|Year : 2019 | Volume
| Issue : 4 | Page : 566-571
|Morphological characterization and molecular profiling of malignant pericardial effusion in patients with pulmonary adenocarcinoma
Bing Zhou1, Lin Li2, Dayou Shi3, Tao Jiang4, Guohui Xue3, Jianping Xiong3
1 Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang; Department of Pathology, The Affiliated Jiujiang Hospital of Nanchang University, Jiujiang, Jiangxi, P.R. China
2 Department of Gerontology, Wuhan No. 1 Hospital, Wuhan, Hubei, P.R. China
3 Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, P.R. China
4 Department of Pathology, The Affiliated Jiujiang Hospital of Nanchang University, Jiujiang, Jiangxi, P.R. China
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|Date of Web Publication||14-Oct-2019|
| Abstract|| |
Context: Malignant pericardial effusions (MPCEs) is a common complication observed in advanced pulmonary adenocarcinoma. In such cases, investigating molecular alterations can have significant therapeutic implication in determining anticancer drugs. Aim: The objective was to evaluate the significance of cell block technique in the diagnosis of MPCE and further investigate the morphological and molecular profiles of MPCE in patients with pulmonary adenocarcinoma. Setting and Design: Cytopathological and molecular profiles of 19 MPCE cases in patients with pulmonary adenocarcinoma were retrospectively analyzed. The control group consisted of 14 malignant pleural effusion (MPE) cases in patients with pulmonary adenocarcinoma. Materials and Methods: Anaplastic lymphoma kinase (ALK) and tyrosine-protein kinase Met (C-MET) expression was evaluated by fluorescence in situ hybridization (FISH). Epithelial growth factor receptor (EGFR) and K-Ras (KRAS) mutations were detected by ARMS real-time polymerase chain reaction (RT-PCR). Statistical Analysis Used: Associations between MPCE and MPE were analyzed using Fisher's exact test. Results: MPCE was found to have micropapillary and solid pattern predominant with mucin secretion compared to acinar patterns, as seen in MPE. Seventeen MPCE cases (89.5%) and all MPE cases (100%) underwent molecular analysis. Mutations in EGFR and KRAS, ALK rearrangement, and C-MET amplification were observed in MPCE and MPE with statistical differences. Additionally, two MPCE cases demonstrated EGFR T790M mutation and multiple insertions at L858. Conclusions: MPCE shows micropapillary and solid cytological patterns predominant with mucin secretion. MPCE are suitable to analyze oncogenic mutations and to develop targeted therapy for patients with pulmonary adenocarcinoma. Further molecular investigations may reveal novel molecular alterations.
Keywords: Cytology, malignant pericardial effusion, oncogene mutation, pulmonary adenocarcinoma
|How to cite this article:|
Zhou B, Li L, Shi D, Jiang T, Xue G, Xiong J. Morphological characterization and molecular profiling of malignant pericardial effusion in patients with pulmonary adenocarcinoma. Indian J Pathol Microbiol 2019;62:566-71
|How to cite this URL:|
Zhou B, Li L, Shi D, Jiang T, Xue G, Xiong J. Morphological characterization and molecular profiling of malignant pericardial effusion in patients with pulmonary adenocarcinoma. Indian J Pathol Microbiol [serial online] 2019 [cited 2020 Nov 27];62:566-71. Available from: https://www.ijpmonline.org/text.asp?2019/62/4/566/269079
| Introduction|| |
Lung cancer has high morbidity and mortality worldwide. Non-small-cell lung cancer (NSCLC) accounts for about 80% of all lung cancer. Approximately 50% of NSCLC subtype is pulmonary adenocarcinoma. Malignant pericardial effusion (MPCE) is identified as a common complication observed in pulmonary adenocarcinoma and is estimated to affect about 40–60% terminally ill patients. However, upon diagnosis with MPCE, surgery is not preferred as a treatment for cancer due to its poor prognosis. Excess pericardial effusion can lead to impairment of the cardiac function or even cardiac tamponade which accounts to high mortality rate in cancer patients. Thus, MPCE treatments are highly significant as they can improve the lifestyle of patients and prolong their survival time. At present, pericardiocentesis and instillation of anticancer drugs is a simple and effective treatment. Although conventional chemotherapy with platinum antitumor drugs have achieved valuable results in treating MPCE, severe adverse reactions and intolerance in frail patients are recorded, thereby affecting the prospects for clinical application. Thus, as an alternative to perfusion drugs, we urgently need to find a highly selective treatment with less side effects and better clinical results for MPCE. The investigations of molecular alterations in MPCE will provide us with a suitable research direction. Using cell block technique in combination with immunohistochemistry can be useful to improve the accuracy in diagnosing patients with pleural effusion and also in the classification and primary tumor site assessment for further prognosis of MPCE. Sampling of MPE to identify molecular alteration is usually easy, safe, consistent, highly specific, and can provide novel source for the detection of genetic alterations in lung adenocarcinoma.,
This, in our knowledge, is the first study that evaluates of the significance of cell block technique in the diagnosis of MPCE and compares it with the control group (MPE). The objective of our study was to investigate the morphological characteristics and molecular profiling of MPCE in patients with pulmonary adenocarcinoma and to provide a new proposal for prognosis assessment and clinical screening thereby contributing toward the development of a targeted therapy.
