Lung cancer is the most common cancer worldwide, and is the principal cause of mortality-related cancer in men. Lung carcinomas are categorized into small cell carcinomas of the lung (SCCL) and nonsmall cell carcinomas according to morphological criteria such as cellular prototype, cell size, nucleomegaly, chromatin pattern, and the presence or absence of nucleoli (Brambilla et al., 2001). SCCL is classically a lesion of the innermost regions of the lung and thus bronchoscopic biopsy is often constructive. NSCLC encompasses adenocarcinoma (AdC), large cell carcinoma, and squamous cell carcinoma, and this category represents about 80% of all lung cancer (Kerr, 2011).
Morphological information to validate the diagnosis of small cell carcinoma can be obtained using neuroendocrine markers, such as synaptophysin, chromogranin A, CD57, neuron-specific enolase, and most recently CD56 (Yun et al., 2005).
Thyroid transcription factor-1 (TTF-1) is a nuclear transcription factor that is part of the 40 kDa member of the Nkx2 gene family. It is present in the forebrain, thyroid, and lungs. It serves a major function in morphogenesis of the lungs (Pelosi et al., 2001). In the lung, TTF-1 regulates the expression of surfactant proteins and Clara cell secretory protein genes. TTF-1 expression is highly definite for thyroid (follicular tumors and medullary carcinomas) and lung tumors, particularly lung AdCs (Agoff et al., 2000). On the basis of the points mentioned above, TTF-1 was selected as a part of an immunohistochemical panel to support the diagnosis of SCCL and AdC in the present study.
Napsin-A is a serviceable aspartic proteinase involved in the prosurfactant protein B maturation in pneumocytes type II and in the maturation of surfactant protein B. It is normally expressed in pulmonary, that is alveolar macrophages and pneumocytes type II and extrapulmonary tissues such as exocrine glands, renal tubules, and pancreatic ducts (Woischnik et al., 2008). Positive immunohistochemical staining shows intense granular cytoplasmic reactivity (Yang and Nonaka, 2010). On the basis of this, Napsin-A was selected among the panel to confirm the diagnosis of AdC.
p63 is a p53-homologue nuclear transcription factor that is located on 3q27–29 and encodes six different isoforms, which harbor either transactivating or negative-dominant effects on p53 reporter genes (Mills, 2006). p63 protein (p63) is a nuclear protein, a transcription factor that plays a critical role in the growth and development of many epithelial organs. p63 is confined to basal cells of squamous epithelia including epidermis, hair follicles, lung, and urothelium, as well as basal cells/myoepithelial cells in the breast, sweat glands, salivary glands, and prostate. The TP63 gene encodes for six isoforms that contain (TA) or lack (ΔN) the transactivation domain because of the use of two different promoters and three alternative splices of the C-terminal end (Varma and Jasani, 2005).
This work aimed to assess the expression of TTF-1, Napsin-A, and p63 in SCCL and AdC of the lung in an attempt to find a panel for accurate diagnosis of both and also to find correlations of the results of these antibodies with those of clinical findings.
Material and methods
Thirty-six cases of formalin-fixed, paraffin-embedded tissue specimens of SCCL and 30 cases of AdC of lung were studied. These tissue specimens were collected from the archival material of the pathology departments, Al-Baha province hospitals, from the period 2010 to 2014. For each case, clinical data and staging were obtained from patients’ files.
For hematoxylin and eosin staining, all selected paraffin-embedded specimens were cut into 4 μm thick sections and stained by hematoxylin and eosin stain and re-examined by two histopathologists to obtain more diagnostic confirmation.
Before proceeding to immunohistochemical staining with the TTF-1 antibody, all cases of SCCL were stained by synaptophysin for further confirmation of histopathological diagnosis. Cases that showed positive staining for synaptophysin were subjected only to the presenting study.
