|Year : 2021 | Volume
| Issue : 2 | Page : 362-368
|Clinical characteristics and gene mutation analysis of clear cell tumor of the lung
Shibo Wu1, Deng Pan2, Weizhuang Chen1, Feng Ren3, Dawei Zheng4, Kaitai Liu5
1 Department of Respiratory Medicine, Lihuili Hospital, Ningbo Medical Center, Ningbo, China
2 Department of Diagnosis, Ningbo Diagnostic Pathology Center, Ningbo, China
3 Department of Medical Imaging, Lihuili Hospital, Ningbo Medical Center, Ningbo, China
4 Department of Cardio-Thoracic, Lihuili Hospital, Ningbo Medical Center, Ningbo, China
5 Department of Radiation Oncology, Lihuili Hospital, Ningbo Medical Center, Ningbo, China
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|Date of Submission||26-Jan-2019|
|Date of Decision||27-Mar-2019|
|Date of Acceptance||15-Sep-2020|
|Date of Web Publication||9-Apr-2021|
| Abstract|| |
There were rare clinical reports on clear cell tumor of the lung (CCTL). The clinical characteristics and underlying genetic mutation status of CCTL are poorly understood. From 2012 to 2017, patients pathologically diagnosed with CCTL in our hospital were investigated and analyzed based on clinical manifestations, pathological characteristics, prognosis and full gene mutation status through next generation sequencing (NGS) technology. During a 6-year period, four eligible patients were diagnosed with CCTL through surgical resection and were included in this study. All patients showed solitary nodules or lumps located in the left lung. The average maximum diameter of lesions was 2.5 ± 1.1 cm. Computed tomography (CT) imaging characteristics of these nodules/lumps demonstrated the features of benign tumors. The hematoxylin-eosin (HE) morphology and immunohistochemistry were consistent with the histopathological features of benign CCTL. Subsequent NGS analysis showed frame shift mutations of F2421/E2419, K1466E mutation, and p. 1450_1456 deletion mutation in mTOR gene in two of four patient samples and amplifications of MCL1 were observed in three of four samples. CCTL is a rare type of primary pulmonary mesenchymal tumor with good prognosis. Preliminary diagnosis on CT is usually sclerosing pneumocytoma. It is still unclear whether the occurrence and development of the disease are related to specific gene mutation. In this study, the genomic findings of frame shift mutation of mTOR genes and amplification of MCL1 gene in CCTL suggest that these mutations might play a role in proliferation of CCTL.
Keywords: CT imaging, MCL1 mutation, mTOR mutation, pathology, prognosis, sugar cell tumor
|How to cite this article:|
Wu S, Pan D, Chen W, Ren F, Zheng D, Liu K. Clinical characteristics and gene mutation analysis of clear cell tumor of the lung. Indian J Pathol Microbiol 2021;64:362-8
|How to cite this URL:|
Wu S, Pan D, Chen W, Ren F, Zheng D, Liu K. Clinical characteristics and gene mutation analysis of clear cell tumor of the lung. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 May 16];64:362-8. Available from: https://www.ijpmonline.org/text.asp?2021/64/2/362/313331
| Introduction|| |
The clear cell tumor of the lung (CCTL) is an extremely rare type of primary pulmonary mesenchymal tumor. It was first described by Liebow and -Castleman in 1963. According to 2015 World Health Organization, CCTL is an important member of the PEComa family, characterized by mesenchymal tumors arising from perivascular epithelioid cells in histology and immunology. These particular tumors are described as "sugar tumor" because this type of tumor contains large amounts of glycogen thus showing extreme positivity to periodic-acid-Schiff staining in their diagnostic features and usually are considered benign. To date, only few cases were reported, and these were mainly focused on the diagnostic feature, along with a small sample size and the underlying molecular basis of the tumor is not studied yet.