| Materials and Methods|| |
The archives of cytopathology database were searched and 19 patients were selected who were cytologically diagnosed for lung adenocarcinoma with MPCE at First Affiliated Hospital of Nanchang University and Affiliated Jiujiang Hospital of Nanchang University between September 2013 and October 2018. The control group included MPE diagnosed patients with pulmonary adenocarcinoma during the same period. The clinicopathological parameters recorded include gender, age, smoking history, clinical staging, volume, tumor cell content, and histological subtype. The study was approved by the Medical Ethical Committee of Nanchang University (Jiangxi, China). Informed consent was obtained from all the patients.
All samples were kept at room temperature before decanting the supernatant. Fraction of the sample was used for ThinPrep cytology test (TCT) to prepare the slides and then stained with the hematoxylin and eosin (HE). The remaining fraction of sample was centrifuged to collect cell pellets which were then used to prepare the cell blocks. The blocks were then fixed with formalin, embedded in paraffin, sectioned at 3 μm thickness, and stained with HE. Immunohistochemical staining was performed on the cell block slides with primary antibodies against thyroid transcription factor-1 (TTF-1), Napsin A, cytokeratin 7 (CK7), p40, CK5/6, CK20, calretinin, homeobox protein CDX2 (CDX2), estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). All the antibodies were monoclonal and obtained from Zhongshan Golden Bridge Biotechnology Co., Ltd (Beijing, China). The phosphate-buffered saline solution was used for negative control and the positive control slides were used as positive controls.
All the slides were carefully studied by expert cytopathologists (Z.B. and J.T.) who were blinded to the histopathological diagnosis. These samples were analyzed for cytological features including background, number of neoplastic cells, cellular pleomorphism, cellular arrangement, cell shape and size, cytoplasm characteristics, intracytoplasmic vacuoles, nuclear features, and the presence of nucleoli. Microscopically, samples were evaluated for the presence of cytomorphological features and categorized based on the classification of lung adenocarcinoma proposed by International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS). The five different histological characteristics observed in MPCE and MPE included lepidic, acinar, papillary, micropapillary, and solid with mucin secretion.
DNA was extracted from the cell block according to the manufacturer's instructions (Cat No. 56404; QIAamp DNA FFPE tissue kits; Qiagen, Hilden, Germany). The concentration and purity of DNA were assessed at OD260/OD280 between 1.8 and 2.0. EGFR and KRAS mutations were detected using ARMS real-time polymerase chain reaction (PCR) which was obtained from YZY Biopharma Co., Ltd (Wuhan, China). The EGFR mutation analysis kit detected 11 mutations in exons 18–21 which included G719S, G719C, G719A, S768I, T790M, L858R, and L861Q; 19 deletions in exon 19; and three insertions in exon 20. The KRAS mutation analysis kit detected seven mutations which included G12C, G12S, G12R, G12V, G12D, G13A, and G13D. The fixed detection limit for mutations in EGFR and KRAS was 1–2.5%. If no mutation was detected in KRAS or EGFR, fluorescence in situ hybridization (FISH) was performed to detect ALK rearrangement and C-MET amplification using Vysis ALK Break Apart FISH Probe and Vysis MET SpectrumRed FISH Probe following manufacturer's instructions (Abott, Chicago, USA). Two hundred tumor cells were analyzed for each sample.
