INTRODUCTION:

Histopathological diagnosis is needed to determine the prognosis and most appropriate therapy for patients with lung and mediastinal tumors. The collection of specimens for examination can be done with procedures such as FNAB and core biopsy¹. Fine needle aspiration biopsy (FNAB) is one of the procedures to obtain cytological specimens with a simple technique, generally using needle sizes 22-27 gauges.

However, FNAB procedures still have limitations in obtaining specimens, in some cases the amount of tissue obtained may not be sufficient for the additional diagnostic tests needed for accurate diagnosis. That leads to an indispensable tissue biopsy procedure for proper diagnosis in some cases^1,2. Core biopsy is an invasive procedure that is performed under local anesthesia and uses a large needle (14-18 gauge). In many cases where FNAB results are indeterminate, a core biopsy can help obtain an accurate histological diagnosis²^,3. Core biopsy specimens also facilitate the assessment of the histological architecture and supporting tests which are often important for the classification of such tumors^4,5. A study based on a meta-analysis of more than 20 publications demonstrated a variation of FNAB sensitivity, around 35-95% and generally lower than core biopsy, which ranged from 85-100%^6,7. Core biopsy as a diagnostic modality of thoracic masses is still a rare examination in Indonesia. That is because not all health care centers have the facilities and experts which are competent to perform the procedure. Dr. Soetomo Hospital Surabaya, Indonesia as a tertiary referral hospital has routinely performed thoracic core biopsy over the past 5 years. However, core biopsy procedure still requires further evaluation of the accuracy of the diagnosis and benefits of the technique. Furthermore, histopathological features of lung and mediastinal tumors obtained from core biopsy in Indonesia are still scarce data. Therefore, this study aims to determine the histopathological features of core biopsy specimens in patients with lung and mediastinal tumors.

MATERIALS AND METHODS:

The study was designed as a descriptive study using a retrospective approach. We collected the medical records of core biopsy results in all patients with a diagnosis of lung and mediastinal tumors at Dr. Soetomo Hospital Surabaya, Indonesia during the period 1 July 2015-June 30 2020 which met the criteria of inclusion and exclusion through total sampling. The core biopsy procedure is done with ultrasound and CT-scan guidance. Of all specimens obtained from the core biopsy procedure, as many as 320 cases are eligible for this study sample. From the data that has been obtained, we conduct descriptive analysis on several variables such as age, gender and histopathological features of lung and mediastinal tumors. The histopathological classifications of lung and tumors are based on the 2015 WHO Classification of Tumors of the Lung, Pleura, Thymus and Heart by International Agency for Research on Cancer. The collected data analyzed using descriptive statistical tests. The data analysis process is carried out with IBM Statistical Product and Service Solution (SPSS) 23 version software. This study has been approved by the ethics committee of Dr. Soetomo General Hospital, Surabaya, Indonesia.

RESULTS AND DISCUSSION:

From all samples obtained in this study, 217(67.8%) samples of lesions are located in the lung and 103 (32.2%) samples are located in the mediastinum.

Histopathological features in different age group:

From a total 217 cases of lung tumors, most of them were found in the range of 51-60 years, amounting to 34.9% (n = 75). Lung adenocarcinoma (43.6%, n=44), neuroendocrine tumors (66.7%, n=2), and indeterminate (25.5%, n=13) showed the largest numbers in the 51-60 age group. Adenosquamous carcinoma (100%, n=1), NSCLC (41.7%, n=5), neurogenic tumors (100%, n=2), and sarcoma (100%, n=1) were most commonly found in the 41-50 age group. The most SCLC images were found at the age of 61-70 years, 41.7% (n = 5). Squamous cell carcinoma and malignant round cell tumor were more commonly found at the age of >50 years. The metastatic picture showed a similar proportion in young age groups (11-20 years) and young adults (21-30 years) with 33.3% (n=2) each (Table 1).

