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    -  Kumar R
    -  Shetty O
    -  Desai S
    -  Rane S

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FISH patterns of ROS1, MET, and ALK with a correlation of ALK immunohistochemistry in lung cancer: a case for introducing ALK immunohistochemistry 'Equivocal' interpretation category in the Ventana anti-ALK (D5F3) CDx assay - A tertiary cancer center experience

 Division of Molecular Pathology, Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India

Date of Submission23-May-2019
Date of Decision27-Aug-2019
Date of Acceptance27-Aug-2019
Date of Web Publication24-Nov-2020

Correspondence Address:
Swapnil Rane,
Division of Molecular Pathology, Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_470_19

PMID: 33402590


Background: Mutations in ROS1, ALK, and MET genes are targetable alterations in non-small cell lung cancer (NSCLC). They can be evaluated by different techniques, most commonly fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).
Methods: We explored the prevalence of ROS1, ALK, MET mutations, discuss clinicopathological associations and FISH signal patterns on 413 consecutive cases of EGFR negative lung carcinoma from March 2016 to April 2017 using FISH for ALK, ROS1, and MET along with ALK (D5F3) IHC.
Results: ROS1 gene rearrangement, ALK positivity (IHC and/or FISH), and MET amplification were seen in 18/358 (5%) cases, 76/392 cases (19.4%), and 10/370 (2.7%) cases, respectively. ALK FISH and ALK IHC were positive in 51/300 (17%) and 58/330 cases (17.57%), respectively, while 8/330 (2.4%) cases were ALK IHC “equivocal” of which 3/8 (37.5%) were ALK FISH positive. Of ALK FISH and IHC co-tested cases, 43/238 (18.07%) cases were positive by both techniques, while 15/43 (34.88%) of ALK positive cases showed discordant ALK FISH and IHC results. All ROS1 rearranged and MET amplified cases were adenocarcinoma. Signet ring cell histology was associated with 78.57% likelihood of being either ALK or ROS1 positive. Genomic heterogeneity was seen in 30% of MET amplified cases.
Conclusions: ALK/ROS1/MET gene alterations were found in 25.18% of NSCLC cases. An ALK IHC “equivocal” interpretation category should be incorporated into practice. Atypical patterns of ROS1 and genomic heterogeneity need to be evaluated further for any clinical relevance.

Keywords: ALK rearrangement, fluorescence in situ hybridization, lung adenocarcinoma, MET amplification, ROS1 rearrangement
Key Message: Discordance between ALK immunohistochemistry and fluorescence in situ hybridization is a significant problem. Reflex testing by a second technique in case of negative first test could increase the number of patients eligible for targeted therapy.

How to cite this URL:
Singh A, Kumar R, Shetty O, Desai S, Rane S. FISH patterns of ROS1, MET, and ALK with a correlation of ALK immunohistochemistry in lung cancer: a case for introducing ALK immunohistochemistry 'Equivocal' interpretation category in the Ventana anti-ALK (D5F3) CDx assay - A tertiary cancer center experience. Indian J Cancer [Epub ahead of print] [cited 2022 Oct 1]. Available from:

  Introduction Top

Lung cancer is a leading cause of mortality with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all lung cancers.[1],[2] NSCLC often harbors molecular alterations, which can be targeted using tyrosine kinase inhibitors. The decision to administer targeted therapy rests solely on the results of molecular testing. Testing for ALK and ROS1 gene rearrangements has been incorporated in the National Comprehensive Cancer Network (NCCN) guidelines for NSCLC while MET is listed among genetic alterations with emerging targeted agents [Version 4.2018]. According to College of American Pathologists (CAP)/International Association for Study of Lung Cancer (IASLC)/Association of Molecular Pathologists (AMP) guidelines, ALK and ROS1 are in the “must test category” for NSCLC, and immunohistochemistry (IHC) is an equivalent alternative to fluorescence in situ hybridization (FISH) for ALK testing.[3] IHC can be used as a screening tool for ROS1; however, confirmation by FISH or molecular methods is mandatory.[3] FISH is the most widely used method to assess MET amplification. Therefore, it is essential to not only understand the prevalence, clinicopathological associations but also the methodologies involved and limitations of the techniques being used. To the best of our knowledge, this is the first ever study of ROS1 and MET gene alterations in NSCLC in an Indian population.

  Materials and Methods Top

Case selection

We have retrospectively studied 413 consecutive cases of EGFR negative lung carcinoma tested for ROS1, ALK gene rearrangement, and MET amplification by FISH from March 2016 to April 2017. ALK IHC was performed in 330 of these cases. Institutional Ethics Committee (IEC) approval was granted for this study. Hematoxylin and eosin sections were reviewed for histological tumor subtype and morphological patterns.