For immunohistochemical staining, tissue sections were cut into 4 μm and mounted on poly-L-lysine-coated slides. Slides were run with 3% hydrogen peroxide and subjected to microwave antigen retrieval for 15 min in a citrate buffer of 0.01 mol/l concentration at pH 6.0; then, slides were cooled at room temperature for 20 min and rinsed with deionized water. Subsequently, the slides were immersed in hydroxymethyl aminomethane/buffered saline at pH 7.6 for 5 min and all slides were subjected to an automated immunostainer by Dako (Carpinteria, California, USA). Primary antibodies included anti-Napsin-A, anti-TTF-1 antibody, and anti-P63 monoclonal antibody 4A4 (all at a 1 : 200 dilution, mouse monoclonal antibody; Dako, Carpinteria, California, USA). Negative controls for Napsin-A and TTF-1 were carried out by omitting the primary antibody. The positive controls were previously known Nap-A+ or TTF-1+ lung tissues. Scoring: for Napsin-A, only a granular cytoplasmic staining pattern was considered positive, whereas for TTF-1 and p63, only a nuclear staining pattern was considered to be positive. The stained slides were observed microscopically by two experienced pathologists. Results were scored in accordance with the parameters of Ueno et al. (2003) and staining was scored negative if it was less than 5% of tumor cells, 1+ if the tumor cells stained was less than 10%, 2+ if 10–50% of tumor cells stained, and 3+ if more than 50% of tumor cells stained.
Qualitative data were determined using Fisher’s exact test (‘t’-test). Two-sided P values were used and values less than 0.05 was considered statistically significant. SPSS version 17 (SPSS Inc., Chicago, Illinois, USA) was used for analysis.
Patients with SCCL ranged in age from 59 to 78 years, median age 67 years. In terms of sex distribution, there were 26 men and four women. AdC patients ranged in age from 54 to 80 years, with a median age of 66 years, mostly in men (25 cases).
Assessment of history indicated that all patients had initial symptoms of 3–6 months’ duration before the first hospital visit. Eighty-four percent of the cases presented were heavy smokers. Clinical symptoms were in the form of cough and dyspnea in all cases, hemoptysis (13 cases), hoarseness of voice, stridor (10 cases), dysphagia (11 cases), and head, neck, and upper limb swelling (seven cases). Neurological symptoms in the form of headache, photophobia, blurred vision, and slurred speech and confusion were found in two cases. Back pain was present in three cases and abdominal pain in four cases.
Indicated signs of respiratory distress in all cases, pleural effusion and dullness (seven cases), elevated Jugular venous pulsation (eight cases), jaundice (four cases), clubbing (nine cases), and cyanosis (14 cases). Ipsilateral supraclavicular lymph nodes’ enlargement (10 cases) and axillary lymph nodes’ enlargement (four cases) were recorded.
Of 36 specimens collected, 30 cases were found to have SCCL and further confirmation was obtained from synaptophysin results; six cases were excluded from the presenting study as it showed negative staining for synaptophysin.
Staging of cases of SCCL according to AJCC was as follows: stage Ia (nine cases), stage Ib (five cases), stage IIa (six cases), stage IIb (six cases), and stage IIIa (four cases). Staging of AdC was as follows: Ia (seven cases), stage Ib (four cases), stage IIa (five cases), stage IIb (six cases), stage IIIa (four cases), and stage IIIb (four cases).
Results of thyroid transcription factor-1
In the 30 cases that remained after excluding the SCCL synaptophysin-negative cases, TTF-1 staining was positive in 25 of 30 (83%) cases of SCCL (Fig. 1). The pattern of staining was nuclear and ranged from weak to intense or strong (Figs 2–4). The intensity of staining was as follows: seven cases showed weak staining, 10 cases showed moderate staining, and eight cases showed strong immunostaining. Five out of 30 cases were negative despite their strong positivity to synaptophysin (Tables 1 and 2). The reactivity of SCCL was present in all stages and the intensity of staining was observed to be increased in higher stages.
