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ORIGINAL ARTICLE  
Year : 2018  |  Volume : 61  |  Issue : 2  |  Page : 187-191
Diagnostic and prognostic impact of mucin 1–6 expression in non-small cell lung cancer


1 Department of Pathology, Hospital Bayreuth, Bayreuth, Germany
2 Department of Internal Medicine, Division of Hematology and Oncology, Medical University Innsbruck, Innsbruck; Department of Internal Medicine, Oncology and Geriatrics, Hospital Hochrum, Rum, Austria
3 Department of Pathology, University Hospital Basel, Basel, Switzerland

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Date of Web Publication20-Apr-2018
 

   Abstract 


Background: The prognostic significance and clinico-pathological characterization of mucin (MUC) expression in non-small cell lung cancer (NSCLC) is controversial and little studied. Aims: This study aims at elucidating this issue on the largest and most detailed cohort so far. Settings and Design: We examined the expression of MUC 1, 2, 4, 5AC and 6 on 371, well documented, surgically resected NSCLC cases. Materials and Methods: Immunohistochemical results were correlated with several of our previously studied, relevant parameters on this cohort including a follow-up period of up to 20 years. An additional point we examined for practical reasons that has not been addressed so far, was the possible assistance of MUC expression for the differentiation between a primary lung adenocarcinoma and metastasis from a known pancreatobiliary primary tumor. Statistical Analysis Used: Cronbach's Alpha reliability correlation, Spearman's correlation, ANOVA means of comparison with additional Kruskall–Wallis H-test, and Kaplan–Meier survival analysis were employed as statistical analyses in this study. Results and Conclusions: MUCs were associated with histologic subtypes, tumor differentiation and members of the epidermal growth factor receptor signaling pathway, although they were not found to be significant for prognosis. Expression of MUC1 correlated with certain other markers and may point to a group of patients relevant for upcoming treatment strategies involving MUC1. According to our findings, we also recommend additional MUC5AC staining for a thyroid transcription factor 1-negative adenocarinoma in the lung for the differentiation of a possible metastasis in the presence of a pancreatic ductal adenocarcinoma.

Keywords: Immunohistochemistry, mucin expression, non-small cell lung cancer, pancreatic ductal adenocarcinoma, prognosis

How to cite this article:
Sterlacci W, Fiegl M, Veits L, Tzankov A. Diagnostic and prognostic impact of mucin 1–6 expression in non-small cell lung cancer. Indian J Pathol Microbiol 2018;61:187-91

How to cite this URL:
Sterlacci W, Fiegl M, Veits L, Tzankov A. Diagnostic and prognostic impact of mucin 1–6 expression in non-small cell lung cancer. Indian J Pathol Microbiol [serial online] 2018 [cited 2020 Feb 21];61:187-91. Available from: http://www.ijpmonline.org/text.asp?2018/61/2/187/230563





   Introduction Top


Mucins (MUCs) are high molecular weight, glycosylated proteins expressed on many epithelial cells and can be generally classified as membrane bound (e.g., MUC1, MUC4) or secretory (e.g., MUC 2, MUC5, MUC6). MUC1 epithelial membrane antigen is a glycoprotein involved in cellular adhesion via intercellular adhesion molecule-1 and is expressed by various normal epithelial tissues and malignant counterparts, however with a different structure in malignancies.[1],[2],[3] Several researchers have reported that MUC1 expression correlates with poor outcome in many human neoplasms.[4],[5],[6] In the lung, MUC1 immunoreactivity has been demonstrated in normal type II pneumocytes as well as atypical lesions deriving from type II cells and also in many non-small cell lung carcinomas (NSCLC).[7] Intense expression was hereby reportedly associated with adenocarcinoma (ACA) histology but did not correlate with survival.[7] MUC1 expression has also been classified as polarized (localized to the membrane), associated with better survival, and depolarized (diffuse, cytoplasmic staining), being reported as a marker of poor prognosis, progressive disease stage, and lymph node metastasis.[4],[5] Depolarized expression of MUC1 has been shown to correlate with hypoxia and angiogenesis (vascular endothelial growth factor [VEGF] and microvessel density) and expression of epidermal growth factor receptor (EGFR).[4] Another group reported high polarized expression in ACA and better-differentiated tumors.[5] MUC2 is expressed in many normal organs including the colon, the small intestine and the respiratory tract and is also found in carcinomas of the intestine and pancreatobiliary system.[8] MUC4 is expressed in the foregut before epithelial differentiation takes place and is found in normal adult airway epithelium, as well as in other organs such as the colon, the cervix and the prostate. MUC4 has been demonstrated in NSCLC and interestingly, has been mainly characterized in other malignant tumors that lack MUC4 in their organs of origin (e.g., pancreas, breast, ovary).[9],[10] MUC4 expression has been associated with ACA histology, however its correlation with prognosis is controversial.[9],[10] MUC4 expression in NSCLC has also been shown to correlate with various regulators of the cell cycle.[10] MUC5AC is a gastric-type MUC and is often used in pancreatobiliary diagnostics, since it is not expressed in normal pancreas tissue in contrast to various pancreatobiliary precursor lesions and carcinomas.[8] In NSCLC, MUC5AC overexpression has been found in ACA but has been associated with squamous lesions as well.[11] Although data are sparse, overexpression of MUC5 genes has been linked to tumor recurrence and metastasis in NSCLC.[12] Expression of MUC6 is seen in various normal tissues including stomach, gallbladder, duodenum, pancreas and bile ducts and also in carcinomas of the pancreatobiliary system, cervix, and breast.[8]