In this study, the relevant clinical features, histopathology, immunohistology, and full gene mutation status of four confirmed CCTL cases were analyzed. To our knowledge, this is the study with the larger number of samples and attempt to study the underlying genetic basis of CCTL.
| Case Presentation|| |
Part of the clinical and imaging information of the four patients with the CCTL were summarized in [Table 1].
|Table 1: Clinical and imaging information of the four patients with the CCTL|
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A 46-year old female presented the symptom of coughing for over a month before she came to our hospital. She denied history of smoking and family history of tumor. The following contrast-enhanced lung CT showed solitary lesion at lingular bronchus of the upper left lung, with a maximal diameter of 3.8 cm and the CT value was 41.0 hounsfield units (HU). The mass showed a clear homogeneous enhancement in the arterial phase with a CT value of 143.0 HU, and continuous enhancement in the venous phase with CT value being 108.5 HU. No pathologically enlarged mediastinal or hilar lymph nodes were observed. The preliminary diagnosis was considered as sclerosing pneumocytoma [Figure 1]a and [Figure 1]b. The blood test showed normal levels of CEA, Ca125, and Ca199. A lobectomy of upper left lobe of lung was then performed followed by frozen section biopsy the result of which suggesting vascular leiomyoma. Postoperative pathology and immunohistology of the biopsy further confirmed the diagnosis of CCTL. No evidence of either tumor recurrence or metastasis was identified during the 60-month follow-up period after the surgery.
|Figure 1: (a and b) A mass at the basal segment of the lower left lung. Obvious homogeneous enhancement in the arterial phase. (c-e) A mass with a plain CT value of 25HU at lingular bronchus of the upper left lung. Obvious homogenous enhancement in the arterial phase. A vascular adherence sign via three-dimensional reconstruction. (f-g) A nodule at the basal segment of the lower left lung. (h and i) A well-circumscribed nodule was located in the peripheral area of the left lower lobe. Homogeneous enhancement in the arterial phase|
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In the physical examination, a 60-year-old male was found to have a lesion on lingular bronchus of the upper left lung. The diameter of the lesion grew from 1.9 cm when it was identified two years ago to 2.6 cm. The male has a smoking index of 50 pack-year and no other underlying diseases. He was admitted to -our hospital because of the gradual growth of the nodule located in upper lobe of the left lung. The chest CT plain scan revealed a solitary, smooth-margined mass with a CT value of 25 HU which showed obvious homogenous enhancement in the arterial phase of 82.5 HU. The mass was persistently enhanced with a relatively homogenous appearance in the venous phase of 96.7 HU and a vascular adherence sign could be found via three-dimensional reconstruction [Figure 1]c,[Figure 1]d,[Figure 1]e. Besides, no lymphadenopathy or pleural effusion could be found. The blood test results of CEA, Ca125 and Ca199 were normal. Then, the patient was subjected to a wedge resection of the upper left lung through thoracoscope. The intraoperative collected frozen biopsy through the diagnosis of CT showed that the patient with CCTL was sclerosing pneumocytoma. Histopathology and immunohistochemistry further confirmed the diagnosis result of CCTL. The patient now lives healthy showing no evidence of either recurrent or metastatic disease during the 42-month follow-up period after the surgery.
An asymptomatic nodule at basal segment of the lower left lobe of lung was identified in a 51-year-old female through physical examination and the female had no history of smoking and no family history of tumor. No swollen lymph nodes could be observed in the lung hilum or mediastinum. We found that the CT results of the patient obtained from previous hospital which admitted the patient could not be used for the evaluation of the lesion intensity or enhanced HU [Figure 1]f and [Figure 1]g. On the other hand, we examined the imaging results from previous hospital and found that it might be the sclerosing pneumocytoma. The patient had normal levels of CEA, Ca125 and Ca199 in blood test results. Intraoperative frozen biopsy further suggested that the nodule might be angiomyolipoma. Therefore, wedge resection of the upper left lung was recommended. Histological and immunohistological examinations finally confirmed the diagnosis of CCTL. During the 42-month follow-up period, neither recurrences nor metastases could be observed.
A 50-year-old male nonsmoker with left back pain for more than 3 years was referred to our hospital. He had hypertensive disease and no family history of tumor. Physical examination showed that the blood test results of CEA, Ca125, and Ca199 levels were normal. Through CT examination, a well-circumscribed and solid nodule (1.0 × 0.8 cm) was found in the peripheral area of the left lower lobe. The mass showed homogeneous enhancement (18.8 HU on pre-contrast, 45.9 HU on post-contrast arterial and 17.8 HU on venous phase image) [Figure 1]h and [Figure 1]i and there was no significant mediastinal or hilar lymph node enlargement. Our final radiological diagnosis suggested sclerosing pneumocytoma. A wedge resection undergoing thoracoscopic was carried out and the vascular leiomyoma was considered after snap-frozen biopsy. Pathology analysis via microscopic examination and histopathology confirmed diagnosis of CCTL. No evidence of tumor recurrence or metastasis was found during the 36-month follow-up period after the surgery.