From a total 103 cases of mediastinal tumors, the most common age is in the range of 11-20 years, which is 20.4% (n=21). Neurogenic tumors (100%, n=1), sarcoma (100%, n=1), and malignant round cell tumors (35.3%, n=6) are most common in young age (11-20 years). Hodgkin lymphoma (50%, n=2) and GCT (46.7%, n=7) were found mostly in the young adult (21-30 years). Most indeterminate sample is found at the age of 31-40 years, which is 23.3% (n=10). Thymoma is most commonly found between the ages of 51 and 60, at 46.7% (n=7). Non-Hodgkin lymphoma was found with a similar proportion in the age group of ≤ 10 years and 51-60 years, by 50% (n=1) respectively (Table 1).

Gender-related histopathological features:

From 217 patients with lung tumors, 167(77.0%) were male and 50(23.0%) were female. While from 103 patients with mediastinum tumor, 63(61.2%) were male and 40(38.8%) were female (Table 2).

Table 1: Histopathological features in different age group

Histopathological Features	Age group (years)
	≤10		11-20		21-30		31-40		41-50		51-60		61-70		71-80		˃80
	N	%	N	%	N	%	N	%	N	%	N	%	N	%	N	%	N	%
Lung (n=217)
Lung adenocarcinoma	0	0	0	0	2	2.0	4	4,0	17	16.8	44	43.6	27	26.7	7	6.9	0	0
Squamous cell carcinoma	0	0	0	0	0	0	0	0	3	16.7	5	27.8	5	27.8	3	16.7	2	11.1
Adenosquamous carcinoma	0	0	0	0	0	0	0	0	1	100.0	0	0	0	0	0	0	0	0
Non-Small Cell Lung Carcinoma	0	0	0	0	0	0	0	0	5	41.7	3	25.0	2	16.7	2	16.7	0	0
Small Cell Lung Carcinoma	0	0	0	0	0	0	0	0	1	8.3	4	33.3	5	41.7	2	16.7	0	0
Neuroendocrine tumor	0	0	0	0	0	0	0	0	1	33.3	2	66.7	0	0	0	0	0	0
Hamartoma	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	100.0	0	0
Hemangioma	0	0	0	0	1	100.0	0	0	0	0	0	0	0	0	0	0	0	0
Neurogenic tumor	0	0	0	0	0	0	0	0	2	100.0	0	0	0	0	0	0	0	0
Malignant round cell tumor	0	0	0	0	0	0	0	0	0	0	4	50.0	4	50.0	0	0	0	0
Sarcoma	0	0	0	0	0	0	0	0	1	100	0	0	0	0	0	0	0	0
Metastasis	0	0	2	33.3	2	33.3	1	16.7	0	0	0	0	0	0	1	16.7	0	0
Indeterminate	0	0	1	2.0	8	15.7	6	11.8	11	21.6	13	25.5	7	13.7	4	7.8	1	2.0
Total	0	0	3	1.4	13	6.0	11	5.1	42	19.4	75	34.6	50	23.0	20	9.2	3	1.4
Mediastinum (n=103)
Thymoma	0	0	0	0	0	0	1	6.7	3	20	7	46.7	4	26.7	0	0	0	0
Hodgkin lymphoma	0	0	1	25.0	2	50.0	0	0	1	25.0	0	0	0	0	0	0	0	0
Non-hodgkin lymphoma	1	50	0	0	0	0	0	0	0	0	1	50	0	0	0	0	0	0
Germ Cell Tumor (GCT)	0	0	5	33.3	7	46.7	1	6.7	2	13.3	0	0	0	0	0	0	0	0
Neurogenic tumor	0	0	1	100.0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Neuroendocrine tumor	0	0	0	0	0	0	0	0	1	100.0	0	0	0	0	0	0	0	0
Spindle mesenchymal tumor	0	0	1	25.0	0	0	1	25.0	0	0	1	25.0	1	25.0	0	0	0	0
Sarcoma	0	0	1	100	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Malignant round cell tumor	1	5.9	6	35.3	1	5.9	2	11.8	2	11.8	1	5.9	3	17.6	1	5.9	0	0
Indeterminate	0	0	6	14.0	9	20.9	10	23.3	5	11.6	9	20.9	4	9.3	0	0	0	0
Total	2	1.9	21	20.4	19	18.4	15	14.6	14	13.6	19	28.4	12	11.7	1	1.0	0	0