Fluorescence in situ hybridization

FISH was performed according to manufacturer's instructions using Vysis 6q22 ROS1 Break Apart FISH probe (Abbott Molecular Inc.), Vysis ALK Dual Color Break Apart Rearrangement probe (Abbott Molecular Inc.), and ZytoLight ® SPEC MET/CEN 7 Dual Color probe (Zytovision GmbH) for the detection of ROS1, ALK gene rearrangement, and MET amplification. FISH slides were analyzed using Olympus BX53 microscope (Olympus, Tokyo, Japan) equipped with three filters (DAPI/FITC/TRITC). Analysis was done on the microscope as well as after image capture using Q-Capture Pro 7 (QImaging, Canada) by a pathologist according to guidelines.[3] Genomic heterogeneity for ALK, ROS1, and MET was defined as non-uniform signal pattern distribution. Polysomy for ALK and ROS1 was defined as >3 sets of signals/cell when seen in more than 5% cells. The classical pattern of ALK/ROS1 gene rearrangement was defined as consisting of largely split signals with occasional loss of green for ALK/loss of orange for ROS1 signals. Mixed pattern was defined as the presence of split signals and loss of green for ALK/loss of orange for ROS1 signals in similar proportions of tumor cells. An atypical pattern was defined as consisting of predominant loss of green for ALK/loss of orange for ROS1 signals in tumor cells.

MET amplification was defined if any of the following criteria were met, i.e., MET/CEN7 ratio ≥2.0, or average MET copy number per cell of ≥6.0, or ≥10% of tumor cells containing ≥15 MET signals. [Supplementary Table 1] for detailed interpretation criteria for ROS1, ALK, and MET).
Table 1: Summary of clinicopathologic characteristics of study population

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Wherever intermixed type of genomic heterogeneity was seen, an additional 40 cells were counted and the average was taken into consideration. Cluster was defined as a contiguous area of increased MET signals comprising >10% of tumor. In case of cluster-type genomic heterogeneity, counting was done in both hotspot l and non-hotspot areas and counts from both areas were separately calculated. If the hotspot area met the criteria described above, then the tumor was considered as MET amplified. Polysomy for MET was defined as an average CEN-7 copy number >3.


VENTANA anti-ALK (D5F3) Rabbit Monoclonal Primary Antibody (VENTANA anti-ALK (D5F3) IHC assay), used with the OptiView DAB IHC Detection Kit and OptiView Amplification Kit, was performed as a fully automated assay. ALK IHC positive was defined as the presence of strong granular cytoplasmic staining in tumor cells (any %). ALK IHC “equivocal” was defined as the presence of weak to moderate granular cytoplasmic staining in tumor cells (any %). The absence of granular cytoplasmic staining in any tumor cell was defined as ALK IHC negative. In our study, ALK positivity was defined as being either ALK FISH and/or ALK IHC positive.

Statistical analysis

The association of demography, clinical features, FISH, and histopathological parameters was assessed using Pearson's Chi-square test and independent sample t-test, and considered significant at P ≤ 0.05. All statistical tests were performed using SPSS for Windows v23 (SPSS Inc., Chicago, USA).

  Results Top

We have studied 413 consecutive cases of EGFR negative lung carcinoma. The clinicopathological features are summarized in [Table 1].


The results are summarized in [Table 2]. ROS1 rearrangement was seen in 18 (5%) cases, MET amplification was seen in 10 (2.7%) cases while ALK rearrangement by FISH was seen in 51 (17%) cases.
Table 2: Summary of FISH results and clinicopathologic correlations

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ALK IHC was performed in 330 cases, of which 58 (17.6%) were positive. Eight cases were classified as “equivocal” (2.4%), of which 3/8 (37.5%) were subsequently positive on FISH while 5 were negative. Among 238 cases co-tested by ALK IHC and FISH, 15/238 (6.3%) showed discordant results between the two techniques [Table 3]. These 15 discordant cases comprised 15/43 (34.88%) of co-tested ALK positive cases. Combining ALK FISH and IHC results, the total ALK positivity was 76/392 cases (19.4%).
Table 3: ALK IHC and FISH comparison

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Clinicopathological correlation

Patients with ROS1 (P = 0.074) or ALK rearrangements (P < 0.0001) were younger as compared to those without the rearrangement with a 1.8 and 1.4 fold higher prevalence in women, respectively [Table 2]. All cases positive for ROS1 and MET were adenocarcinoma. All except two (1 case each of sarcomatoid carcinoma and small cell carcinoma) ALK positive cases were adenocarcinoma. Signet ring cell histology was seen in 14 cases, of which 10 (71%) cases were rearranged either for ALK or ROS1 (both statistically significant P < 0.05) with a positive predictive value of 57.14% and 27.27%, respectively. All 4 cases with mucinous histology showed ALK positivity (P = 0.002). Solid pattern also showed a statistically significant association with ALK positivity (P = 0.008). The PPV of solid, signet ring, and mucinous histology for ALK rearrangement was 23.90%, 57.14%, and 100%, respectively.

