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Year : 2021  |  Volume : 14  |  Issue : 4  |  Page : 397-402  

Utility of Napsin-A in diagnosis of non-small cell lung carcinomas and its addition with thyroid transcription factor-1 (TTF-1) in small biopsies of lung: Does it help in morphologically challenging situations?

1 Department of Pathology, Command Hospital (CC), Lucknow, Uttar Pradesh, India
2 Malignant Disease Treatment Centre, Command Hospital (CC), Lucknow, Uttar Pradesh, India
3 Department of Pathology, King George Medical University, Lucknow, Uttar Pradesh, India

Date of Submission25-May-2020
Date of Decision08-Sep-2020
Date of Acceptance21-Sep-2020
Date of Web Publication17-Jun-2021

Correspondence Address:
Sankalp Singh
Malignant Disease Treatment Centre, Command Hospital (CC), Lucknow - 226 002, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_283_20

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Background: Lung cancer is the leading cause of cancer-related deaths in the world. Primary lung carcinomas were being divided simply as small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) in recent past as the chemotherapy offered in NSCLC was not majorly different in the various subtypes. With the advent of targeted therapy, the management of primary lung adenocarcinomas (PLA) and squamous cell carcinomas (SqCCs) became divergent and hence a stringent separation of the two subgroups is imperative. This study was designed to see whether inclusion of immunohistochemistry (IHC) for Napsin-A in the panel of CK7, CK20, p40, and thyroid transcription factor-1 (TTF-1) improves the diagnostic rates of lung adenocarcinomas. Materials and Methods: A total of 56 cases of primary lung malignancies were studied and subtyped, based on Hematoxylin and Eosin stained slides along with IHC for CK 7, CK 20, p40, TTF-1, and Napsin-A. NSCLC was divided into five groups-PLA, SqCC, NSCLC–favor adenocarcinoma, NSCLC–favor SqCC, and NSCLC–not otherwise specified (NOS). Results: Out of the total, 38 cases were diagnosed to be NSCLC. Of these 38, only 55% cases were diagnosed using histomorphology alone. The rest required immunohistochemical stains for classification. The NSCLC-NOS group comprised 11% in this study. It was observed that by including Napsin-A in the panel, 01/04 (25%) cases in NSCLC-NOS group could be included in NSCLC–favor adenocarcinoma group. Conclusions: This study finds that Napsin-A labels additional cases as adenocarcinomas in NSCLC-NOS group. Napsin-A is more sensitive but less specific than TTF-1 in diagnosis of PLA and has a definite use, in conjunction with TTF-1 to classify NSCLC.

Keywords: Adenocarcinoma, Napsin-A, non-small cell lung carcinoma, thyroid transcription factor-1

How to cite this article:
Ranjan R, Prashar M, Taur N, Singh S, Lohia N, Sivasubramananian R, Sundaram V, Subramananiam A. Utility of Napsin-A in diagnosis of non-small cell lung carcinomas and its addition with thyroid transcription factor-1 (TTF-1) in small biopsies of lung: Does it help in morphologically challenging situations?. Med J DY Patil Vidyapeeth 2021;14:397-402

How to cite this URL:
Ranjan R, Prashar M, Taur N, Singh S, Lohia N, Sivasubramananian R, Sundaram V, Subramananiam A. Utility of Napsin-A in diagnosis of non-small cell lung carcinomas and its addition with thyroid transcription factor-1 (TTF-1) in small biopsies of lung: Does it help in morphologically challenging situations?. Med J DY Patil Vidyapeeth [serial online] 2021 [cited 2022 Jun 25];14:397-402. Available from: https://www.mjdrdypv.org/text.asp?2021/14/4/397/318689