SPSS 20.0 software (SPSS Inc., Chicago, IL, USA) was used for data analysis. The Fisher's exact test was used to analyze the associations between MPCE and MPE groups. P= 0.05 was considered statistically significant.
| Results|| |
We identified 19 cases with MPCE which included 13 males and six females with an average age of 64 years (range, 36–84 years) and 14 cases with MPE that included nine males and five females with an average age of 66 years (range, 39–82 years). Gender, age, and smoking history did not show any statistically significant difference between the two groups (P = 0.891). In terms of sample volume, MPCE had six cases with less than 100 mL, nine cases with 200 mL, and four cases with more than 200 mL while MPE had nine cases with more than 200 mL, four cases with 200 mL, and one case with less than 100 mL. MPE sample volume was observed to be relatively more compared to MPCE sample volume (P = 0.011). Further, tumor cell content of MPCE was found to be less than 10% in five cases, 20% in eight cases, and more than 20% in six cases, whereas MPE had three cases with less than 10%, five cases with 20%, and six cases with more than 20% of tumor cell content. No statistical difference was observed between the two groups with respect to tumor cell content (P = 0.381). All cases were diagnosed for advanced pulmonary adenocarcinoma from their biopsy samples. Overall, cellularity of 19 MPCE and 14 MPE cases were identified where molecular analysis was required. The clinical data for all cases analyzed are summarized in [Table 1].
Under clean, hemorrhagic, and/necrotic background, MPCE showed heterogenous tumor cell population that were single-scattered or displaying three-dimensional clustering structure. The cells showed pleomorphism, high nucleocytoplasmic ratio, nuclear membrane irregularities, hyperchromatism, and prominent nucleoli along with dissimilarity in number of lymphocytes and mesothelial cells. Eight cases were classified to show predominance in micropapillary (42.1%) with tight cohesive nests of tumor cells and without discrete fibrovascular cores [Figure 1]a. Six cases were identifed to have predominant solid pattern with mucin secretion (31.6%). The tumor cells were distributed in cauliflower-like structure and flat sheets without a cribriform or papillary architecture. In addition, they were dense and larger in size with intracytoplasmic vacuolation [Figure 1]c. In five cases, only acinar or papillary pattern was found to be predominant. Half of the control group cases showed acinar pattern (50.0%) [Figure 1]e. The heterogenous tumor cells of MPE were distributed predominantly in flat 2D sheets with smooth nuclear contours and acinar-like architecture which was statistically different when compared to the architecture of MPCE group (P = 0.005) [Table 1]. When compared with the cytological slides, tumor cells in the cell block were distributed concentrically and maintained their original cytological structure along with tumor cells showing heterogeneity [Figure 1]b, [Figure 1]d, and [Figure 1]f.
|Figure 1: Cytologic features of MPCE and MPE. (a) Cohesive small nests of neoplastic cells showing micropapillary features, and the nuclei is located at the periphery. (H and E, × 400). (b) The cell block shows tumor cells with micropapillary pattern. (H and E, × 400). (c) Cluster of solid neoplastic cells are shown with abundant vacuolated cytoplasm and eccentric nuclei. (H and E, × 400). (d) The cell block shows tumor cells in solid with mucin secretion pattern. (H and E, × 400). (e) Cluster of neoplastic cells are shown with glandular lumens and cribriform formation. (H and E, × 400). (f) The cell block shows tumor cells in an acinar pattern or scattered arrangement. (H and E, × 400)|
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Immunohistochemical analysis of the MPCE group (n = 19) showed positive staining for TTF-1 (16 cases, 84.2%) [Figure 2]a, Napsin A (15 cases, 78.9%) [Figure 2]b, CK7 (17 cases, 100%), and CK20 (1 case, 5.3%). The control group (n = 14) was positive for TTF-1 (12 cases, 85.7%), Napsin A (13 cases, 92.9%), and CK7 (14 cases, 100%). All other markers negatively stained for MPCE and MPE.