Patterns of FISH signals

Classical pattern was most commonly seen in ALK and ROS1 rearranged cases [Figure 1]. The results are summarized in [Table 4]. Polysomy for ROS1 locus was seen in 20 cases (5.5%), with 19 of them being negative for ROS1 translocation by FISH. Overall, 63 cases (12.5%) exhibited polysomy for ALK locus, of which 12 (19%) were positive while 51 cases (80%) were negative for ALK by FISH (P > 0.05). Genomic heterogeneity, intermixed type was seen in a single case of ALK FISH but none of the ROS1 rearranged cases.
Figure 1: ALK FISH (1000×) (a) shows classical split pattern (arrow), arrowhead shows fused yellow signals. (c) ALK FISH shows atypical pattern with predominant isolated red (loss of green) signals. (b) FISH for ROS1 (1000×) showing classical split pattern (arrow), arrowhead shows fused yellow signals. (d) ROS1 FISH shows atypical pattern with predominant isolated green (loss of orange) signals. (e) FISH for MET (1000×) shows a case with high level MET amplification while (f) shows another case with intermediate level MET amplification

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Table 4: Observed FISH patterns in study population

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The least frequent genetic alteration detected was MET amplification, seen in 10/370 (2.7%) cases. Genomic heterogeneity was seen in 3/10 (30%) cases with MET amplification in contrast to 1/370 cases without MET amplification. Intermixed-type genomic heterogeneity was seen in 3 cases while cluster-type heterogeneity was noted in a single case. CEN-7 polysomy was seen in 32/370 (8.6%) cases, of which 5/32 (15.6%) cases were MET amplified.

  Discussion Top

We performed a comprehensive study of the frequency and patterns of ROS1, ALK, MET FISH, and ALK IHC in 413 consecutive NSCLC cases. ROS1 gene rearrangement, ALK positivity (by IHC and/or FISH), and MET amplification were seen in 18/358 (5%) cases, 76/392 cases (19.4%), and 10/370 (2.7%) cases, respectively. ROS1 gene rearrangement in the literature is reported in 1–2% of NSCLC while ALK gene rearrangement varies from 3.5–15%.[4],[5],[6],[7],[8],[9],[10],[11],[12] The higher incidence seen in our study can be attributed to the preselection of study population (EGFR negative). Incidence of MET amplification in our study is consistent with that observed in the literature.[13],[14],[15],[16],[17],[18] ALK rearrangement occurred in a younger age group (P < 0.001) and in never smokers (P < 0.001). All ROS1 rearranged and majority of ALK positive cases were adenocarcinoma. Signet ring, mucinous, and solid histology was significantly associated with ALK positivity. Signet ring cell histology was also significantly associated with ROS1 rearrangement. These findings are in line with those reported in the literature.[4],[5],[6],[12],[19],[20],[21],[22]

We found discordance between ALK FISH and IHC in 15 of 43 ALK positive cases (34.88%) co-tested by both methods [Table 3], which was similar to that reported in the literature, i.e., 25% and 36.6% in two other studies.[10],[21] Among these 15 cases, 3 were ALK IHC-/FISH+, 4 cases ALK IHC+/FISH- while 8 were ALK IHC “equivocal.” Notably, polysomy for ALK was seen in only 4/15 (26.6%) discordant cases in our study, suggesting that it alone cannot explain the cause of discordance. In addition, among these 15 discordant cases, the total numbers of rearranged cells were between 15% and 20% (borderline positive) in 2 cases only. Therefore, borderline positive FISH results also cannot explain discordance between the two methodologies in our cohort. This is in contrast to another study which found discordance between IHC and FISH in 7/28 (25%) of ALK positive cases. Of these 7 cases, 5 were FISH+/IHC– and in contrast to our study, all 5 of these cases were borderline positive FISH cases.[10]

