 1.2 0.0 0.0
Clear cell (tubulo)papillary renal cell carcinoma 26 25 100.0 0.0 0.0 0.0
Chromophobe renal cell carcinoma 170 157 100.0 0.0 0.0 0.0
Oncocytoma 257 229 100.0 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 80 100.0 0.0 0.0 0.0
Adenocarcinoma of the prostate, Gleason 5 + 5 85 85 100.0 0.0 0.0 0.0
Adenocarcinoma of the prostate (recurrence) 258 258 100.0 0.0 0.0 0.0
Small cell neuroendocrine carcinoma of the prostate 19 12 100.0 0.0 0.0 0.0
Seminoma 621 593 100.0 0.0 0.0 0.0
Embryonal carcinoma of the testis 50 42 97.6 2.4 0.0 0.0
Leydig cell tumor of the testis 30 30 100.0 0.0 0.0 0.0
Sertoli cell tumor of the testis 2 2 100.0 0.0 0.0 0.0
Sex cord stromal tumor of the testis 1 1 100.0 0.0 0.0 0.0
Spermatocytic tumor of the testis 1 1 100.0 0.0 0.0 0.0
Yolk sac tumor 50 42 97.6 2.4 0.0 0.0
Teratoma 50 36 97.2 0.0 0.0 2.8
Squamous cell carcinoma of the penis 80 80 100.0 0.0 0.0 0.0
Tumors of endocrine organs Adenoma of the thyroid gland 114 113 100.0 0.0 0.0 0.0
Papillary thyroid carcinoma 392 369 100.0 0.0 0.0 0.0
Follicular thyroid carcinoma 154 150 100.0 0.0 0.0 0.0
Medullary thyroid carcinoma 111 104 100.0 0.0 0.0 0.0
Parathyroid gland adenoma 43 41 100.0 0.0 0.0 0.0
Anaplastic thyroid carcinoma 45 41 100.0 0.0 0.0 0.0
Adrenal cortical adenoma 50 45 100.0 0.0 0.0 0.0
Adrenal cortical carcinoma 26 22 100.0 0.0 0.0 0.0
Pheochromocytoma 50 45 100.0 0.0 0.0 0.0
Appendix, neuroendocrine tumor (NET) 22 14 100.0 0.0 0.0 0.0
Colorectal, neuroendocrine tumor (NET) 12 11 100.0 0.0 0.0 0.0
Ileum, neuroendocrine tumor (NET) 49 48 100.0 0.0 0.0 0.0
Lung, neuroendocrine tumor (NET) 19 18 100.0 0.0 0.0 0.0
Pancreas, neuroendocrine tumor (NET) 97 80 100.0 0.0 0.0 0.0
Colorectal, neuroendocrine carcinoma (NEC) 12 11 100.0 0.0 0.0 0.0
Gallbladder, neuroendocrine carcinoma (NEC) 4 4 100.0 0.0 0.0 0.0
Pancreas, neuroendocrine carcinoma (NEC) 14 14 100.0 0.0 0.0 0.0
Tumors of hematopoietic and lymphoid tissues Hodgkin lymphoma 103 76 100.0 0.0 0.0 0.0
Small lymphocytic lymphoma, B cell type (B-SLL/B-CLL) 50 46 100.0 0.0 0.0 0.0
Diffuse large B cell lymphoma (DLBCL) 114 106 100.0 0.0 0.0 0.0
Follicular lymphoma 88 85 100.0 0.0 0.0 0.0
T-cell Non Hodgkin lymphoma 24 24 100.0 0.0 0.0 0.0
Mantle cell lymphoma 18 18 100.0 0.0 0.0 0.0
Marginal zone lymphoma 16 12 100.0 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 25 100.0 0.0 0.0 0.0
Granular cell tumor 53 32 100.0 0.0 0.0 0.0
Leiomyoma 50 47 100.0 0.0 0.0 0.0
Leiomyosarcoma 87 75 100.0 0.0 0.0 0.0
Liposarcoma 132 110 100.0 0.0 0.0 0.0
Malignant peripheral nerve sheath tumor (MPNST) 13 12 100.0 0.0 0.0 0.0
Myofibrosarcoma 26 26 100.0 0.0 0.0 0.0
Angiosarcoma 73 59 98.3 0.0 0.0 1.7
Angiomyolipoma 91 88 100.0 0.0 0.0 0.0
Dermatofibrosarcoma protuberans 21 17 100.0 0.0 0.0 0.0
Ganglioneuroma 14 14 100.0 0.0 0.0 0.0
Kaposi sarcoma 8 6 100.0 0.0 0.0 0.0
Neurofibroma 117 103 100.0 0.0 0.0 0.0
Sarcoma, not otherwise specified (NOS) 74 69 100.0 0.0 0.0 0.0
Paraganglioma 41 41 100.0 0.0 0.0 0.0
Ewing sarcoma 23 18 100.0 0.0 0.0 0.0
Rhabdomyosarcoma 6 6 100.0 0.0 0.0 0.0
Schwannoma 121 113 100.0 0.0 0.0 0.0
Synovial sarcoma 12 11 100.0 0.0 0.0 0.0
Osteosarcoma 43 35 100.0 0.0 0.0 0.0
Chondrosarcoma 38 17 100.0 0.0 0.0 0.0
Rhabdoid tumor 5 5 100.0 0.0 0.0 0.0
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Fig. 2.