|Figure 2: (a) TTF-1 immunostaining with a nuclear pattern (Envision ×200) (b) NapsinA immunostaining with a cytoplasm pattern (Envision ×200)|
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Of the 19 MPCE cases, two cases (10.5%) were excluded from molecular analysis due to insufficient tumor cell content. Overall, 17 cases were analyzed for lung adenocarcinoma-associated genes, such as EGFR, KRAS, ALK, and C-MET. Genetic abnormality was detected in 82.4% (14/17) cases which included mutations in EGFR(10 cases, 58.8%), KRAS(1 case, 5.9%), ALK rearrangements (2 cases, 11.8%) [Figure 3]a, and C-MET amplification (1 case, 5.9%) [Figure 3]b. EGFR mutations included point mutations in exons 18, 20, and 21 (G719A, 1 case; T790M, 1 case; L858R, 3 cases; respectively); deletion in exon 19 (4 cases); and multiple mutations in exon 20 and exon 21 (1 case) [Figure 3]c. Only one case showed G12C point mutation in codon 12 of KRAS [Figure 3]d. The control group detected nine out of 14 cases with genetic abnormality. Six cases (42.9%) were identified with EGFR mutations, two cases (14.3%) with KRAS mutations, one case (7.1%) with ALK rearrangements, and none with C-MET amplification. EGFR mutations included point mutations in exons 20 and 21 (S768I, 1 case; L858R, 2 cases) and a deletion in exon 19 (3 cases). Further, point mutations in KRAS were found in codon 12 (2 cases) for G12C and G12D. All cases expressed mutations with only one particular type of gene.
|Figure 3: (a) ALK rearrangement was identified by a split green-red signa. (b and c) MET amplification was identified by high polysomy; red was c-MET gene and CEP7was green. (c) ARMS analysis of EGFR multiple mutations in exons 20 and 21. (d) ARMS analysis of KRAS multiple mutations in G12C|
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Of the total 33 cases detected with MPCE and MPE, 19 cases showed EGFR and KRAS mutations while four cases revealed ALK rearrangement and C-MET amplification. In our study, the frequency of EGFR mutations was found high in lepidic and micropapillary subtype while lower mutation rates in other subtypes (P = 0.011). Furthermore, micropapillary subtype was found to be prevalent in EGFR mutations compared to EGFR mutations observed in solid with mucin secretion subtype (P = 0.024). Meanwhile, ALK rearrangement and C-MET amplification did not show any correlation with the histological subtypes [Table 2].
|Table 2: Correlation among EGFR mutation, KRAS mutation, ALK rearrangement, and cytologic features|
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| Discussion|| |
Due to recent developments in detecting molecular alterations and novel targeted therapies, significant advances have been made in understanding the molecular mechanisms in lung adenocarcinoma. New targeted therapies toward EGFR mutations and ALK rearrangements has dramatically changed the therapeutic strategy for advanced lung adenocarcinoma. In its 2018 guidelines, American Society of Clinical Oncology (ASCO) recommended molecular detection of all functional genes such as EGFR, ALK, ROS1, and HER2 in patients with advanced NSCLC disease. In addition, as being a relatively independent prognostic factor, KRAS and C-MET have also been associated with drug resistance, tumor invasion, and metastasis. Effective prognosis and evaluation of drug efficacy has been the current focus in detecting target molecules involved in pulmonary adenocarcinoma., However, acquired drug resistance and unfamiliar molecular alterations toward newly developed treatments is another troubleshooting area to solve. MPCE is defined by the presence of pulmonary adenocarcinoma with pericardial metastasis in terminally ill patients. Targeted molecular therapy has been shown to be effective in improving the survival rate. Previous studies have revealed that morphological characteristics and molecular profiles vary significantly in metastatic tumors.
In our study, the number of MPCE cases were lower than MPE control cases. However, there was no significant difference in the tumor cell content between the two groups which is consistent with the previous reports that show no correlation between volume and cellularity exists in pleural effusion. It has been shown that although inadequate tumor cell content is associated with false-negative results, low volume of MPCE cases should not discourage further molecular analysis. However, there were two cases (10.5%) which were excluded for molecular analysis due to insufficient tumor cell content in MPCE. Further, we can collect additional samples to prepare cell blocks and perform immunohistochemical stains to track a larger scale study. In addition, next-generation sequencing (NGS), which requires limited amount of DNA from pleural effusions for molecular analysis should also be taken into consideration.
