| Abstract|| |
Introduction: Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutational analysis in adenocarcinoma lung are growing in importance as these tests are essential in guiding the use of targeted therapy. However, the prevalence of these mutations in various populations in India has not been studied. Furthermore, the correlation of histologic pattern with the mutation is not clear. Materials and Methods: A total of 64 biopsy-proven lung adenocarcinomas were selected. In 51 of these, EGFR mutational analysis was performed using Qiagen EGFR pyrosequencing kit and in 56 cases of these ALK1 immunohistochemistry (IHC) was done using ALK (D5F3) antibody and the Ventana Benchmark® XT automated IHC slide staining system for the detection of overexpression. The adenocarcinomas were classified into well, moderate, and poorly differentiated, and the histological pattern was recorded according to the WHO 2014 classification. Results: EGFR mutation was positive in 23 cases (45.10%) and positive ALK1 expression by IHC in 12 cases (21.43%). Both mutations were positive in two cases. Both mutations were seen in well-differentiated and moderately differentiated adenocarcinoma, and the expression was highest in tumors with a predominant acinar pattern. Conclusions: The incidence of both EGFR and ALK1 mutations is higher in the population studied and seem to correlate with a well differentiated, acinar pattern on morphology.
Keywords: Anaplastic lymphoma kinase, epidermal growth factor receptor, lung adenocarcinoma
|How to cite this article:|
Gupta P, Gowrishankar S, Swain M. Epidermal growth factor receptor and anaplastic lymphoma kinase mutation in adenocarcinoma lung: Their incidence and correlation with histologic patterns. Indian J Pathol Microbiol 2019;62:24-30
|How to cite this URL:|
Gupta P, Gowrishankar S, Swain M. Epidermal growth factor receptor and anaplastic lymphoma kinase mutation in adenocarcinoma lung: Their incidence and correlation with histologic patterns. Indian J Pathol Microbiol [serial online] 2019 [cited 2019 Jul 17];62:24-30. Available from: http://www.ijpmonline.org/text.asp?2019/62/1/24/251261
| Introduction|| |
Lung cancer is one of the leading causes of cancer-related deaths worldwide with over 1 million cases diagnosed every year.,,, Nonsmall cell lung carcinoma (NSCLC) accounts for approximately 75%–80% of all lung carcinomas.,,, Adenocarcinoma comprises 40% of all lung cancers. The molecular genetics of NSCLC is complex and heterogeneous. Recently, there have been major advances in our understanding of the pathogenesis of NSCLCs, and in adenocarcinomas have led to the identification of many of the key molecular pathways that promote tumor growth.
A considerable fraction of lung adenocarcinoma develops through the acquisition of mutations either in the epidermal growth factor receptor (EGFR), v-Ki-ras2 Kirsten rat sarcoma viral oncogene, or anaplastic lymphoma kinase (ALK) genes.
EGFR belongs to erb-B family of closely related tyrosine kinase (TK) receptor., EGFR is a 486 amino acid receptor protein of 170 kDa with a single transmembrane sequence between 4 extracellular and three intracellular domains.,,,,, Ligand binding activity is in the extracellular domain 3. On binding of a specific ligand, the normally functioning EGFR undergoes some conformational changes and phosphorylation of intracellular domain, leading to downstream signal transduction by various pathways. The result is cell proliferation or inhibition of apoptosis.,
EGFR gene mutations are commonly seen in nonsmoker females and frequencies are considerably higher in Asians than in Europeans and Americans. It occurs commonly in adenocarcinoma, but may also be seen in adenosquamous carcinoma or squamous cell carcinoma.
In 2007, Sodaet al. identified an echinoderm microtubule associated protein-like 4 (EML4)-ALK gene fusion in specimens from five lung cancer patients and revealed the role of ALK fusion protein as an important oncogenic driver in a subset of NSCLC.,,
ALK is a 1620 amino acid transmembrane protein, which encodes a receptor TK. It is member of the insulin receptor superfamily. ALK was first described in 1994 in non-Hodgkin's lymphoma, where it was shown to acquire transforming capability when fused to another protein, nucleophosmin, as a consequence of a chromosomal rearrangement.,,
ALK rearrangement has been identified in around 4% of cases of NSCLC. According to some studies the ALK rearrangement can be detected up to 20% of adenocarcinoma cases in the lung. They are found most commonly in young, nonsmokers or light smokers with adenocarcinoma. ALK rearrangements are usually mutually exclusive of EGFR mutation, but cases of coexistent mutations have been reported.,, The Food and Drug Administration (FDA) has approved immunohistochemical method using “Ventana anti-ALK (D5F3) rabbit monoclonal primary antibody” on the Ventana Benchmark ® XT automated immunohistochemistry (IHC) slide staining system as an alternative to fluorescence in situ hybridization for the detection of ALK1 mutation.