Twenty-four of 30 cases (80%) were positive for TTF-1 whereas the remaining six cases showed negative results (Figs 5–7). Also, the intensity of staining ranged from weak to intense as follows: weak (four cases), moderate (eight cases), and strong (10 cases). The intensity of staining was marked in six cases of stage IIb, four cases of stage IIIa, and two of four cases of stage IIIb.
Results of cytoplasmic Napsin-A
All cases were negative. No positive cases were found, whereas AdC cases were positive in 28 of 30 cases (93%) (Fig. 8). The intensity of staining ranged from weak to intense as follows: weak (six cases), moderate (nine cases), and strong (13 cases). The intensity of staining was the highest in stage IIa and IIb cases.
Results of nuclear p63
Twenty-seven of 30 of SCCL cases were negative for p63. (Fig. 9) The remaining three cases showed weak and focally nuclear positivity in scattered cells. Close observation of these cells showed that focal positivity was because of the presence of scattered bronchial reserve cells (Table 1). The three negative cases were distributed according to the SCCL stage as follows: one case in stage 1b, one case in IIb, and one case in stage IIIa. The distribution of cases in relation to staging is summarized in Table 3.
Our results showed that 24 cases were negative whereas six cases showed weak positivity.
There was no significant correlation between presenting symptoms and signs with either histopathological or immunohistochemical findings. There was a significant correlation between intensity of staining and both TTF-1 and Napsin-A in SCCL and AdC cases, with a P-value of 0.001. Also, there was no significant correlation between p63 reactivity and staging of SCCL and AdC. In terms of staging and reactivity of the three antibodies, no significant correlation was obtained in both SCCL and AdC cases.
The histopathologic advantage of SCCL and AdC is not only important for diagnosis per se but also for therapeutic purposes. However, such characteristic features may not always be clear-cut for the diagnosis of SCCL; consequently, the diagnosis of SCCL may be very difficult. For such instances immunohistochemical markers had been used to help in identifying the accurate diagnosis of the conflicting cases. Of these stains, TTF-1, Napsin-A, and p63 have been found to be useful because of their role in enabling accurate diagnosis of both SCCL and AdC of the lung.
SCCL and TTF-1: our results for TTF-1 indicated that 83% of SCCL showed positive nuclear reactivity. This result is in agreement with many studies such as Ordóñez (2000), Zamecnik and Kodet (2002), Wu et al. (2003), Kalhor et al. (2006), Jagirdar, 2008, Zhang et al. (2010), Biran et al., 2014, HooKim et al. (2014), Kostovski and Petrushevska (2014), and Zhang et al. (2014).
Ordóñez (2000), Zamecnik and Kodet (2002), Kalhor et al. (2006) reported that TTF-1 was expressed in 90, 89, and 92% of SCCL cases in their study. Wu et al. (2003) found that 87% of SCCL cases were positive for TTF-1, and that TTF-1+/p63− will hold up the SCCL diagnosis. Jagirdar (2008) reported that most SCCL have the phenotype CK5/CK8/TTF-1 and expression of these markers including TTF-1 for SCCL is highly diagnostic. Zhang et al. (2010) reported that a positive expression of TTF-1 was observed mostly in SCCL. Biran et al. (2014) showed that 81% of SCCL patients were TTF-1+. HooKim et al. (2014) found that TTF-1 was positive in 97% of SCCL patients. Kostovski and Petrushevska (2014) found that there was a strongest expression of TTF-1, namely, in 100% of SCCL cases. Zhang et al. (2014) found that five of seven SCCL cases showed positivity for TTF-1, with intensity ranging from 80 to 100%.