The cytomorphological criteria proposed by the IASLC/ATS/ERS classifies cytological samples of pulmonary adenocarcinoma in five primary patterns. However, majority of the pleural effusions are found to have a mixed subtype, which makes it difficult to categorize the tumor in single patterns. Often in practice, the predominant type of cytological pattern is emphasized in classification. Interestingly, majority of MPCE cases in our study were classified as predominant in micropapillary pattern and solid with mucin secretion pattern while two cases showed acinar-like pattern. While acinar subtypes are considered as the main type of MPCE, two cases showed associated micropapillary architecture and one showed predominance in solid patterns with mucin secretion in this study. Prior studies that have examined pulmonary adenocarcinoma with micropapillary and solid pattern show an aggressive clinical behavior with poor prognosis. Thus, detection of the cytological pattern is essential for suitable treatment and better prognosis., Immunohistochemically, studies have shown that inconsistency in CK7, TTF-1, and Napsin A staining is a helpful measure to diagnose pulmonary adenocarcinoma. However, no significant difference was observed between the two groups and further molecular studies are currently required to guide new targeted therapies.
We found that EGFR was the most frequent molecular alteration observed in MPCE and mainly consisted of deletion in exon 19 and point mutation (L858R) in exon 21. Frequency of EGFR mutation was high in MPCE (27%) compared to EGFR mutation rate in MPE (13%), which is in accordance with earlier studies and do not show any statistical significance., Several researchers have found inconsistency in EGFR mutations between primary and metastatic tumor, and high mutation rate has been shown to assist tumor metastasis. Our results were consistent with the previous studies in such findings., A novel T790M mutation in exon 20 was detected which might be contributing as secondary resistance to tyrosine kinase inhibitor (TKI) treatment. Thus, it was found to occur predominantly in metastatic and relapsed tumors. Meanwhile, multiple mutations were found in exons 20 and 21 in MPCE. However, the clinical significance and sensitivity to TKIs with respect to these mutations is unknown. EGFR mutations were found higher in lepidic, micropapillary, and acinar patterns while lower in other subtypes. The frequency of EGFR mutation in patients with micropapillary was significantly higher compared to EGFR mutation rate in solid with mucin secretion pattern (P = 0.024). Consistent with the outcomes of earlier study, we revealed that EGFR mutations vary with adenocarcinoma subtypes. By contrast, the frequency of KRAS mutation was found lower in MPCE compared to KRAS mutation rate in MPE, which is also similar with frequencies (19%) reported earlier. All KRAS alterations were found to be point mutations at G12C and G12D. However, their correlation with cytological subtypes is not clear and requires to be verified with large scale study. ALK rearrangement was found more in MPCE compared to ALK rearrangement observed in MPE. Nevertheless, statistical analysis shows that there was no significant difference between the two groups. Two cases of ALK rearrangement were found to show solid predominant pattern with mucin secretion and one with acinar predominant pattern. Consistent with the previous study, our study revealed that ALK rearrangement is higher in tumors with solid predominant pattern with mucin secretion compared to rearrangement in solid patterns without mucin secretion. As a rare molecular mutation in lung cancer, C-MET amplification is observed in patients who develop resistance after anti-EGFR therapy. It has been suggested that C-MET amplification accounts only 1% ~ 7% in primary adenocarcinomas; however, it explains 20% of EGFR-TKI resistant adenocarcinomas. In our study, C-MET amplification was found in one MPCE case with micropapillary cytology. Due to its potential therapeutic implications, more samples should be further investigated.
The present study had several shortcomings. It was a retrospective study with a relatively small number of MPCE cases. In addition, the concurrent molecular and cytological features were not studied or confirmed with tissue biopsies. Finally, a prospective study of a large number of MPCE cases is required to reveal relation between the cytological features and molecular profile.
In this study, the cytological and molecular changes in MPCE of patients with pulmonary adenocarcinoma were studied. Comparing cytological characteristics, we found that acinar type is predominant in MPE while MPCE shows micropapillary and solid pattern with mucin secretion. Further in MPCE, mutation rate of EGFR is higher, whereas that of KRAS is less compared to those in MPE. In addition, C-MET amplification was also found in one case. There is correlation between the cytologic features and molecular profile, mutation rate of EGFR is higher in lepidic and micropapillary subtypes, while lower in solid with mucin secretion. Therefore, we suggest that MPCE is suitable for oncogene mutation analysis and further investigations may reveal novel acquired molecular alterations.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Oncology, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Road, Nanchang, Jiangxi - 330 006
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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