Table 2. Gender representation from different tumors location

Tumors Location	Gender				Total
	Male		Female
	N	%	N	%
Lung	167	77.0	50	23.0	217
Mediastinum	63	61.2	40	38.8	103

In lung tumors, male patients were more common in lung adenocarcinoma (79/101), squamous cell carcinoma (14/18), NSCLC (10/12), SCLC (11/12), malignant round cell tumor (7/8), and indeterminate (36/51). All adenosquamous carcinoma (n=1), hamartoma (n=1), hemangioma (n=1), and metastasis (n=6) were male patients. While most patients with neuroendocrine tumors were female (2/3) and all neurogenic tumors patients were female (n=2) (Figure 1).

In mediastinal tumors, female patients were more common with thymoma (9/15) and Hodgkin lymphoma (3/4). Male patients were found more common in gct (13/15), malignant round cell tumor (14/17), and indeterminate (22/43). All patients with non-Hodgkin lymphoma (n=2), neuroendocrine tumor (n=1), neurogenic tumor (n=1), and sarcoma (n=1) were male. The mesenchymal spindle tumor has an equivalent proportion of male and female (n=2). (Figure 2).

Figure 1: Gender proportion of different lung tumors histopathological features

Figure 2: Gender proportion of different mediastinal tumors histopathological features

Histopathological features in different tumors location

Of the overall lung tumors (n=217), the most common histopathological features were lung adenocarcinoma (46.5%), followed by indeterminate (23.5%), and squamous cell carcinoma (8.3%) (Figure 3). Of the overall mediastinal tumors (n=103), the indeterminate (41.7%) is the most common histopathological feature, followed by malignant round cell tumors (16.5%) and thymoma (14.6%). (Figure 4)

Histopathological features of indeterminate cases:

The results showed that 94 patients from all cases (n = 320) had specimens that could not be classified into certain histopathological features or called indeterminate. Overall indeterminate samples (n=94), 54.3% (n=51) were found in the lung and 45.7% (n=43) were located in the mediastinum. The most common diagnosis of indeterminate samples led to malignant tumors 41.5% (n=39), followed by some differential diagnosis of 26.6% (n=25) and thymoma suspicions by 10.6% (n=10).

Figure 3: Lung tumors histopathological features distribution

Figure 4: Mediastinal tumors histopathological features distribution

Table 3: Gender representation from different tumors location

Histopathological Feature	Tumors Location				Total
	Lung		Mediastinum		Total
	N	%	N	%	N	%
Squamous cell carcinoma suspicions	0	0	1	1.1	1	1.1
NSCLC suspicions	1	1.1	0	0	1	1.1
SCLC suspicions	2	2.1	0	0	2	2.1
Thymoma suspicions	2	2.1	8	8.5	10	10.6
Lymphoma suspicions	0	0	1	1.1	1	1.1
Hodgkin lymphoma suspicions	4	4.3	3	3.2	7	7.4
GCT suspicions	0	0	1	1.1	1	1.1
Carcinosarcoma	0	0	1	1.1	1	1.1
Necrotic tissue	4	4.3	2	2.1	6	6.4
Malignant Tumor	24	25.5	15	16.0	39	41.5
Differential diagnosis	14	14.9	11	11.7	25	26.6

In this study, the results showed the mean age of patients with lung tumors (n =217) is 54.53 years which ranges from 17-84 years. The most frequent distribution is in the 51-60 age group with 34.9% (n=75). Those are different from United States National Cancer Institute's SEER data in 2012-2016 which showed a percentage of new cases in lung and bronchial cancers were most diagnosed in the 65-74 age group (33.7%). Data from lung cancer statistics in 2018 showed about 53% cases of lung cancer occurred in individuals aged 55 to 74 years and 37% occurred over 75 years. Older age is associated with cancer development due to biological factors that include DNA damage over time and telomere shortening⁸.