In terms of the percentage and intensity of staining, our results showed that 18 out of 25 positive cases showed moderate to strong intensity, whereas it was weak in seven cases. This is in agreement with many studies such as Cheuk et al. (2001), Kontogianni et al. (2005), Zhang et al. (2005). Cheuk et al. (2001) found that 88% of SCCL patients showed positive staining and in TTF-1+ cases, the percentage of positive cells was wide, ranging from 10 to 100%. Kontogianni et al. (2005) reported that 90% of cases were moderately to weakly positive for TTF-1, but staining was heterogeneous and focal, ranging from 25 to 50% of tumor cells. Zhang et al. (2005) found that 93% of SCCL showed diffuse moderate staining. In 21/26 of the TTF-1+ SCCL, more than 90% of tumor cells expressed TTF-1 and the staining intensity was usually strong.
In the present study, we found that in SCCL cases, expression of TTF-1 was more observed in higher AJCC stages as 90% of cases were positive compared with 80% in lower stages. This is in agreement with the result obtained by Biran et al. (2014), who found that positivity of cases with extensive disease was 87% in relation to 71.4% in limited disease, and TTF-1 expression in SCCL showed a tendency to correlate with the disease stage.
The negativity of 5 cases in our study was attributed to the presence of many extensive crush artifacts. This observation was also made in the study of Zhang et al. (2005).
AdC and TTF-1: our results showed that 24 out of 30 cases of AdC showed positive reactivity for TTF-1, which is in agreement with many studies such as those of Hecht et al. (2001), Yatabe et al. (2002), Liu and Farhood (2004), Bishop et al. (2010), Stoll et al. (2010), Tacha et al. (2010), Zhang et al. (2010), and Rekhtman et al. (2011), whereas our results are not in agreement with those of Kostovski and Petrushevska (2014).
Hecht et al. (2001) found that 89% of pulmonary AdCs were positive for TTF-1. Yatabe et al. (2002) studied the expression of TTF-1 in 64 AdC cases and found that 72% of AdC were positive for TTF-1. Liu and Farhood (2004) reported TTF-1 positivity in 86% of lung AdC and Bishop et al. (2010) reported positivity in 73% of AdC. Stoll et al. (2010) found that TTF-1 was detected in 81% of AdC and found that both sensitivity and specificity were 81%. Tacha et al. (2010) reported 79% sensitivity of AdC to TTF-1. Zhang et al. (2010) reported a positive expression of TTF-1 mostly in AdC and the glandular component of adenosquamous cell carcinomas, and the sensitivity and specificity of TTF-1 to AdC were 84.4 and 83.9%, respectively. Rekhtman et al. (2011) found that 89% of AdC showed significant positivity for TTF-1.
Kostovski and Petrushevska (2014) observed positive expression of TTF-1 in 50% of the AdC cases.
Napsin-A and SCCL versus AdC: in the present study, all cases of SCCL were negative. No positive cases were found, whereas cases of AdC were positive in 28 of 30 cases (93%). This is in agreement with the result obtained by Bishop et al. (2010), Stoll et al. (2010), Zhang et al. (2010), Siddiqui (2012), Turner et al. (2012), HooKim et al. (2014), and Zhang et al., 2014.
Bishop et al. (2010) found that 83% of AdCs were positive for Napsin-A. Stoll et al. (2010) found that Napsin-A was detected in 65.3% of cases, with a sensitivity and specificity of 96 and 65%, respectively, and no cases of SCCL were positive for Napsin-A. Zhang et al. (2010) found Napsin-A expression in 84.9% of lung AdC and 87.5% of the glandular component of adenosquamous cell carcinomas, but negative expression in other types of primary lung cancer including SCCL as well as metastatic lung cancer cases; the specificity to lung AdC was 93.8%.
Siddiqui (2012) found that all cases of SCCL were completely negative for Napsin-A, and reported that both TTF-1 and Napsin-A were highly positive and useful markers for AdC and Napsin-A is more superior than TTF-1 in the diagnosis of AdC of lung. Turner et al. (2012) also found that all SCCL cases were negative for Napsin-A and concluded that Napsin-A is more useful than TTF-1 in distinguishing primary lung AdC from other carcinomas (except kidney), particularly primary SCCL, and primary thyroid carcinoma.
