Introduction:
At present, lung cancer is a leading cause of cancer deaths in the world(1). Most patients are asymptomatic at the early stages of the disease and manifest with advanced stage. In developed and developing countries, lung cancer is significantly rising from time to time(2,3). Although previously, in the United States and other developed countries, lung cancer incidence and mortality rates were found to be highest, in recent years, there has been a significant increase in lung cancer cases in developing countries(3,4). In India, in 2018, approximately 67795 new cases were found, and approximately 63478 people died of lung cancer. The world scenario was 2093876 new cases, and 1761007 people died of lung cancer(5,6).
Lung cancer is a malignant lung tumor characterized by uncontrolled cell growth. This growth can further spread to the surrounding tissues or other body organs if left untreated(7). Lung cancer is broadly classified into two types based on histopathology, Non-small cell lung carcinoma (NSCLC) and Small cell lung cancer (SCLC), each type contributing about 85% and 15%, respectively. Based on histopathology, non-small cell lung cancer is further divided into three major subtypes: adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma (8).
The evaluation of tissue density can be assessed by the Hounsfield unit (HU) on a CT scan. The thoracic cavity consists of different organs or tissue. Each organ or tissue has a different density. Soft tissue, air, solid, or liquid can be differentiated based on HU. Tumor density can be obtained before, and after contrast injection; the density of the tumor varies depending on its vasculature, solidity, and tumor cell type(2). Benign and malignant lesions can be differentiated by evaluating HU value during various phases of the CT study.
This study evaluated the HU value of malignant lung tumors on plain and contrast CT. It was hypothesized that based on the enhancement pattern of the malignant lung tumor, the histopathological subtype of lung cancer could be predicted.
Methods:
Patient Selection:
This Cross-Sectional study was carried out from April 2019 to March 2020 at Justice K.S. Hegde Charitable Hospital, a unit of NITTE University (Deemed to be University) Mangaluru. The study included a total of 34 patients. Patients referred for CECT Thorax with a clinical history of lung cancer were included in the study. The sample size was calculated using G*power sample size software where: Effective size = 0,5, Level of significant = 5%, Power = 80%. The Inclusion Criteria were all patients with clinical suspicion of lung cancer and histopathological proven cases. Patients with a clinical history of other pathology related to the lung were excluded from the study.
Statistical Analysis:
Paired "t" test was used to compare pre and post-contrast enhancement. Paired "t" test was used to compare pre and post-contrast enhancement according to a subtype of Lung cancer. One-way ANOVA was used to compare the effectiveness of pre and post-contrast enhancement of contrast according to the type of lung cancer. Post-Hoc Tukey Test was used for the multiple comparisons of effectiveness pre-, post-contrast enhancement on type of cancer.
Methodology
The study was performed on 16 SLICE MDCT- GE Bright Speed Elite scanners. Informed and written consent for the study was taken from all subjects. The procedure was explained to the subjects. The scan was performed by16 slice MDCT for the patients with histology of lung cancer who were referred for CECT thorax to the department of Radio-diagnosis at K.S. Hegde Hospital attached to K.S Hegde Medical Academy.
Results
In this study, we included 34 patients with lung cancer referred to our department between the period of April 2019 to March 2020 for CECT Thorax after satisfying inclusion and exclusion criteria. CT enhancement pattern was correlated with histopathology report.
Gender distribution: among the 34 patients, 27 patients were males (79%), and 7 were females. Most of the patients were male. Out of 34 patients, 14 patients (41.17%) were between the age group 60-69 years, followed by 11 patients (32.35%) in the age group of 50-59 years. Six patients between the age group of 70-79 years, two patients were in the age group of 80-89, and 1 patient was between 30-39 years.
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| Graph 1: Bar chart showing distribution of type of lung cancer |
NSCLC was the most frequent lung cancer type seen in 30 (88.2%) patients. Squamous cell carcinoma and Adenocarcinoma were the most common type of NSCLC in this study and, 15 patients were in each group, whereas small cell carcinoma was found in 4 patients. The overall prevalence of adenocarcinoma and squamous cell carcinoma was 44.1% and 44.1%,respectively, and the prevalence of small cell carcinoma was 11.8%.