  Introduction Top

Lung cancer is the leading cause of cancer related deaths, accounting for over 150,000 deaths per year in the United States and approximately 1.3 million deaths in the world.[1],[2] In India, about 6.9% of new cancer cases registered and 9.3% of cancer-related deaths, are due to lung carcinomas.[3] Primary lung carcinomas were divided simply as small cell lung carcinomas (SCLCs) and non-small cell lung carcinomas (NSCLCs) till not very long ago. The latter predominantly includes adenocarcinomas and squamous cell carcinomas (SqCCs), both of which did not have much difference in their chemotherapeutic treatment protocols.[4] This classification lost its relevance with the development of personalized and targeted therapy.[3],[5],[6] Targeted therapy for primary lung adenocarcinomas (PLA) with epidermal growth factor receptor gene (EGFR) mutations are managed with EGFR tyrosine kinase inhibitors (TKIs).[5] 3%–7% of PLA have been shown to have echinoderm microtubule-associated protein 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion protein which is also a therapeutic option for cases with this mutation.[7] At the same time, SqCCs of lung (SqCC) do better with gemcitabine-based therapy and certain chemotherapy agents can cause life-threatening hemorrhage in patients of SqCC.[3] Even with all the CT agents, the prognosis (5-year survival rate) of lung carcinomas remain abysmally low ranging from 15% in developed countries to 5% in developing countries. This is more so with poorly differentiated lung cancers, which are often associated with shorter survival and more advanced stage.[8]

Understandably, it is imperative that histological classification of NSCLC be done very stringently. Significant changes in pathologic classification of lung cancer resulting from the recommendations by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS), in 2011, resulted in landmark changes in NSCLC categorization. The new classification stresses on a multidisciplinary effort in diagnosis of lung cancers, importance of histological classification, and molecular testing in stratifying patients for specific therapies.[9] For tumors exhibiting classic morphological features such as mucin production, gland formation, or a papillary and pseudo-papillary architecture, a diagnosis of adenocarcinomas can be given while a tumor showing squamous pearl formation and intercellular bridges can safely be labeled SqCCs.[10],[11] However, not all neoplasms show a classical morphology and when confronted with a tumor without above-mentioned morphological features, it is classified as NSCLC-Not Otherwise Specified (NOS) and the use of special stains and immunohistochemistry (IHC) is mandatory.[12] To meaningfully classify the NSCLC-NOS one can use IHC for thyroid transcription factor-1 (TTF-1) or Napsin-A (markers of PLA) and p40 or p63 (for SqCC).[10]

TTF-1 is a protein with DNA-binding activity and is a nuclear marker which stains PLA with a high sensitivity and specificity, while in cases of SqCC it is a negative stain. Its use has been validated by many studies and it forms a valuable marker for NSCLC.[13],[14] Napsin-A is an enzyme of the pepsin family and is a cytoplasmic marker, shown to be positive in lung adenocarcinomas while negative in all SqCCs.[15],[16] Napsin-A is a newer marker and there have been studies which find it better than TTF-1 in diagnosing PLAs.[17],[18],[19],[20] P40 and p63 both are established markers of SqCCs which do not overlap much with PLAs or SCLC.[21]

While the expression of TTF-1 has been widely researched and published, studies regarding Napsin-A in primary carcinomas of lungs are few in the Indian setting. In this study, we compared Napsin-A with TTF-1 with an objective to see whether it adds any benefit in picking up cases of PLAs in the group of lung carcinomas classified on histomorphology as NSCLC-NOS.[22] This is important because we are in an era of “tissue management,” as the lung biopsies are small and great stress has been laid on conservation of tissue for molecular studies such as EGFR and EML 4-ALK mutations.[9],[23],[24],[25]

  Materials and Methods Top

Case selection

Approval from Institutional Ethical Committee was taken vide their letter number 28/CH/IEC/2020. Cases of primary lung malignancies were accrued from surgical pathology files of a tertiary care hospital in northern India, over the duration of 1 year. It included SCLC, NSCLC and other primary lung neoplasms. The primary material was small biopsies of lungs-both endobronchial and transbronchial. The surgical resection specimens were excluded from the study. A total of 56 cases were present in the archives. Hematoxylin and Eosin (H and E) stained slides were reviewed by two independent pathologists and only those cases were included where both the observers concurred with the diagnosis of malignant lesion of lungs. Nine cases were excluded as the diagnosis of primary lung malignancy was not possible in 3 cases and 6 did not have sufficient tissue for further study. Thus, a total of 47 cases were included in the study.