Identification of the above mutation is important in guiding the use of recently developed targeted therapies.
In carcinoma breast, it is now accepted knowledge that histologic patterns predict estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 neu status. It is therefore recommended that the IHC tests be repeated if the results do not conform to the morphologic pattern of breast cancer.
Lung adenocarcinomas are now typed according to the predominant histological pattern. It is not clear if these patterns of tumor have a correlation with the EGFR and ALK1 mutation status like in breast cancer and there are not many studies in the literature documenting the correlation of histology with mutational status, especially in Indian literature. Furthermore, not many studies have looked at both mutations in a given population. This prospective study was, therefore, undertaken to study the prevalence of EGFR and ALK1 mutation in lung cancer and to correlate the predominant histological pattern, according to the latest classification with the mutational status.
| Materials and Methods|| |
A total of 107 cases of diagnosed lung adenocarcinoma including primary and metastatic, were identified from the biopsy records of our hospital over a period of 1 year from August 2014 to July 2015. Sixty-four consecutive cases of these fulfilled the following criteria and were selected.
Study inclusion criteria
Cases of lung adenocarcinoma diagnosed on biopsies of lung masses or metastases in lymph nodes, vertebrae, pleura, etc.
Lobectomy or metastatectomy.
Study exclusion criteria
Inadequate material and unsatisfactory samples.
Lung carcinomas other than adenocarcinoma.
In all cases, the diagnosis of adenocarcinoma was made by brightfield microscopy on H and E stained slides.
Histological patterns of acinar, papillary, micropapillary, lepidic, solid, cribriform, mucinous, and signet ring type were assigned in all cases, as defined in the WHO classification of lung cancers, 2014 [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d, [Figure 1]e, [Figure 1]f, [Figure 1]g.
|Figure 1: Histological patterns and immunohistochemistry in lung adenocarcinoma: (a) solid pattern (b) papillary pattern (c) acinar pattern (d) micropapillary pattern (e) lepidic pattern (f) mucinous adenocarcinoma (g) cribriform mucinous adenocarcinoma (h) anaplastic lymphoma kinase positivity on immunohistochemistry (i) anaplastic lymphoma kinase negativity on immunohistochemistry|
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For this study, we also graded the tumors, using the system in endometrial cancers into well differentiated (Grade I), moderately differentiated (Grade II), and poorly differentiated (Grade III), depending on the extent of glandular differentiation, using cutoffs of:
- Greater than 95% glands – well differentiated
- 50%–95% glands – moderately differentiated
- Less than 50% glands – poorly differentiated.
We increased the histological grade by one in cases where marked nuclear atypia was present and where a solid pattern was seen.
Immunohistochemistry for anaplastic lymphoma kinase protein
Out of the total of 64 cases, IHC was performed in 54 cases using the FDA approved “Ventana anti-ALK (D5F3) rabbit monoclonal primary antibody;” OptiView DAB IHC detection kit and Ventana Benchmark ® XT automated IHC slide staining system [Figure 1]h and [Figure 1]i.
Pyrosequencing for epidermal growth factor receptor mutation detection
PCR was done in 51 cases to detect EGFR mutation, using “Qiagen EGFR pyrosequencing kit.” This detects mutation in exons 18–21, which are the common mutations described in lung cancer [Figure 2].
|Figure 2: Results of epidermal growth factor receptor by pyrosequencing: (a) Nomutation at exon 18 codon 719 (b) Mutation at exon 18 codon 719|
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In the remaining cases, the tissue was insufficient and not available for testing.
| Results|| |
In the present study, a total of 64 cases were studied. EGFR mutation and ALK1 IHC study was done on 43 cases. EGFR mutation alone was studied in 8 cases and ALK-1 mutation alone was done on 13 cases.
Epidermal growth factor receptor mutation in lung adenocarcinomas
The results of the EGFR mutation were analyzed according to the age, gender, grade, and predominant histological pattern [Table 1].