Fig. 2

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FABP1 immunostaining in cancer. The panels show a cytoplasmic FABP1 immunostaining of variable intensity in samples from hepatocellular carcinoma (A), cholangiocarcinoma (B), gastric adenocarcinoma (C), esophageal adenocarcinoma (D), colorectal adenocarcinoma (E), and an adenocarcinoma of the papilla of Vater (F). In several samples, FABP1 expression is so high that contamination artifacts occur in adjacent cells/tissues. FABP1 staining is completely absent in samples from a ductal adenocarcinoma of the pancreas (G) and an adenocarcinoma of the lung (H)

Fig. 3.

Fig. 3

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Ranking order of FABP1 immunostaining in tumors. Both the frequency of positive cases (blue dots) and the frequency of strongly positive cases (orange dots) are shown

Table 2.

FABP1 immunostaining and tumor phenotype in colon cancers

FABP1 IHC result
n Negative (%) Weak (%) Moderate (%) Strong (%) P
Colon adenocarcinoma (all cancers) Primary Tumor pT1 78 29.5 14.1 17.9 38.5 0.5175
pT2 403 28.8 16.9 23.1 31.3
pT3 1144 27.6 15.7 22.9 33.7
pT4 413 32 18.4 20.3 29.3
Grade 1 5 20 0 40 40  < 0.0001
2 523 26 17 22.9 34.1
3 65 64.6 12.3 7.7 15.4
Regional lymph nodes pN0 1073 28.2 17.6 22.4 31.8 0.6035
pN +  956 29.5 15.5 22.2 32.8
Lymphatic invasion L0 659 31.6 15.2 21.4 31.9 0.3808
L1 1348 28.1 17.2 22.1 32.6
Tumor localization Left colon 1112 25.4 15.9 23.4 35.3  < 0.0001
Right colon 417 36.9 18.2 20.4 24.5
MMR status Defective 84 56 21.4 11.9 10.7  < 0.0001
Proficient 1067 25 16.2 23.7 35.1
RAS mutation status Mutated 325 26.8 18.8 23.4 31.1 0.058
Wild type 414 24.2 13 23.9 38.9
BRAF mutation status Mutated 14 78.6 7.1 7.1 7.1 0.001
Wild type 90 23.3 15.6 27.8 33.3
Colon adenocarcinoma (microsatellite stable cancers) Primary TUMOR pT1 41 34.1 17.1 22 26.8 0.7281
pT2 221 24.4 18.1 24.4 33
pT3 587 23.2 15.3 24.5 37
pT4 207 28 16.4 21.3 34.3
Grade 1 0 - - - -
2 26 23.1 15.4 38.5 23.1 0.3235
3 4 25 50 25 0
Regional lymph nodes pN0 550 25.3 16 26 32.7 0.2234
pN +  498 24.7 16.3 21.3 37.8
Lymphatic invasion L0 423 26.5 13.9 25.5 34 0.2894
L1 602 24.6 17.4 22.1 35.9
Tumor localization Left colon 819 23 16.1 24.1 36.9 0.0372
Right colon 243 31.7 16 23 29.2
RAS mutation status Mutated 262 24.4 17.9 23.7 34 0.0631
Wild type 326 19.3 12.9 24.8 42.9
BRAF mutation status Mutated 6 50 16.7 16.7 16.7 0.4871
Wild type 71 21.1 16.9 28.2 33.8
Colon adenocarcinoma (microsatellite instable cancers) Primary tumor pT1 6 66.7 0 0 33.3 0.1955
pT2 19 57.9 21.1 5.3 15.8
pT3 40 57.5 25 15 2.5
pT4 19 47.4 21.1 15.8 15.8
Regional lymph nodes pN0 54 55.6 22.2 9.3 13 0.3852
pN +  28 57.1 21.4 17.9 3.6
Lymphatic invasion L0 37 73 16.2 2.7 8.1 0.0203
L1 45 44.4 26.7 20 8.9
Tumor localization Left colon 36 41.7 16.7 19.4 22.2 0.0023
Lymphatic invasion Right colon 48 66.7 25 6.3 2.1
RAS mutation status Mutated 8 37.5 12.5 37.5 12.5 0.5705