Since the prognostic significance of MUC expression in NSCLC is controversial and little studied for certain types, we aimed to examine this issue on a large cohort of well documented, surgically resected NSCLC cases. Furthermore, we correlated our results with several of our previously studied parameters on this cohort, which have been reported by others to play a role in connection with MUC expression. An additional important point we examined for practical reasons in daily diagnostics, and that has not been addressed so far, was the possible differentiation between a primary lung ACA and a metastasis from a known pancreatobiliary primary tumor.


   Materials and Methods Top


Patients and tissue sampling

The archival samples were derived from 371 NSCLC patients with radical surgical resection in curative intent between 1992 and 2004 and diagnosed at the Institute of Pathology, Medical University of Innsbruck.[13],[14],[15] Carcinoids were excluded from this analysis. Cases were selected only based on tissue preservation. Hematoxylin and eosin -stained slides from all available specimens were reclassified by two pathologists (WS and AT) without the knowledge of patient data, according to the current (2015) WHO classification of tumors of the lung.[16] Tumor differentiation was graded as well, moderate, or poor. The clinical information was documented within the TYROL (20 years Retrospective of Lung Cancer) survey, a project aiming to analyze various features of a large number of lung cancer patients.[17] Approval for data acquisition and analysis was obtained from the Ethics Committee of the Medical University of Innsbruck.

Tissue microarray construction

Tumor material consisted of paraffin-embedded tissue after fixation in 10% neutral buffered formalin. The Tissue microarray was constructed as previously described.[13] The first sections were stained by H and E to confirm validity, the following used for immunohistochemistry.

Immunohistochemistry

Staining protocols of the primary antibodies MUC1, MUC2, MUC4, MUC5AC, and MUC6 are listed in [Table 1]. Immunohistochemistry was performed using the automated staining system Benchmark XT (Roche/Ventana Medical Systems, Tucson, USA).
Table 1: Primary antibodies and staining protocols

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Immunohistochemical evaluation

Only cores containing at least 20 vital tumor cells were evaluated. If all four spots of a case did not meet this criterion it was excluded, thus the minimum tumor cell count of evaluated cases was eighty (4 cores with ≥20 tumor cells). Tumor cells were scored independently by W. S. and L. V., and A. T. for MUC1 to study agreement between observers. The percentage of positively stained cells with clearly visible membranous staining was noted for each spot, followed by the calculation of the arithmetic mean value. In addition, cytoplasmic staining was taken into account for MUC1 and characterized as depolarized. Cases were considered positive if any amount of membranous staining was seen. For MUC1, an additional cutoff for low (<50% membranous staining) and high (≥50% membranous staining) positive (polarized) tumors was calculated.