Out of a total of 34 patients, squamous cell carcinoma was seen in 13 males (48.15%) and 2 (28.57%) females, adenocarcinoma was seen in 10 males (37%), and 5 females (71.43%), and small cell carcinoma was seen in 4 males (14.81%). In our study, there were no females with small cell carcinoma. (Table 1)
There was a significant increase in the HU value of lung mass during the post-contrast study. The mean HU value of mass during the pre-contrast study was 36.35 HU (SD= 4.03 HU) and the mean HU value on contrast-enhanced CT was 66.56 HU (SD= 6.58HU). The significance of the change in density of the mass during pre and post-contrast study was analyzed using paired t-test (p<0.05), which showed that there was a significant increase in the density of the mass during post contrast study.
| Table 1: Comparison of pre and post contrast HU value of lung carcinoma. |
| Type of study |
Mean HU |
S.D. HU |
't' |
p value |
Pre contrast |
36.35 |
4.03 |
-33.475 |
<0.001* |
Post contrast |
66.56 |
6.58 |
| (*Significant) |
The pre contrast mean HU value of the adenocarcinoma was found to be 39.53 HU (SD=2.95HU) and post contrast value was 72.13HU (SD=4.21HU), squamous cell carcinoma had pre contrast mean HU value of 34.60HU (SD=2.61HU) and post contrast value was 63.87HU (SD=2.88HU) and small cell carcinoma had a pre contrast mean HU value of 31.00HU (SD=1.41HU) and post contrast value was 55.75HU (SD=2.75HU). A paired t-test was used to compare the pre and post-contrast measurements according to the type of cancer, and hence we found that there was a difference in HU values before and after contrast administration irrespective of the type of cancer with p value<0.001(p<0.05).
| Table 2: Correlation of pre and post contrast HU value based on histopathological type of lung cancer. |
|
Mean HU |
S.D. HU |
"t" |
p value |
Squamous cell carcinoma |
Pre contrast |
34.60 |
2.61 |
40.267 |
< 0.001* |
Post contrast |
63.87 |
2.88 |
Adenocarcinoma |
Pre contrast |
39.53 |
2.95 |
-19.657 |
< 0.001* |
Post contrast |
72.13 |
4.21 |
Small cell carcinoma |
Pre contrast |
31.00 |
1.41 |
-33 |
< 0.001* |
Post contrast |
55.75 |
2.75 |
| (*Significant) |
On comparing the pre and post-contrast HU value of lung mass, adenocarcinoma showed mean increase of 32.60 HU, squamous cell carcinoma showed a mean increase of 29.27 HU and small cell carcinoma with a mean enhancement of 24.7 HU. One-way ANOVA was used to compare the effectiveness of pre and post-contrast enhancement according to the type of lung cancer there was a difference in effectiveness according to the type of lung cancer (p<0.05).
 |
| Graph 2: Bar chart showing comparison of pre and post contrast according to the type of cancer. |
Multiple comparisons of the effectiveness of pre and post-contrast enhancement according to the histopathological type of lung cancer were performed using the Post hoc Turkey test. We found that the mean difference in the density between adenocarcinoma and small cell carcinoma was 7.850HU and the mean difference in the density between adenocarcinoma and squamous cell carcinoma was 3.333HU. Between squamous cell carcinoma and small cell carcinoma, the mean difference in the density was 4.517HU. Hence, we found that there was a significant difference in effectiveness between adenocarcinoma and small cell carcinoma (p<0.05).