The Food and Drug Administration (FDA) approved Ventana anti-ALK (D5F3) CDx assay interpretation criteria incorporates a binary scoring system, i.e., either positive or negative. In our experience of using the anti-ALK (D5F3) CDx assay, occasional cases show weak or moderate cytoplasmic staining in tumor cells and a significant proportion of these cases are positive for translocation on FISH testing. This category of cases should be reported as “equivocal” for ALK IHC. The utility of this category was elucidated in the course of our study as 3/8 (37.5%) of ALK IHC “equivocal” cases were positive for ALK FISH, in contrast only 3/193 (1.5%) of ALK IHC negative cases were positive for ALK FISH (true discordance). Hence, we suggest a modification in the criteria for interpretation of anti-ALK (D5F3) CDx assay by incorporating an “equivocal” interpretation category. This incorporation significantly reduced the negative likelihood ratio of ALK IHC (from 0.16 to 0.09) and the occurrence of false negative ALK IHC (from 2.98% to 1.62%, calculating using prevalence of 19.4% from our results). It also improved the sensitivity of the D5F3 anti-ALK IHC from 84.62% to 91.67%. A few studies have interpreted ALK IHC in a four-tier system with scores of 0, 1+, 2+, and 3+. One study with anti-ALK antibody D5F3 (Cell Signaling Technology, MA, USA) with Dako EnVision detection kit found 5 of 9 (55.5%) of ALK IHC 2+ cases to be FISH positive.[23] Another study used anti-ALK (clone 5A4, Novocastra, UK) with an i-view detection kit (Ventana Medical Systems).[24] They found 6 of 16 (37.5%) ALK IHC 2+ cases to be positive for ALK FISH. None of the 1+ cases were FISH positive in both studies. These findings are similar to our study. Currently, the IASLC Atlas of ALK and ROS1 Testing in Lung Cancer follows a binary scoring system for the companion diagnostic assay (CDx) and a four-tier reporting system for a laboratory developed IHC test.[25] In our study, we have devised and followed a three-tier scoring system for the CDx assay in which 8/330 (2.4%) cases were classified as “equivocal.” Thus, by excluding the 8 ALK IHC “equivocal” cases, we can bring down the discordance between the two methodologies by more than half from 15/43 (34.88%) to 7/43 (16.27%) of ALK positive cases.

Classical pattern in ROS1 FISH (11/18, 61% cases) is characterized by widely split signals. ALK split pattern can be more difficult to recognize as few cases show narrow signal separation (between 2 and <3 signal diameters). The distribution of ROS1 FISH pattern in our study is similar to that seen by Shaw et al. although a higher incidence of atypical pattern is seen in a few other studies.[6],[19],[26],[27] Interestingly, in the study by Shaw et al., next generation sequencing (NGS) was performed on the sample with atypical FISH pattern. It revealed normal, non-rearranged ROS1 gene, and the same patient exhibited progressive disease on crizotinib.[19] We have not performed NGS in our case with an atypical pattern of ROS1 FISH. Furthermore, this patient did not receive crizotinib.

MET amplification in lung cancer is seen in a small proportion of cases. In the study by Ou et al., cases defined to have high-level MET amplification (MET/CEN-7 >5) showed durable partial response to crizotinib while in another study 3/6, i.e., 50% cases with high-level MET amplification and 1/6, i.e., 16.7% cases with intermediate-level amplification (MET/CEP7 ratio >2.2 to <5) showed partial response to crizotinib.[28],[29] In our study, high-level amplification was seen in a single case who did not receive crizotinib.

In conclusion, ALK positivity was the most common mutation, followed by ROS1 rearrangement and MET amplification. All were mutually exclusive. If we include the EGFR mutation incidence in our population (about 23%), then close to half (49%) of Indian NSCLC patients could benefit from targeted therapy.[30] Sequential testing for ALK, ROS, and MET after EGFR results are in hand is a practice followed at our center due to our resource poor setting. IHC and FISH concordance could not be studied for ROS1 and MET as IHC for these was not performed. Squamous carcinoma comprised a small proportion of our cases {6/413 cases (1.5%)}; hence, prevalence of these mutations in it cannot be commented upon. The presence of solid, signet ring, and mucinous histology is a very strong predictor of ALK positivity with a PPV of 23.90%, 57.14%, and 100%, respectively. Signet ring cell histology also strongly predicts ROS1 gene rearrangement with a PPV of 27.27%.

We suggest that testing for ALK should be done using both FISH and IHC as discordance between them was observed in 34.88% of ALK positive cases. In a resource poor setting, ALK IHC can be done first, followed by FISH. Dependence on FISH testing can be reduced by using a three-tier scoring system for ALK IHC and identifying the cases with “equivocal” staining on IHC for further FISH testing. This will enable maximum patients to benefit from targeted therapy. We suggest an algorithm for ALK testing in lung cancer [Figure 2]. In the end, we would like to reiterate that molecular testing for ALK and ROS gene alterations should be performed in all NSCLC.
Figure 2: Suggested algorithm for ALK testing in NSCLC. *Further testing of ALK IHC negative cases by FISH may be done on clinical characteristics and suspicion. FISH: Fluorescence In-Situ Hybridization

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We would like to thank Mr. Sandeep Dhanavade (Molecular Pathology laboratory, Tata Memorial Centre) for his expert technical assistance in performing FISH.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4]


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