Anaplastic lymphoma kinase mutation in lung adenocarcinomas
The results of the ALK1 mutation were analyzed according to the age, gender, grade, and predominant histological pattern [Table 2].
|Table 2: Results of anaplastic lymphoma kinase 1 mutational analysis by immunohistochemistry|
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[Table 3] compares our results with that of other studies.
|Table 3: Comparison of results of epidermal growth factor receptor mutation in the present study with similar studies|
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Forty-three cases were analyzed for EGFR and ALK mutations. Of these, 2 cases harbored both mutations. Both patients were male, of age 60 years and 62 years, respectively. Both had acinar pattern with one having histological Grade I and the other having histological Grade II.
| Discussion|| |
The use of molecular targeted therapy in genetically defined subsets of cancer patients is emerging as an effective therapeutic strategy for many cancers. Many studies have reported that mutations in the EGFR and ALK genes in lung adenocarcinomas make the disease more responsive to the treatment with specific TK inhibitors. We analyzed EGFR and ALK-1 mutations in 64 cases of lung adenocarcinoma to assess the incidence of these mutations in our population and its distribution according to sex, age, histological grade, and histological pattern.
Epidermal growth factor receptor mutation
The incidence of EGFR mutation was 45.10% in our study. This figure is higher than that reported in other studies, where the positivity has ranged from 10% to 45%.
The mean and median age in this group was 58.26 and 58 years, respectively, which is similar to that in other studies.
The mutations were more common in males unlike other studies where they were more frequent in females.
Unlike other tumors, a widely accepted grading system for lung cancer [Figure 2] has not yet been established. In 2011, the International Association for the study of lung cancer, American Thoracic Society, and European Respiratory Society proposed a new classification for lung adenocarcinoma based on the presence and the proportion of histological patterns. This classification is more applicable to resection specimens, with three grades – Grade I: Lepidic predominant, Grade II: Acinar or papillary predominant, and Grade III: Solid or micropapillary predominant. These grades correspond to well differentiated, moderately differentiated, and poorly differentiated adenocarcinoma, respectively.
Since a definitive grading system for resected specimens has not yet been established, there is no widely accepted grading system for small biopsy specimens either. In our study we had 5 resection specimens, all the others being either small guided biopsies or pleural fluid. So, for this study we classified adenocarcinomas depending on the extent of glandular differentiation. Grade I for tumors with more than 95% glandular differentiation, Grade II for those with 95% to 55% glandular differentiation, and the tumors with <55% glandular differentiation were categorized as Grade III. We upgraded the tumor by one grade in the presence of a solid pattern or when nuclear atypia was present.
Histological grade and epidermal growth factor receptor mutation mutation
In our study, 51% of cases (26/51) were histological Grade I, 37% of cases (19/51) were histological Grade II and 12% of cases (6/51) were histological Grade III. In EGFR mutation positive cases 61% (14/23) had histological Grade I and 39% (9/23) had histological Grade II. No case with Grade III morphology had EGFR mutation.
The study results are similar to the study by Kosaka et al. showing that EGFR mutations were significantly more frequent in well differentiated to moderately differentiated adenocarcinoma (58%) than in poorly differentiated adenocarcinoma (30%). However, it is important to note that the criteria used for grading were not specified in this study.
Histologic patterns in epidermal growth factor receptor mutation mutation
According to the recent WHO classification of 2015, lung adenocarcinoma is classified into five patterns as follows: Acinar, solid, papillary, micropapillary, and lepidic predominant. Due to the heterogeneity of lung cancer, in the nonresection specimens a “predominant pattern” cannot be concluded, and hence, all patterns present in the biopsy have to be enlisted.
As the majority of the specimens in our study were biopsies, a predominant pattern was not assigned and all patterns were recorded. When more than one pattern was present, a diagnosis of the mixed pattern was made.
Of the 51 cases, 32 cases (62.74%) showed only acinar pattern, 2 cases (3.92%) showed only papillary pattern, 5 cases (9.80%) showed only solid pattern, 2 cases (3.92%) had mucinous adenocarcinoma, 1 case (1.96%) had mucinous cribriform, and 1 case (1.96%) had adenosquamous carcinoma. The remaining 8 cases (15.68%) showed a mixed pattern. The mucinous cribriform pattern had no EGFR mutation.
In EGFR positive cases, the acinar pattern was most frequent, seen in 16 out of 23 cases (69.57%). Two cases (8.7%) showed mucinous adenocarcinoma. One case each of solid and papillary was positive for EGFR. Remaining 3 of the EGFR positive cases (13.04%) had mixed patterns.
Anaplastic lymphoma kinase mutation
[Table 4] compares our results with that of other studies.
|Table 4: Comparison of results of anaplastic lymphoma kinase 1 mutation in the present study with similar studies|
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The incidence of ALK mutation was 21.43% in our study. This figure is higher than that reported in other studies, where the positivity has ranged from 2% to 33%.
The mean and median age in this group was 62.58 and 62 years, respectively, which is similar to that in other studies.
This was more common in males as seen in other studies.
In the absence of widely accepted grading system, we used the same grading system described earlier.