The tumors were subtyped according to the guidelines of the IASLC/ATS/ERS, 2011. The cases of SCLC were readily picked up both on morphology and the robust IHC available. For NSCLC, tumors were divided into five groups-those with classic morphologic features were labeled as “adenocarcinomas” and “SqCCs.” For a case to qualify as adenocarcinomas either one of the morphologic adenocarcinoma patterns had to be clearly present such as acinar, papillary, solid micropapillary, and lepidic (nonmucinous) or mucin production was documented. Mucin production in H and E stains appeared as light basophilic to foamy appearance of the cytoplasm, apical clearing with a goblet cell-like appearance or showed mucin lakes. A diagnosis of SqCC was rendered when keratin pearls and intercellular bridges were present. Tumors that did not exhibit the above-mentioned features of adenocarcinomas, but were positive for an adenocarcinomas IHC marker (TTF-1), were classified as NSCLC–favor adenocarcinoma. Tumors that were positive for a SqCC marker (p40) with negative adenocarcinoma marker were classified as NSCLC–favor SqCC. If an NSCLC did not show definite glandular or squamous morphology and neither TTF-1 nor p40 was positive the case was classified as NSCLC-NOS. Any cases that showed Napsin-A positivity was also diagnosed as NSCLC–favor adenocarcinoma. For clinical decision making, both PLAs and NSCLC–favor adenocarcinoma were included under adenocarcinoma group, while both SqCC and NSCLC–favor SqCC were included under squamous carcinoma group.

Immunohistochemical analysis

All the cases were further subjected to immunostaining by antibodies to TTF 1, Napsin-A, p40, cytokeratin 7 (CK 7), and CK 20. IHC for chromogranin, synaptophysin, pan CK (Pan CK), and other markers were put up in relevant cases.

IHC was done on formalin-fixed, paraffin-embedded tissue sections, using a standard streptavidin biotin-peroxidase technique along with appropriate positive and negative controls in each batch. For each case, the percentage of positive cells was noted and when more than 10% cells showed moderately positive expression of the marker in the tumor cells, it was labeled as a positive case. Cases with <10% of cells staining or only focal areas staining, were considered negative.

  Results Top

Of a total of 47 cases, there were 38 cases of NSCLC (n = 38, 80%), 4 cases of SCLC (9%) and 05 cases of “other tumors” (11%). Other tumors comprised of 2 cases of malignant mesenchymal tumor, 2 cases of mesothelioma, and one case of primary Hodgkin's disease of lungs. Among the NSCLC, 13 were PLAs (34%), 8 were NSCLC–favor adenocarcinomas (21%), 8 SqCCs (21%), 5 NSCLC–favor SqCC (13%), and 4 were cases of NSCLC-NOS (11%). In the 13 PLAs diagnosed on H and E and substantiated by IHC, most of them were moderately differentiated (9/13,) while others were well-differentiated showing predominant gland with mucin formation, a definite lepidic or an acinar pattern (4/13) [Figure 1]a. In this study, a case was called adenocarcinoma based on morphology or NSCLC-–favor adenocarcinomas based on TTF-1 positivity, so one can say that the present study has taken TTF-1 positivity as gold standard for diagnosing adenocarcinomas [Figure 1]b. Eight cases were diagnosed as SqCCs on histomorphology, while 5 were diagnosed as NSCLC–favors SqCC on IHC (p40) [Figure 1]b. To put simply, of all NSCLC only 21 out of 38 cases (55%) were diagnosed without help of IHC.
Figure 1: (a) Adenocarcinoma with prominent and easily identifiable gland formation. (b) thyroid transcription factor-1 1- Nuclear positivity in adenocarcinoma

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Immunohistochemistry in biopsy specimens

The histological category of NSCLC group and IHC staining in each subgroup is shown in [Table 1]. CK7 was positive and CK 20 was negative in all the 21 cases of adenocarcinoma group and all the 4 cases of NSCLC-NOS. TTF-1 was positive in all the 21 cases of adenocarcinoma group and 2 out of 4 cases of SCLC (50%). It was observed that the staining was less intense and in fewer number of cells in the NSCLC–favor adenocarcinomas cases. All of 13 biopsies from squamous carcinoma group were positive for p40. None of the adenocarcinoma groups, SCLC or NSCLC-NOS was positive for p40.
Table 1: Distribution of cases in the non-small cell carcinoma group along with immunohistochemistry results