|
Table 3: Multiple comparison of effectiveness (pre-, post) of contrast according to type of cancer. |
|
Type of cancer |
Mean HU Difference |
p value |
Adenocarcinoma |
Small cell carcinoma |
7.850 |
0.016* |
Squamous cell carcinoma |
3.333 |
0.148 |
Small cell carcinoma |
Squamous cell carcinoma |
4.517 |
0.223 |
| (*Significant) |
 |
| Figure 1: (A) Pre contrast CT scan shows enhancement pattern of adenocarcinoma on a histologically proven case. (B) post contrast CT scan shows enhancement pattern of adenocarcinoma on a histologically proven case |
 |
| Figure 2: (A) Pre contrast CT scan shows enhancement pattern of squamous cell carcinoma on a histologically proven case. (B) post contrast CT scan shows enhancement pattern of squamous cell carcinoma on a histologically proven case |
 |
| Figure 3: (A). Pre contrast CT scan shows enhancement pattern of small cell carcinoma on a histologically proven case. (B) post contrast CT scan shows enhancement pattern of small cell carcinoma on a histologically proven case |
Discussion
In the present cross-sectional study, we evaluated a total of 34 cases of histopathologically confirmed lung cancer, who were referred for CECT Thorax to our department from April 2019 to March 2020. Patients with clinical suspicion of lung cancer based on physical examination findings and/or chest radiography suggestive of the mass lesion were referred for CT examination. Cases were selected after satisfying inclusion and exclusion criteria. CT thorax was performed by GE Brightspeed Elite 16 multislice CT machine and both plain and contrast (arterial phase) axial images were acquired. Multiplanar reformatted images were obtained before further evaluation by the radiologist. Pre and post-contrast HU value of the lung mass was measured using specific software available in the workstation. HU values were recorded along with a radiological report. Subsequently, patients underwent image-guided or Bronchoscopic biopsy for histopathological confirmation of lung cancer. Finally, the pre and post-contrast HU values of the lesions were compared with the histopathological type of lung cancer.
In our study consisting of a total of 34 cases (100%) of lung cancer, 27(79%) were males, constituted the majority and 7 (21%) were females. In an epidemiological study of lung cancer in India by Noronha et al consisting of 489cases, there were 380(77.7%) males and 109(23.3%) females(9), which is almost similar to our study. In a study by Agus Suryanto et al majority of the patients were males(73.2%)(2). Also in a study by Yangsean Choi et al majority of the patients were males (62.22%)(10)
In the present study most frequent cancer cell type was NSCLC, which was seen in 30(88.2%) patients, both squamous cell carcinoma and adenocarcinoma contributed equally with 15(44.1% and 44.1)) cases each. Small cell lung carcinoma was seen in 4(11.8%) patients. An almost similar distribution was seen in a study by Malik PS et al, in which 434 pathologically confirmed cases were included for clinical and pathological profiles, management, and outcome, among these 85.3% cases were NSCLC and 14.7% SCLC with the most common subtype being adenocarcinoma (37.3%)(11). In a study by Krishnamurthy et al, which analyzed 258 cases of histopathologically proven lung carcinoma, 224 cases were NSCLC, being the predominant type and 34 SCLC, among NSCLC most common subtype was adenocarcinoma, followed by squamous cell carcinoma(12) . At present incidence of adenocarcinoma is increasing compared to squamous cell carcinoma in most Western and Asian countries. A similar trend is also seen in many of the institutional studies of India (13). In a study by Agus Suryanto et al. consisting of 41 patients with lung cancer, there were 17(14.5%) patients with squamous cell carcinoma, 8(19.5%) adenocarcinoma, 7(17.5%) large cell, 7(17.5%) small cell and 2(4.5%) undifferentiated cell carcinoma (2). In the present study, we did not encounter any patients with large cell and undifferentiated cell types; this might be due to the small sample size.
In our study, the pre-contrast mean HU value of lung masses was 36.35 and the post-contrast mean HU was 66.56 with a 30.20 mean increase in the HU after contrast administration, and statistically, a significant difference was seen with paired „t‟ test (p<0.05). In a similar study by Agus Suryanto et al., the mean increase in the enhancement of malignant lung masses was 26.8HU with pre and post-contrast mean HU values of 60.0 and 86.8 HU respectively, and statistically, a significant difference was observed (p<0.0001) (2). Which is almost in agreement with our study.