Pathological characteristics of the patients
The pathological characteristics were summarized in [Table 2].
|Table 2: The pathological characteristics and gene mutations information of the four patients with the CCTL|
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The pathology results showed that the tumor was composed of round and polygonal cells. The cell had clear boundary with rich and transparent cytoplasm. It was observed that the cells were separated by thin blood vessels and blood sinusoids. The nucleic of the cell were relatively uniform and some cells had visible nucleolus. However, mitotic phases and necrosis were not observed [Figure 2]. In case 1, Perivascular growth characteristics were observed with radial arrangement of tumor cells and involvement of the vascular subendothelial wall [Figure 2]A1[Figure 3]. Immunohistochemistry (IHC) results revealed CK-pan (-), HMB45 (+) and SMA (+) supporting a diagnosis of CCTL [Figure 3]A1,[Figure 3]A2,[Figure 3]A3. In case 2, Tumor cells were involved in the walls of blood vessels with the presence of a population of spindle-shaped tumor cells [Figure 2]B1,[Figure 2]B2,[Figure 2]B3. IHC results revealed positive results in Calponin (+), Melan-A (+), Melanoma (+), supporting a diagnosis of CCTL [Figure 3]B1,[Figure 3]B2,[Figure 3]B3. In case 3, epithelioid tumor cells were observed with abundant and transparent cytoplasm and distinct blood sinus [Figure 2]C1,[Figure 2]C2,[Figure 2]C3. IHC results revealed positive results in Melanoma (+) and negative results in CK-pan and Desmin, indicating a diagnosis of CCTL [Figure 3]C1,[Figure 3]C2,[Figure 3]C3. In case 4, clear boundary between tumor tissue and surrounding normal lung tissue was observed. Hyperplasia of perivascular collagen was obvious with noticeable collagenization of the focal interstitium [Figure 2]D1,[Figure 2]D2,[Figure 2]D3. IHC results revealed positive results in Melanoma (+), S-100 (+), SMA (+) [Figure 3]D1,[Figure 3]D2,[Figure 3]D3. Upon consideration of the staining results and the clinical history of the patient, evidences neither supports melanoma nor metastatic clear cell sarcoma. Therefore, it is a helpful diagnosis of CCTL. Of all four cases, Ki-67 expression of the tumor cells was less than 5%. All the pathological characteristics were consistent with CCTL which was described in the 2015 World Health Organization classification of lung tumors.
|Figure 2: A1-3. Perivascular growth characteristics were observed with radial arrangement of tumor cells and involvement of the vascular subendothelial wall. B1-3: Tumor cells were involved in the walls of blood vessels with the presence of a population of spindle-shaped tumor cells. C1-3: Epithelioid tumor cells were observed with abundant and transparent cytoplasm and distinct blood sinus. D1-3: Clear boundary between tumor tissue and surrounding normal lung tissue was observed. Hyperplasia of perivascular collagen was obvious with noticeable collagenization of the focal interstitium|
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|Figure 3: A1-3. IHC results revealed positive results in CK (pan) (-), HMB45 (+), SMA (+) supporting a diagnosis of clear cell tumor of the lung. B1-3: IHC results revealed positive results in Calponin (+), Melan-A (+), Melanoma (+), supporting a diagnosis of clear cell tumor of the lung. C1-3: IHC results revealed positive results in Melanoma (+) and negative results in CK-pan and Desmin, indicating a diagnosis of clear cell tumor of the lung. D1-3: IHC results revealed positive results in Melanoma (+), S-100 (+), SMA (+)|
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| Materials and Methods|| |
The samples of the four patients collected during surgeries were then subject to immunohistochemical (IHC) analysis and NGS analysis. It was available for clinical research. Material and methods for NGS was presented in detail as a supplement.