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Napsin-A was positive in 18 of 21 adenocarcinoma group (85.7%). One out of 13 (7.6%) cases of squamous carcinoma group were Napsin-A positive while none of the SCLCs yielded positive result with Napsin-A. The Napsin-A-positive case was not considered to be adenocarcinoma as it was p40 positive which is highly specific for SqCC. Of the 13 cases in PLAs, 12 showed cytoplasmic positivity for Napsin-A (92%). Another observation was that intensity of staining for Napsin-A in most of the cases was moderate. Of the 8 cases of NSCLC–favor adenocarcinomas, 6 were positive for Napsin-A (75%) and of the 4 NSCLC-NOS group cases 1 case (25%) showed Napsin-A positivity [Figure 2]a and [Figure 2]b. This case was included under the adenocarcinoma group as it is Napsin-A positive but negative for p40.
Figure 2: (a) Non-small cell lung carcinoma - not otherwise specified without any evidence of gland formation, mucin, squamous pearl formation or individual cell keratinization. (b) Napsin A positivity in non-small cell lung carcinoma-not otherwise specified

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Another case in NSCLC-NOS showed focal and weak TTF-1 positivity, but was negative for Napsin-A. None of the cases of PLAs were Napsin-A positive and TTF-1 negative. A few isolated Napsin-A-positive cells (<10%) were seen in 2 cases of malignant mesenchymal tumor. The intensity of Napsin-A was at best moderate with only occasion cases showing intense staining.

  Discussion Top

Morphology classification and role of classification on treatment

With targeted therapies in lung cancers being the order of the day a requirement of accurate subtyping of NSCLCs is an essential requirement. The previous division of lung carcinomas as SCLC and NSCLC did not have much bearing on outcome as the therapy was similar for both the groups.[26] With the undeniable evidence, that the 5-year survival rates improve when differentiation between adenocarcinoma and SqCC is done and appropriately treated, it is now important to precisely subclassify the NSCLC group. To elaborate and understand the newer therapeutic options is important for a practicing pathologist. EGFR inhibitors, Gefitinib and Erlotinib, are more likely to be effective in PLAs than in SqCC. The new therapies also have distinct adverse effects. If one uses bevacizumab, an antivascular endothelial growth factor agent, it can result in a higher incidence of life threatening pulmonary hemorrhage in SqCCs and is hence not recommended in SqCCs.[3],[4],[5],[6],[27] The addition of the antifolate agent, pemetrexed to conventional chemotherapy provides increased efficacy in nonsquamous carcinomas but not in SqCC.[28]

Our study shows that 80% of cases were NSCLC, 9% were SCLC and 11% were cases of “other malignancies” which is similar to other studies.[9],[17] The WHO classification of lung carcinomas is largely based on H and E stain characteristics which is easier to do on a resection specimen compared to small biopsies. The precise subtyping of the latter is most challenging due to factors such as poor sampling or limited amount of tumor that may not show specific features of differentiation. Most NSCLCs are easily subtyped as PLAs and SqCC on biopsies and special stains or IHC is not required. In this study, we could diagnose only 55% of cases on compared to other studies which found that 60%–80% can be diagnosed with ease.[15],[29],[30] Guidelines of the IASLC/ATS/ERS 2011 advocates the classification into five categories– PLA, SqCC, NSCLC–favor adenocarcinomas, NSCLC–favor SqCC and NSCLC-NOS, as elaborated earlier.[9] For the last three categories, the use of IHC is must. Various studies have used CK 7, TTF-1 (adenocarcinomas markers) and p40, p63, CK 5/6 (SqCC markers). With the negative staining with all markers, it is labeled as NSCLC-NOS.[18],[26],[31],[32]