Tumor localization

BRAF mutation status

 Wild type 21 57.1 19 14.3 9.5
Mutated 5 100 0 0 0 0.1174
RAS mutation status Wild type 9 44.4 11.1 33.3 11.1
Hepatocellular carcinoma Primary tumor pT1 90 20.0 5.6 4.4 70.0 0.0002
pT2 100 37.0 1.0 3.0 59.0
pT3 62 51.6 4.8 8.1 50.0
Regional lymph nodes pN0 81 40.7 6.2 3.7 49.4 0.0042
pN +  44 72.7 2.3 4.5 20.5
Grade G1 45 13.3 6.7 6.7 73.3 0.0728
G2 160 36.9 3.1 4.4 55.6
G3 56 30.4 1.8 3.6 64.3
Histology NOS 138 4.3 2.2 5.1 88.4 0.0994
Carcinosarcoma 1 0.0 0.0 0.0 100.0
Clear cell 4 0.0 0.0 0.0 100.0
Lipid-rich 3 33.3 0.0 0.0 66.7
Lymphocyte-rich 2 0.0 0.0 0.0 100.0
Scirrhous 9 33.3 22.2 11.1 33.3
Steatohepatitic 21 0.0 0.0 0.0 100.0
Growth pattern Solid 64 3.1 1.6 4.7 90.6 0.0645
Trabecular 77 2.6 3.9 2.6 90.9
Macrotrabecular 10 10.0 10.0 0.0 80.0
Pseudoglandular 26 19.2 0.0 11.5 69.2
Fatty change No 142 6.3 3.5 4.9 85.2 0.2848
Yes 37 2.7 0.0 2.7 94.6
Gender Male 203 27.6 3.9 3.4 65.0 0.0002
Female 81 53.1 3.7 6.2 37.0
Age (yrs)  ≤ 50 27 40.7 11.1 3.7 44.4 0.0648
51–60 55 34.5 0.0 5.5 60.0
61–70 93 32.3 4.3 4.3 59.1
71–80 91 35.2 4.4 3.3 57.1
 > 80 19 36.8 0.0 5.3 57.9
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Discussion

Considering the large scale of our study, emphasis was placed on the appropriate validation of our FABP1 immunohistochemistry assay. Based on recommendations of the International Working Group for Antibody Validation (IWGAV), we compared our FABP1 staining data with expression data obtained by another independent method [26]. Normal tissue RNA expression data derived from three different publicly accessible databases [27–30] were therefore compared with immunostaining results in 76 different normal tissue categories. This broad range of tissues is likely to contain most proteins that are normally expressed at relevant levels in cells of adult humans and should therefore enable the detection of most undesired cross-reactivities of tested antibodies. Specificity of our assay was supported by the limitation of FABP1 immunostaining to kidney, liver, and the intestine. These are the only organs for which significant FABP1 RNA expression had been described.