Statistical analysis

The degree of agreement between observers was evaluated by interclass correlation coefficients, using reliability Cronbach's Alpha analysis. Correlation analysis of clinicopathological and immunohistochemical parameters was performed using the Spearman's test corrected for multiple testing, considering P < 0.01 as statistically significant. For the major histology types (squamous cell carcinomas [SCC], ACA and large cell carcinomas), the mean percentage of positively stained cells was compared by means of ANOVA and further analyzed using the Kruskal–Wallis H-test. Kaplan–Meier curves were calculated for survival estimates and the log-rank statistics were used to determine differences between groups. When not corrected for multiple testing, P < 0.05 were considered as statistically significant. Two-sided tests were used throughout the analysis. Statistical calculations were performed using SPSS 22.0 software (SPSS, Chicago, IL, USA).


   Results Top


Histopathology and patient characteristics

Histological subtypes consisted of 215 ACA, 123 SCC, 14 large cell carcinomas, 8 large cell neuroendocrine carcinomas, 8 adenosquamous carcinomas, 2 sarcomatoid carcinomas, which were both of the pleomorphic type and 1 mucoepidermoid carcinoma. Patients' characteristics have been presented in detail previously.[18] For reliable results, only the major histologic subtypes [ACA and SCC, as shown in [Figure 1] were assessed for correlation analyses and compared when assessing overall survival (OS) regarding histology.
Figure 1: Hematoxylin and eosin stains of (a) a squamous cell carcinoma (b) and a adenocarcinoma (×100)

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Immunohistochemistry

Cronbach's Alpha for interobserver reproducibility of the immunohistochemical markers was excellent (highest = 1.0 for MUC2, lowest = 0.980 for MUC1). Quantitative and qualitative immunohistochemical data are shown in [Table 2] and [Figure 2]. An additional staining interpretation for MUC1 incorporating the polarized and depolarized pattern is shown in [Table 3].
Table 2: Immunohistochemical expression profiles

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Figure 2: Immunohistochemical expression of (a) mucin 1 polarized and (b) depolarized (c) MU2, (d) mucin 4, (e) mucin 5AC, (f) mucin 6 (×360)

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Table 3: Differentiated mucins 1 expression

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The mean and median percentage of stained cells according to the main histologic subtype is shown in [Table 1], revealing that MUC1, MUC5AC, and MUC6 were more common in ACA and MUC4 more common in SCC. MUC expression of ACA according to thyroid transcription factor (TTF1) status is shown in [Table 4].
Table 4: Expression of mucins in adenocarcinomas according to thyroid transcription factor 1 status

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For the comparison with MUC expression in ductal pancreatic cancer, we related to widely published data showing that this cancer type is generally positive for MUC1, MUC4, and MUC5AC.[19],[20]

Correlations between variables

In addition to the presently studied markers, previously assessed relevant molecular parameters were integrated as well.[21],[22] MUC1 and MUC5AC were more frequently found in better differentiated (lower grade) tumors (correlation coefficient rho ρ = 0.239, P < 0.001; ρ = 0.165, P = 0.004, respectively), and MUC1 was also associated with lower proliferation rates determined by Ki67 (ρ = 0.146, P = 0.013). MUC1 and MUC5AC were also associated with lacking EGFR expression (ρ = 0.174, P = 0.003; ρ = 0.192, P = 0.001, respectively) and an increase in the expression of cytoplasmic p27 (ρ = 0.247, P < 0.001; ρ = 0.187, P = 0.001, respectively), mTOR (ρ = 0.287, P < 0.001; ρ = 0.254, P < 0.001, respectively), and E-cadherin (ρ = 0.350, P < 0.001; ρ = 0.214, P < 0.001, respectively) (Cyline). MUC1 was correlated with loss of p21 (ρ = 0.182, P < 0.002). No correlations with markers of angiogenesis or microvessel density (D2-40, VE-cadherin, CD34, VEGF, VEGFR1, VEGFR2, CD146, CD105) were found.[21]

Survival analysis

Expression of the studied MUCs was not associated with OS. This applied to the entire group as well as to the subgroups including histology, tumor stage, recurring disease, and sex (results not shown). The various described patterns of MUC1 staining did not influence the outcome.


   Discussion Top


We analyzed the expression of the most commonly used MUCs in diagnostic pathology on a large cohort of well documented NSCLC cases. We found that certain MUCs correlated with histologic subtypes, tumor differentiation, and members of the EGFR signaling pathway, but are not significant for prognosis.