Corresponding antibodies were used for IHC detection of the expression of corresponding protein in tissue samples according to the process as follows: IHC examinations were carried out on 3 mm thick sections. For anti-LATS1 IHC, unmasking was performed with 10 mM sodium citrate buffer, pH 6.0, at 90°C for 30 min. Sections were incubated in 0.03% hydrogen peroxide for 10 min at room temperature, to remove endogenous peroxidase activity, and then in blocking serum (0.04% bovine serum albumin, A2153, Sigma-Aldrich, Shanghai, China and 0.5% normal goat serum X0907, Dako Corporation, Carpinteria, CA, USA, in PBS) for 30 min at room temperature. Antibodies were used at a dilution of 1:200 and were incubated with slides overnight at 4°C. Sections were then washed three times for 5 min in PBS. Non-specific staining was blocked with 0.5% casein and 5% normal serum for 30 min at room temperature. Finally, staining was developed using diaminobenzidine substrate, and sections were counterstained with hematoxylin. Normal serum or PBS was used to replace the antibody in the negative control.
The antibodies used were as follows: Calponin (EP63, ZSBIO, Beijing, China), Melanoma (HMB-45, MAXIM, Fuzhou, China), S100 (15E2E2 + 4C.9, ZSBIO, Beijing, China), CK-pan (AE1, MAXIM, Fuzhou, China), Desmin (RD301, MAXIM, Fuzhou, China), SMA (SCB3, ZSBIO, Beijing, China), Melan-A (SPM540, ZSBIO, Beijing, China).
Gene mutation status of the patients
The main gene mutation status of the samples were summarized in [Table 2]. It is worth noting in the NGS mutation analysis result that in three out of four cases were found to have amplification of MCL1 gene with the fold change of 2.3, 2.1, and 3.3 times respectively. On the other hand, two cases (case1 and case 2) showed frame shift mutations of mTOR gene. In the case with the biggest mass, both F2421 and E2419 were shown to have frame shift mutations in mTOR gene-, which might cause the dysfunction of mTOR protein. In a case with highest Ki67 expression, K1466E mutation and p. 1450_1456 deletion mutation was observed in mTOR gene. Although TSC1/TSC2 regulate the amplification of mTOR, no mutations were observed in these genes.
| Discussion|| |
CCTL is an extremely rare but benign primary tumor and it occurs mostly in middle-aged and elderly people. Chen et al. showed that a total of 39 cases of CCTL were reported in China from 1979 to 2011, the ratio of male to female was 1.29:1. The average age at diagnosis was 43 ± 17 years old and most of the patients had no symptoms. Furthermore, most tumors were discovered during the physical examination. In our study, the average age of diagnosis was 51.8 ± 17 years old including 2 males and 2 females. Moreover, the ratio of asymptomatic cases to symptomatic cases was 1 : 1.
The imaging manifestations of CCTL usually presented a round or oval peripheral solidary nodule in the lung. The nodule had clear boundary with smooth surface. In general, the maximum diameter of the nodule should be less than 3 cm. Moreover, the density of the nodule was homogenous in most cases and no obvious evidence of hemorrhage, necrosis, cavitation and calcification could be observed. It might occur in any lobe and mainly locate under the pleura without communication with bronchi or blood vessels. In our study, all four cases indicated solitary lesion located in the left lung parenchyma, including two located in the peripheral portion and other two situated in the non-peripheral portion. The maximum diameter of case one was more than 3 cm, however, the maximum diameter of remaining three cases were less than 3 cm. Furthermore, these lesions had smooth boundaries and uniform intensities. Except for the lesion in Case 2 which had blood vessel lining along the lesion, other three patients' tumors did not display calcification, cystic lesions and halo. The key characteristic of CCTL is the intense heterogenous enhancement in the arterial phase and an early washout pattern in delay phases. Another article also reported the typical curvilinear or circular patterns of enhancement in the arterial phase but interestingly, persistent enhancement and homogenous appearance in the venous phase. Retrospective study of enhanced CT features in our two patients' lesions displayed homogeneous and drastic enhancement in the arterial phase enhancement and sustainable enhancement during the venous phase. Nevertheless, one case presented a lesion less than 1 cm in diameter, which seemed to show homogeneous enhancement in the arterial phase and an early washout pattern in delay phase.
To date, the known radiological characteristics diagnostic for sclerosing pneumocytoma are quite nonspecific. Morphological appearance and enhancement characteristics of CT of our cases hardly differentiate from other solitary benign nodules including sclerosing pneumocytoma. Thus, CCTL is easily to be misdiagnosed as sclerosing pneumocytoma radilologically because of the lower morbidity of the former.