Stephen J Swensen et al in their multicenter study consisting of 356 (171 malignant nodules & 185 benign nodules) patients to test the hypothesis of a statistically significant lung nodule, concluded that the absence of significant enhancement (<15HU) is strongly predictive of benignity. Malignant nodules in their study enhanced significantly more (median 38.1HU) than granulomas and benign nodules (median 10.0HU) (14). Though we did not include benign lesions in our study, the mean increase in post-contrast HU value of malignant lesions is almost matching with their study.
In this study, we retrospectively correlated the enhancement pattern of each lesion with a histopathological subtype of lung carcinoma based on pre and post-contrast mean HU values. Significant statistical difference was found in the enhancement pattern of each subtype of carcinoma with a p value<0.001 (p<0.05). Following pre and post-contrast mean HU values were obtained for each histopathological subtype of lung carcinoma; adenocarcinoma: 39.53 and 72.13, squamous cell carcinoma: 34.60 and 63.87, and small cell carcinoma: 31.00 and
55.75 respectively. Hence mean an increase in the post contrast HU value observed in our study was 32.60, 29.27, and 24.75 for adenocarcinoma, squamous cell carcinoma, and small cell carcinoma respectively. In a similar study, Agus Suryanto et al evaluated 41 patients with lung cancer to analyze variation in the CT density of lung mass based on histopathological subtype. Following pre and post-contrast mean HU values were observed in their study, adenocarcinoma: 51 and 68.7, squamous cell carcinoma: 60 and 86.6, and small cell carcinoma: 50.3 and 60.2 with a mean increase in the post-contrast HU of 26.8HU, 17.2HU and 9.9(2)
HU for adenocarcinoma, squamous cell carcinoma, and small cell carcinoma respectively (2). In our study, significant enhancement was observed in all subtypes of lung cancer, which were higher than that mentioned in the study conducted by Agus Suryanto et al. This difference is attributable to software used for HU measurement in our CT machine, phase of post-contrast images (arterial) selected for measurement of density and iodine concentration of intravenous contrast used in our study.
Agus Suryanto et al, the study also mentioned a clear cutoff post-contrast mean HU of 60 HU for differentiation between NSCLC and SCLC. In their study, NSCLC had a density value of > 60 HU, and SCLC had a density value of <60H (2). A similar finding was also observed in our study with all lung lesions of NSCLC showing post-contrast mean HU >60HU and SCLC <60HU, the highest post-contrast mean HU was 55.75HU.
In our study, we found a mean difference in the density of 7.85HU between adenocarcinoma and small cell carcinoma, 3.33HU between adenocarcinoma and squamous cell carcinoma, and 4.51 HU between squamous cell carcinoma and small cell carcinoma. Multiple comparisons of effectiveness were analyzed using the Post Hoc Tukey test, which showed a statistically significant difference in effectiveness between adenocarcinoma and small cell carcinoma (p<0.05). However, we did not get a similar study in the literature for comparison.
The pitfalls are the small sample size and we could not include all histopathological subtype of lung cancer.
Conclusions
Thirty-four cases of histopathologically proven lung cancer were included in this study after fulfilling inclusion and exclusion criteria. Cases were distributed based on histopathological subtypes, there were 30 cases of NSCLC consisting of 15 cases of adenocarcinoma and squamous cell carcinoma each. All subtype cases showed a significant increase in post-contrast enhancement (> 30HU) with maximum enhancement in adenocarcinoma and least in small cell carcinoma. The histopathological subtype of lung cancer can be predicted on CT based on the post-contrast mean HU value.
Therefore, evaluation of the enhancement pattern of lung lesion by measuring pre and post-contrast HU values can help the radiologist to predict and differentiate between various subtypes of lung cancer.
List of abbreviations
- CT: Computed Tomography
- CECT: Contrast Enhanced Computed Tomography
- HU: Hounsfield Unit
- MDCT: Multi-Detector Computed Tomography
- NSCLC: Non-Small Cell Lung Carcinoma
- SCLC: Small Cell Lung Carcinoma
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