A combination of Napsin-A and TTF-1 is useful in the differentiation of primary lung AdC (Nap-A+/TTF-1+) and primary SCCL (Nap-A−, TTF-1+). HooKim et al. (2014) and Zhang et al. (2014) reported that all cases of SCCL subjected to their studies were negative for Napsin-A.
P63 and SCCL: in the present study, 27 of 30 cases of SCCL were negative for p63 and three cases showed only a weak and focal reaction. These findings are in agreement with those of many studies such as those carried out by Wu et al. (2003), Zhang et al., 2005, Kalhor et al. (2006) and in contrast to the results of Au et al. (2004).
Wu et al. (2003) found that 22 of 23 cases of SCCL showed negative p63 staining whereas one case showed focal positivity. Close observation indicated that this focal positivity was a result of the presence of scattered bronchial reserve cells and not tumor cells. These cells served as an internal positive control for our immunostaining.
Zhang et al. (2005) found that all 28 cases of SCCL in their study showed negative staining for p63 and these findings can be used to differentiate between SCCL and squamous cell carcinoma with poor differentiation. Kalhor et al. (2006) studied the expression of p63 in previously Papanicolaou (Pap)-stained cytologic smears and cytospin slides and found that all 13 SCCL cases were completely negative for p63.
In contrast to our findings, Au et al. (2004) studied the expression of p63 in 14 cases of SCCL among 409 lung carcinoma and found that 77% of SCCL were positive for p63 and concluded that the positivity finding of p63 was of prognostic value in neuroendocrine neoplasm predominantly in higher grade tumors.
P63 and AdC: our results showed that p63 was negative in 25 of 30 cases of AdC cases and focally positive in five cases. This is in agreement with Au et al. (2004), Khayyata et al. (2009), Tacha et al. (2010), and Rekhtman et al. (2011).
Au et al. (2004) reported that 30% of AdC showed p63 expression. Khayyata et al. (2009) studied 35 cases of AdC and found that none of the AdC cases showed p63 expression. Tacha et al. (2010) found that two cases (6%) were positive for p63 of 33 cases of AdC in their study. Rekhtman et al. (2011) found 32% of AdC to have significant positivity for p63.
In the present study, five cases were found to be positive for p63; close observation of these cases showed that these cases had poor differentiation, with negligible squamous cell differentiation. This observation was also made by Nonaka (2012), who found that 27 of 150 AdC (18%) were positive for p63 to a variable extent, with a diffuse reaction observed in 13 tumors (8.7%). Also, Nonaka (2012) reported that p63 expression was observed in all subtypes of AdC, except for the mucinous type, and confirmed that p63 expression is not uncommonly seen in AdC.
From the results obtained in the present study, we found that TTF-1+/Nap−/p63− is highly characteristic for the diagnosis of SCCL, whereas TTF-1+/Nap+/p63− is highly useful for the diagnosis of lung AdC, followed to a lesser extent by TTF-1-/Nap+/p63− and minimally TTF-1+/Nap+/p63+. It is obvious that P63 plays no role in the diagnosis or exclusion of both SCCL and AdC, and its positivity among four cases of SCCL and five cases of AdC may be attributed to the presence of desquamated cells among tumor cells because of extensive destruction of lung tissue by tumor or may be erroneously interpreted as evidence of squamous cell differentiation. Therefore, the combination of TTF-1 and Napsin-A is highly characteristic for the diagnosis for AdC and Napsin-A alone can enable differentiation between SCCL and AdC in conflicting cases. The presence of TTF-1−/Nap−/p63− was observed in four cases in SCCL and the tissue sample in these cases were very minimal; thus, the result of these cases may not have affected the efficacy of TTF-1 and Napsin-A in the diagnosis of SCCL and AdC. Positivity of bothTTF-1 and Napsin-A in AdC supports its diagnosis than its positivity for TTF-1 alone, whereas TTF-1 positivity is sufficient to diagnose SCCL.
Conflicts of interest
There are no conflicts of interest.
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