The biological behavior of this neoplasm was traditionally considered as benign tumor; however, malignant CCTL had been reported in several other literatures., Certain manifestations of malignant CCTL were correlated with more aggressive behavior such as diameter >2.5 cm, the presence of symptoms and extensive necrosis or abundant mitoses visible under an optical microscope., In this study, pathology of the patients did not reveal prominent necrosis or rich mitosis. Moreover, immunohistological results showed that Ki-67 expression were less than 1% in three out of four cases (the remaining one was less than 5%). Therefore, they were diagnosed as benign tumor. Furthermore, in this study, all the patients' CCTL were removed through surgery and the post-surgery follow-up- did not reveal the relapse, which suggests satisfactory prognosis.
In this study, it is by far the first report which analyzed the underlying genetic basis of CCTL with NGS technology revealing the detailed genomic mutation status of exonic regions of 416 genes. In previous studies, the sample size and the genomic study of CCTL is very limited. Konrad stopsack et al. reported that the KRAS mutation of one female patient having lung CCTL in 2013. Some research had been done for the genomics of the PEComa to which CCTL belongs. These research revealed that PEComa development was partially correlated with the genes involved in the tuberous sclerosis complex (TSC), which could be characterized by inactivation of TSC and the high expression of the downstream mTOR (which is target of the rapamycin). Generally, TSC was the dominant hereditary disease and heterozygous deletion of the TSC1 (9q34) and TSC2 (16p13.3) might be involved in PEComa. Kenerson et al. suggested that high activation of the mTOR was important in CCTL and mTOR might be considered as important treatment target. In this study, specimens of all the four patients were subject to the NGS analysis in order to determine whether the TSC mutations or other possible genes were present. Interestingly, neither inactivation of the TSC1/TSC2 nor amplification of the downstream mTOR gene could be found on all patients, which suggested the lack of high expression of the corresponding proteins. However, we do observe that one case with the biggest mass showed the frame shift mutations of F2421 and E2419 of mTOR gene, which might cause dysfunction of mTOR protein. Furthermore, a case with the highest Ki67 expression had K1466E mutation and p. 1450_1456 deletion mutation of mTOR. These observations suggested that mTOR gene might also contribute to CCTL tumor development and progression through mutation in their protein products besides amplification alone which requires further investigation. Another novel finding in this study, thanks to the larger sample size and NGS technology, is the amplification of myeloid cell leukemia (MCL1) gene which could be observed in three out of four samples. MCL1 gene belongs to B-cell lymphoma 2 (Bcl-2) family of apoptosis regulating proteins. Its longer isoform would enhance cell survival through inhibiting apoptosis while its shorter isoform would promote apoptosis instead., MCL1 is known to be the target of approved drug Omacetaxine mepesuccinate for treatment of Chronic Myelogenous Leukemia (CML) and Seliciclib which could down regulate the expression of MCL1. The amplification observed in this study suggests that its longer isoform might be over-expressed and induce the inhibition of cell apoptosis, leading to tumor development eventually. Further RNA-seq analysis of the CCTL is needed to confirm the identity of over-expressed MCL1 isoforms and if confirmed, CCTL patients might benefit from current approved drugs targeting MCL1 gene.
| Conclusion|| |
In this study, we presented a CCTL study with the relatively larger number of samples and latest technology exploring the underlying genomics of the disease. All four cases of CCTL patients were comprehensively analyzed from the aspects of clinicopathology, radiology, and genetic mutation status. As a rare type of primary pulmonary mesenchymal tumor with good prognosis, prominent characteristics of CCTL CT imaging included a round, well-defined and homogeneous nodule. Moreover, it tended to show homogeneous, drastic enhancement in the arterial phase and persistently homogenous enhancement in the venous phase. Last but not least, the gene mutation status of CCTL was complex and changeable. Two of the most worthy genomic findings in this study are 1. The frame shift mutations of F2421 and E2419, K1466E mutation and p. 1450_1456 deletion mutation of mTOR gene which might play a role in proliferation of CCTL; 2. Amplification of MCL1 in three out of four patients suggesting that apoptosis process might be disrupted in CCTL which could promote the growth of the tumor. In sum, the large sample size and new technology taken in this study bring an unprecedented opportunity to understand the mechanism and potential treatment improvement of CCTL.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Ethics approval and consent to participate
We have obtained research study participant consent.
The interpretation and reporting of these data are the sole responsibility of the authors.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Radiation Oncology, Lihuili Hospital, Ningbo Medical Center, Ningbo . 315041, China; No. 57, Xingning Road, Ningbo 315041
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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