In lung adenocarcinoma (n=101), more patients were found in the age group ≤ 60 years, with the most frequent distribution in the 51-60 age group, which is 43.6% (n = 44). Other study by Doğan et al. in the overall cases of lung adenocarcinoma, more patients were found in the ˃55 age group by 66.7% (n=42/63) than in the ≤55 age group by 33.3% (n=21/63)⁹. A review of lung cancer by Couraud et al. demonstrated tha 10-25% of all lung cancers are suffered by nonsmoker individuals with adenocarcinoma as the most widely found histopathological feature¹⁰.

In patients with lung tumors, male percentage was triple that of the female group, at 77.0% (n=167). That is in accordance with data from the United States National Cancer Institute's SEER in 2006-2010 which showed the incidence of lung cancer in Asian/pacific islanders was higher in the male group (48.8 per 100,000 individuals) compared to female (28.0 per 100,000 individuals)¹¹. GLOBOCAN 2020 data shows the incidence of lung cancer in Indonesia is higher in male (31.5 per 100,000 individuals) than females (14.6 per 100,000 individuals)¹².

Different incidence in lung cancer based on the gender group may reflect differences in smoking rates in each group^13,14. However, other studies showed a higher lung cancer incidence in nonsmoker females than nonsmoker male, higher EGFR mutations in females with NSCLC, and higher incidence of lepidic adenocarcinoma in females. In addition, some genetic mutations are more commonly found in female patients including the CYPA1 gene, the enzyme glutathione S-transferase M1, thep53 gene, and the X-linked gastrin-releasing peptide receptor^15,16. Overall, females have several factors that are unique to lung cancer rather than in male. Lung cancer in the female group also has different pathological characteristics, outcomes and prognosis compared to those in male^17,18.

Samples with lung tumors (n=217) show lung adenocarcinoma as the most common histopathological feature, which is 46.5% (n=101). That is in line with data from the United States National Cancer Institute's SEER 2006-2010 which shows the incidence of lung adenocarcinoma has increased by >40% of the total incidence of lung cancer in 2015¹⁴. Recent distribution trends in the histopathological features of lung tumors reflect improvements in the determination and classification of the lung tumors in the past decade, including the use of TTF-1 and other markers^19,20. Genetic susceptibility such as EGFR mutations were more common in females with histopathological features of lung adenocarcinoma, particularly in Asian and nonsmoker groups. Kras gene mutations are found in about 20-30% of NSCLC which is dominated by lung adenocarcinoma subtypes. Several other mutations such as ALK, B-RAF, and MEK1 were also more common in lung adenocarcinoma^10,21.

From this study, the mean age of patients with mediastinal tumors (n=103) is 38.09 years which ranges from 5-79 years. The largest proportion of mediastinal tumors is in the ≤ 60 age group, with the highest distribution ranging from 11-20 years at 20.4% (n = 21). This is in accordance with the results of study on the epidemiology of mediastinal tumors at Razi Hospital, Iran, from 2006-2012 which showed mean age of 35.84 years with 7-79 years range^22,23. Study by Vaziri et al. demonstrated that the mean age of patients with mediastinal mass is 34 years with 2-80 years range, but 47% of them are identified in the 3rd and 5th decades of their lifespan^24,25.

With a wide age range of 74 years, the results of mediastinal tumors core biopsy in this study provide a variety of histopathological features. Study by Liu et al. in 2017 comparing between pediatric and adult age groups showed different histopathological distributions of mediastinal tumors. In other words, the age spectrum has an influence on the distribution of histopathological types of mediastinal tumors^26,27.

Study by Liu et al. showed that germ cell tumors (GCTs) have a higher frequency in pediatric populations compared to adults significantly (p<0.01), which is 12.4% in pediatric population (<20 years) and 2.2% in adult population (≥20 years)²⁶. However, different results were found in this study where patients with GCT histopathological feature (n=15) in the mediastinum have largest proportion in age group of 21-30 years by 46.7% (n =7), followed by age group of 11-20 years by 33.3% (n=5). Another study showed that GCT subclassifications have different preferences in age distribution. Mature teratoma, immature teratoma, and mixed GCT generally occur in pediatric patients. In contrast, teratocarcinoma and seminoma are mainly found in patients with age groups of 20–<30 years²⁶.