Histological grade and anaplastic lymphoma kinase mutation
Of the 12 ALK-positive cases (out of 56 tested) 58.33% of cases (7/12) had histological Grade I, 33.33% of cases (4/12) had histological Grade II and 8.33% of cases (1/12) had histological Grade III.
This is in contrast to the study by Inamura et al. which reported that ALK mutations were more frequent in poorly differentiated and moderately differentiated adenocarcinoma (40% each) than in well-differentiated adenocarcinoma (20%). However, it is important to note that the criteria used for grading were not specified in this study.
Histologic patterns in anaplastic lymphoma kinase mutation
As discussed in “pattern in EGFR mutation” above, here also we noted patterns in every case. Whenever more than one pattern was present, we called it a mixed pattern.
Out of a total of 56 cases, 32 cases (57.14%) showed only acinar pattern, 2 cases (3.57%) showed only papillary pattern, 6 cases (10.71%) showed only solid pattern, 2 cases (5.35%) had mucinous, 1 case (1.78%) had mucinous cribriform, and 1 case (1.78%) had adenosquamous carcinoma. Remaining 9 cases (16.07%) showed a mixed pattern. Mucinous, mucinous cribriform and papillary patterns had no ALK1 mutation [Table 2].
In ALK-positive cases, the acinar pattern was most frequent, seen in 8 out of 12 cases (66.67%). One case (8.33%) of solid and one case (8.33%) of adenosquamous carcinoma was positive for ALK mutation. Remaining 2 cases with ALK mutation (16.67%) had a mixed pattern.
The study is supported by the study done by Inamura et al., who reported 3 cases out of 5 ALK-positive cases having an acinar pattern.
Similarly, the study by Li et al. reported that out of a total of 7 cases which were positive for ALK mutation, 3 showed an acinar predominant pattern, 3 showed a solid predominant pattern and 1 showed a papillary predominant pattern. However, 5 out of 7 cases in their study actually had mixed components including papillary or micropapillary, signet-ring cells, and mucous cells.
In the study by Rodig et al. 16 cases were positive for ALK mutation, out of which 11 showed a solid pattern and 4 showed an acinar pattern.
Morán et al. in their review article reported that ALK rearrangement has more frequently been associated with cribriform, signet-ring cells and solid patterns.
In our study, we conclude that acinar pattern was more frequently associated with ALK mutation.
In 43 cases, we have analyzed both, EGFR and ALK mutations. We found two cases harboring both mutations. The patients were males of age 60 years and 62 years, respectively. Both had an acinar pattern with one having histological Grade I and the other having histological Grade II.
To the best of our knowledge, 6–7 patients with both mutations have been reported so far in the world., It was reported in the study by Zhang et al. in 2010. They identified a patient with concurrent EGFR and ALK mutations. This patient was a female from China with histological adenocarcinoma.
In 2012, Tanaka et al. also reported a case of a 39-year-old male diagnosed as acinar adenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene.
It is important to know the mutation status of both the tumor driving receptor genes in a single tumor, especially in assessing the use of targeted therapies, including EGFR inhibitors and/or ALK inhibitors.
Twenty-one patients had metastatic deposits, either distant or nodal metastases. The test was done on the primary site in 10 and on the metastatic site in 11. Distant metastases included liver, brain, vertebra, skeletal, adrenal, and other metastases. Out of a total of 21 cases which had metastasis, four of the cases tested positive for ALK and 11 were positive for EGFR mutation.
Two cases showed psamommatous calcification, one of which was positive for EGFR mutation and the other was positive for ALK mutation.
An important point to note that though 107 cases of lung adenocarcinoma were available in our records in this study period, only 64 cases had adequate tissue for the mutational analysis. We therefore recommend that the tissue in these cases be handled carefully with minimal trimming of blocks and with a minimal panel of immune stains if required, as these molecular tests are essential for targeted therapy now.
| Conclusions|| |
The incidence of EGFR and ALK mutation in our study of 64 cases was 45.1% and 21.43%, respectively, with 2 cases having both mutations.
EGFR mutation and ALK1 mutation were seen commonly in the well-differentiated adenocarcinomas and in the group with a predominant acinar pattern. Notably, the mucinous, mucinous cribriform and papillary were negative for ALK1 mutation. EGFR mutations were seen in all groups except mucinous cribriform.
The numbers, however, in some groups are small to be of statistical significance.
The predominant acinar pattern and well-differentiated adenocarcinomas are, therefore, predictive of EGFR and ALK1 mutation positivity.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Histopathology, 6th Floor Health Street Building, Apollo Hospitals, Jubilee Hills, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]