Tissue management concept

Another important concept by a study based on Travis et al., was the concept of tissue management for small biopsies from lung cancers, the rationale being that the tissue needs to be saved for molecular testing. Tumors that need testing for EGFR mutation, ALK rearrangement and ROS mutation are those diagnosed as adenocarcinoma, NSCLC–favor adenocarcinoma, or NSCLC-NOS. EGFR mutation testing is usually done in advanced stage disease but may also be performed in patients with early-stage disease.[8],[9],[24],[25],[26] New research may also recommend testing for molecular alterations in SqCC and NSCLC–favor squamous carcinomas such as such as FGFR1 amplification and DDR2 mutation in view of targeted therapy.[33],[34] This compels us to look for the “best” IHC markers available to diagnose the correct subtype of the malignancy.[35]

Immunohistochemistry in NSCLC-p40, TTF 1, and Napsin-A

P40 is an established, robust and specific IHC marker in diagnosing SqCCs.[4],[22] Very few cases of overlap and cross reactivity with adenocarcinomas and SCLC has been published (4.6% of PLAs and 1.5% of SCLC).[36] TTF-1 is a nuclear transcription factor, regulating the expression of genes involved in production of surfactant. Besides lung cancers, it is also expressed in other tumors, such as thyroid, breast, and some gastrointestinal carcinomas. Napsin-A is a newer IHC marker for PLAs. It is a 35-kilodalton protein, an aspartic protease involved in the posttranslational modification of surfactant protein B that is expressed not only in lungs (type II pneumocytes and alveolar macrophages) but also renal tubular cells.[4],[9] Studies using surgically resected specimens indicate that Napsin-A is more sensitive and specific than TTF-1 in well to moderately differentiated lung ADCs and also in poorly differentiated ADCs, which may lose TTF-1 expression.[37],[38] Napsin-A coupled with TTF-1, therefore increases the pickup rates of PLAs. Various studies have found TTF-1-positive cases to be as low as 57%, (15, Siddhiki et al.) to as high as 89%,[35] while other studies quote it to be 73%, 86%, and 87%.[13],[14],[18] We found positive TTF-1 expression in 100% (21/21) of adenocarcinoma group and 84% (21/25) of our nonsquamous carcinoma cases. The quoted Napsin-A expression is 83% to 87.1% in previous studies.[13],[15] In our study, we found a positivity of 85.7% (18/21) in the adenocarcinoma group and 76% (19/25) in the nonsquamous carcinoma group which is in concordance with previous literature.

In this study, using a panel of standard IHC stains (TTF-1, p40, and CK7) correct subclassification was possible in about 89% (34/38) cases. With the use of Napsin-A, we could classify a poorly differentiated NSCLC-NOS case into the NSCLC-favors adenocarcinoma group increasing the rate of correct subclassification to 92% (35/38). The advantage of using Napsin-A seems to lie in the fact that it picks up additional cases from NSCLC-NOS group (25%) as brought out in this study. The apparent disadvantage of using Napsin-A exclusively instead of TTF-1 appears to be a lesser specificity as Napsin-A did not stain one case (7%) of PLA diagnosed on morphology and 2 cases of NSCLC–favors adenocarcinoma diagnosed by TTF-1 expression. In addition, a case of NSCLC–favor SqCC also stained positive for Napsin-A but was included in squamous carcinoma group due to p40 expression. Hence, the specificity of Napsin-A alone seems to be less than TTF-1 alone in diagnosing adenocarcinomas.

Another observation in this study is that the staining with Napsin-A is moderate rather than intense in the positive cells which is not reported in previous studies.[15] Another fact emphasized in the Bishop et al.'s study is that Napsin-A positivity could mislead the diagnosis where the differential is a renal cell carcinoma metastasizing to lung. Benign alveolar spaces enclosed by a lung carcinoma can give rise to Napsin-A positivity and has to be accounted for when labeling a tumor as Napsin-A positive.

  Conclusions Top

The accurate and precise histopathological subclassification of NSCLC is of paramount importance due to availability of targeted treatment of lung carcinomas. A tissue saving approach for additional molecular testing is essential for similar reasons. This study finds that Napsin-A labels additional cases as adenocarcinomas in NSCLC-NOS group, helping in improved subclassification of tumors. Napsin-A is more sensitive but less specific than TTF-1 in diagnosis of PLAs and has a definite use, in conjunction with TTF-1 and p40 to subclassify NSCLC.

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Conflicts of interest

There are no conflicts of interest.

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