This study showed that 61.2% (n = 63) of patients with mediastinal tumors were male. The results were slightly higher compared to a study by Asgary, et al. in 101 patients with primary mediastinal tumors which showed 56.4% (n=57) of total samples were male²². From all thymoma samples, a higher proportion of females were found, which is 60% (9/15), followed by male as much as 40% (6/15). That is in line with a study of 250 thymoma cases which showed 52% (n =130) of all cases were found in females and 48% (n=180) in male²⁸.

Non-Hodgkin lymphoma histopathological feature was found in 2 (2.17%) of all mediastinal tumors core biopsy samples (n=103). The incidence rate of non-Hodgkin lymphoma in Indonesia according to GLOBOCAN 2020 is higher in male at 7.7 per 100,000 individuals, compared to females at 3.8 per 100,000 individuals¹². In addition to the female gender itself, gravidity has also been reported to have a protective role against non-Hodgkin lymphoma²⁹.

The most common histopathological feature of mediastinal tumors (n=103) in this study is indeterminate at 41.7% (n=43), followed by malignant round cell tumors at 16.5% (n=17). Different results were obtained from a study by Liu et al. which demonstrated that the most found mediastinal tumors in adult and pediatric patients was thymic lesions at 26.2%, followed by neurogenic tumors at 16.6%²⁶.

The high proportion of indeterminate histopathological features of thoracic lesions can be explained through several matters. Although core biopsy techniques have a good level of safety and low complications, the properties of mediastinal tumors which are often found in anterosuperior compartment tend to limit their accuracy. Subclassification of cell types in thymoma and malignant lymphoma is often impossible to enforce through needle core biopsy because the lesions are often heterogeneous. Therefore, the results interpretation of core biopsy histopathological examination on mediastinal tumors should be carried out with great caution and it is necessary to use specimens from several locations of lesions to give more accurate assessment³⁰.

In addition, the non-homogeneous nature of intrathoracic lesions often displays a feature with a mixture of necrotic areas, vital tumors and atelectasis lung tissue. In such cases, the core biopsy procedure is able to obtain an adequate specimen from a single lesion site, but the specimen is very likely to contain only unrepresentative material to establish a diagnosis of the lesion⁴.

From the overall indeterminate feature (n=94) of lung and mediastinal tumors, the most frequent diagnosis led to malignant tumors at 41.5% (n=39), followed by various differential diagnoses by 26.6% (n=25) and thymoma suspicion/impression by 10.6% (n=10). Final diagnosis of indeterminate cases in this study is carried out with follow-up examination, such as immunohistochemical (IHC) examination. When poorly differentiated carcinoma is encountered, the application of IHC staining in most cases may facilitate such differences^31,32. Some important roles of IHC are to aid effective and accurate classification of tumors (especially for poorly differentiated tumors in small biopsy specimens), minimize potential diagnostic errors, improve the depiction of tumor types suitable for molecular testing, and utilize lineage-specific markers for the exclusion of tumor metastasis origin³¹.

With the core biopsy procedure, 77.5% of lung tumors' final diagnosis are established in this study and as many as 23.5% show indeterminate results. That shows the advantage of thoracic core biopsy procedure which is able to provide adequate tissue specimens for follow-up examination such as IHC needed in the diagnosis enforcement of difficult or indeterminate cases.

CONCLUSION:

The age profile of lung tumors is different from that of mediastinal tumors, both are dominated by male. The core biopsy procedure is very useful in establishing the diagnosis of lung and mediastinal tumors. In the indeterminate result, the tissue sample obtained through the core biopsy procedure allows for further molecular examinations including immunohistochemistry, so that a definitive diagnosis can be established.

ACKNOWLEDGEMENT:

We would like to thank all samples and staff of the Department of Pathological Anatomy, Faculty of Medicine-Dr.Soetomo Hospital, Airlangga University and Department of Pulmonology, Faculty of Medicine-Dr.Soetomo Hospital, Airlangga University for their good participation and cooperation during the research.

CONFLICT OF INTEREST:

There is no conflict of interest.

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Received on 10.10.2022 Modified on 05.11.2022

Research J. Pharm. and Tech 2023; 16(8):3818-3824.

DOI: 10.52711/0974-360X.2023.00630