Our data provide a comprehensive overview on the prevalence and intensity of FABP1 immunostaining across a large variety of human tumor entities. The findings demonstrate that FABP1 expression occurs at highest frequency (65–80%) in hepatocellular carcinomas and colorectal adenocarcinomas, at lower frequency (35%) in mucinous carcinoma of the ovary and in other adenocarcinomas of the digestive tract (10–25%), and only rarely (< 5%) in a limited number of other tumor types. These data not only expand the existing literature but also clarify existing findings which in part are highly discordant with our data. A total of 15 previous studies have reported IHC findings on FABP1 in 12 different tumor entities (results summarized in Fig. 4). While multiple studies describe FABP1 expression frequencies that are in the range of our findings in hepatocellular carcinomas [31–33], colorectal adenocarcinomas [16, 34], pancreatic adenocarcinomas [19], and gastric adenocarcinoma [17], we were unable to detect any FABP1-positive cases among 169 adenocarcinomas of the lung, 12 small cell carcinomas of the lung, and 157 chromophobe carcinomas of the kidney. For all these entities, others have described substantial fractions of FABP1-positive cases [14, 18]. Absence of FABP1 expression in lung and kidney cancer is also supported by RNA expression studies summarized in the ICGC/TCGA databases (https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga) and The Human Protein Atlas [30].

Fig. 4.

Fig. 4

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Fraction of FABP1 positivity per tumor type from previous literature. Colors of the dots represent the numbers of analyzed tumors in these studies: red, n = 1–10; blue, n = 11–25; black, n > 25. X = results of this study, with numbers indicating the sample size

Our comprehensive set of data on FABP1 immunostaining in tumors suggests a potential diagnostic utility of FABP1 immunohistochemistry in surgical pathology. While it is obvious from our data that a positive FABP1 immunostaining in a metastatic tissue of unknown origin would pinpoint towards the liver or the gastrointestinal tract as the most likely sites of cancer origin, the highest diagnostic utility may be derived from the constant absence of FABP1 immunostaining in 169 analyzed adenocarcinomas of the lung. As the lung is a common site of metastases, the distinction of primary lung adenocarcinoma from metastatic adenocarcinoma is a frequent diagnostic problem which has high therapeutic implications. A potential utility for this application is particularly supported by the absence of FABP1 staining in 20 pulmonary adenocarcinomas for which cytokeratin 20, SATB2, and/or villin positivity had suggested a possible intestinal/enteric differentiation. A low likelihood of pulmonary adenocarcinomas to become FABP1 positive is also supported by the complete lack of FABP1 RNA expression in 510 pulmonary adenocarcinomas described in the TCGA Pan Cancer Atlas database (https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga). A positive FABP1 immunostaining in an adenocarcinoma in the lung may therefore be highly suggestive of an extra-pulmonary tumor origin and favor a metastasis derived from a colorectal cancer or another cancer of the gastrointestinal tract. However, considering that only 71% of our colorectal adenocarcinomas were FABP1 positive and the even lower frequency of FABP1 positivity in other gastrointestinal adenocarcinomas, a negative FABP1 staining cannot serve as evidence for a pulmonary origin of an adenocarcinoma in the lung. Moreover, in case of an adenocarcinoma in the pancreas, FABP1 positivity would argue in favor of a carcinoma derived from the ampulla of Vater (23% positive) and against a ductal adenocarcinoma (1.8% positive). Loss of FABP1 expression in a hepatic tumor has been described as a feature of hepatocellular adenoma [35, 36]. However, our data show that 50–70% of advanced and metastatic hepatocellular carcinomas and up to 20% of low-stage and grade carcinomas may be FABP1 negative. These observations are in line with earlier reports [31, 37, 38] suggesting that a lack of FABP1 staining should be interpreted with care to avoid misdiagnosing a well-differentiated hepatocellular carcinoma as hepatocellular adenoma.