MUC expression has been described as a prognostic marker for various tumors, although with somewhat conflicting results.[4],[5],[6],[7] Especially MUC1 is frequently studied with regard to survival. In our group, none of the examined MUCs correlated with OS for the entire cohort; this was also the case when we stratified our collective according to various characteristics, including histology, tumor stage, recurring disease, and sex. Since there are different interpretations of MUC1 staining, we also took this into account. Neither a bivariate scoring system (any amount of membranous expression versus no expression) nor a classification into depolarized (cytoplasmic), polarized (low: <50%, high: >50% membranous staining) or negative resulted in significant differences. Due to the already existing body of controversial data and our additional results, we do not believe that the expression of MUCs is prognostically relevant for NSCLC. Interestingly, MUC1 and MUC5AC were associated with better-differentiated tumors and MUC1 expression also correlated with lower Ki67 percentages, indicating potentially less aggressive tumors. In line with these findings, MUC1 and MUC5AC were also associated with lack of EGFR expression, indicating a possible group with reduced proliferation, which was also reflected by the expression of the known cell cycle “down tuning” factors p21 and p27, and mTOR. Raina et al. have reported that the cytoplasmic domain of MUC1 is associated with PI3K in NSCLC, another key member of the EGFR pathway.[23] By blocking MUC1, constitutive phosphorylation of Akt and mTOR, the latter being more abundantly present in our MUC1 positive cases, was achieved, thus presenting as a potential target for inhibiting tumor growth.[23] Vaccines targeting MUC1 have also been developed and have been shown to successfully generate anti-MUC1 T-cell proliferations and anti-MUC1 antibodies, thus further emphasizing MUC1 as a possible anticancer treatment target.[24],[25] Although most NSCLC do express MUC1, our study shows that around 10% are MUC1 negative. Therefore, a simple immunohistochemical screening test may improve such targeted approaches and should be considered for future anti-MUC1 studies. Since correlations with MUC expression and markers of angiogenesis and microvessel density have been reported, we included various parameters of our previously published work on this issue in the present study, however without significant findings.

When comparing the histologic subtypes, we found MUC1, MUC5AC, and MUC6 more frequently in ACA, and MUC4 more frequently in SCC. MUC2 was only positive in a single case, an ACA, which was diagnosed as a pulmonary ACA of the enteric type after careful clinical exclusion of an intestinal primary;[26] the case was further positive for both cytokeratin 7 and 20 and negative for TTF1 and CDX2. One important point of our study was to find a possible utilization of MUC expression for the differentiation between a primary TTF1-negative pulmonary ACA and a metastasis of a known ACA of the pancreas. This poses a difficult, but clinically very important differentiation, as we have experienced in our routine diagnostics. Literature to date does not explicitly discuss this issue or provide guidelines or useful recommendations. Although next-generation genomic analyses and the study of pathogenic mutations in pancreatic cancer have suggested different molecular pancreatic cancer subtypes, this does not assist in differentiating pancreatic cancer from other cancer entities.[27],[28] Immunohistochemical markers useful for the differentiation of other cancer types (e.g., SATB2) are also not evident for pancreatic cancer to date.[29] MUC5AC expression is present in almost all pancreatic ductal ACA (which are negative for TTF-1), however in only 60% of our TTF-1-negative pulmonary ACA, thus being the most promising (among the studied MUCs) marker for differentiating the two entities. Lack of expression of MUC5AC in a TTF1-negative ACA would therefore strongly favor a pulmonary primary. MUC6 has lower impact in this regard since it is less frequently positive in pancreatic ductal ACA compared to MUC5AC, and also only detectable in 20% of our TTF1-negative pulmonary ACA.


   Conclusions Top


In light of MUC1 becoming a potential treatment target for patients with NSCLC, according to our findings assessment of MUC1 expression singles out certain groups of patients, which could possibly show a different benefit. This should be taken into account for upcoming studies by integrating this parameter when analyzing treatment response. We also recommend additional MUC5AC staining for a TTF1-negative ACA in the lung to falsify (verify) potential metastasis of a pancreatic ductal ACA. A negative MUC5AC stain in this setting would favor a pulmonary ACA and a pulmonary metastasis of a pancreatic ductal ACA would be far less likely, thus drastically alternating the clinical management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
William Sterlacci
Institute of Pathology, Hospital Bayreuth, Preuschwitzerstrasse 101, 95445 Bayreuth
Germany
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_678_17

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