It is of note that FABP1 expression in normal and neoplastic tissues is usually either high or absent. In immunohistochemical analysis, this often results in such an abundant staining reaction that bound antibody can also be seen in the vicinity of FABP1-expressing cells. Such a spill-over of FABP1 protein may either be caused by some physiologic intravital diffusion of the highly abundant FABP1 protein or reflect an ischemia-induced artifact caused by autolytic cell damage occurring between removal of the tissue from the patient and completed tissue fixation. Such “contamination artifacts” must be considered if metastatic tissue is seen in biopsies from the liver because they can lead to questionable staining or false positivity.

The successful analysis of more than 2000 colorectal adenocarcinomas enabled us to analyze the relationship between FABP1 expression, tumor phenotype, and molecular data in this tumor entity. That low FABP1 expression was strongly linked to high-grade, MSI, and right-sided tumor location but unrelated to pT and pN stage is consistent with the results of two earlier studies. In a study on 695 colorectal carcinomas, Wood et al. [39] described a strong link of low FABP1 with MSI and high histologic grade but also failed to find significant associations with advanced stage or patient survival. Lawrie et al. [15] analyzed 249 colorectal adenocarcinomas and found a relationship between low FABP1 and high grade but did not see associations with tumor stage. The mechanism causing low FABP1 expression in colorectal adenocarcinomas with MSI is unclear. Wood et al. [39] suggested a possible role of PPARγ and the interferon γ pathway. It also appears possible that one or several genes that are required for FABP1 expression are inactivated by accumulating mutations in MSI cancers. Silencing of FABP1 expression by specific molecular events is not uncommon. In hepatocellular adenomas, efficient silencing of FABP1 can be caused by biallelic inactivation of hepatocyte nuclear factor 1α (HNF1A) which occurs in 35–40% of cases [40]. That reduced FABP1 expression was driven by high grade—a feature that is commonly related to MSI— and not by MSI in our multivariate analysis may suggest, however, that FABP1 expression loss is merely an indicator of poor differentiation and may not have further biological meanings. With respect to molecular mechanisms for FABP1 inactivation, it is also remarkable that FABP1 expression is virtually absent in kidney cancers, although the protein is abundantly seen in the normal kidney.

In summary, our data show that FABP1 expression has high tumor specificity and preferentially occurs in hepatocellular carcinomas, colorectal carcinomas, mucinous ovarian cancer, and other gastrointestinal adenocarcinomas. As FABP1 expression is virtually absent in adenocarcinomas of the lung, FABP1 immunohistochemistry might be most helpful for its distinction from metastatic adenocarcinoma to the lung.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PPTX 38563 KB) (37.7MB, pptx)
Supplementary file2 (XLSX 11 KB) (11.3KB, xlsx)
Supplementary file3 (XLSX 10 KB) (9.5KB, xlsx)

Acknowledgements

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

Author contribution

DD, RS, GS, TK: contributed to conception, design, data collection, data analysis, and manuscript writing.

FB, NG, VR, ML, AML, EB, AHM, DH, PL, FJ, SM, TSC, CB, NCB, DD, TK: participated in pathology data analysis and data interpretation.

TK, AHM collection of samples.

DD, TK: immunohistochemistry analysis.

RS, ML, AO, CHM: data analysis.

DD, RS, GS, TK: study supervision.

All authors agreed to be accountable for the content of the work.

Funding

Open Access funding enabled and organized by Projekt DEAL.

Data availability

All data generated or analyzed during this study are included in this published article. Raw data are available upon reasonable request.

Declarations

Ethical approval

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

Conflict of interest

The FABP1 antibody clone MSVA-501 M was received from MS Validated Antibodies GmbH (owned by a family member of GS).

Footnotes

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (PPTX 38563 KB) (37.7MB, pptx)
Supplementary file2 (XLSX 11 KB) (11.3KB, xlsx)
Supplementary file3 (XLSX 10 KB) (9.5KB, xlsx)

Data Availability Statement

All data generated or analyzed during this study are included in this published article. Raw data are available upon reasonable request.

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