Analysis of SMARCA4 and SMARCA2 Loss in Lung Sarcomatoid Carcinomas
Halide Nur URER1, Nurcan UNVER2, Neslihan FENER2
1Department of Pathology, University of Health Sciences Turkey, Haseki Training and Research Hospital, ISTANBUL, TURKEY
2University of Health Sciences Turkey
3Yedikule Chest Diseases and Thoracic Surgery Training and Research Hospital, ISTANBUL, TURKEY
Keywords: Lung neoplasm, Carcinosarcoma, Pleomorphic, Pulmonary blastoma, SMARCA4, SMARCA2
Sarcomatoid carcinomas of the lung are a group of aggressive tumors. It has been reported that losses of SMARCA4 and SMARCA2,
which play a role in the repair and remodeling of chromatin, contribute to the initiation, progression, and differentiation of neoplasms. The aim
of our study was to examine SMARCA4 and SMARCA2 profiles in sarcomatoid carcinomas of the lung.
Material and Method: We screened pleomorphic carcinomas (PCs), carcinosarcomas (CSs), and pulmonary blastomas (PBs). The loss of
SMARCA4 and SMARCA2 expression in the tumors was evaluated using immunohistochemical methods. The tumors were also examined
to determine immunophenotype, histological tumor diagnosis, surgical resection, tumor histological component, largest tumor diameter, and
lymph node metastasis status.
Results: Sixty-nine cases were screened, of which 84% were PCs, 13% were CSs, and 2.8% were PBs. In PCs components, 84.4% were biphasic
and 15.5% were monophasic. The PCs showed the most frequent loss of SMARCA4 (25.8%) and SMARCA2 (44.8%). A loss of SMARCA4 and
SMARCA2, respectively, was detected in 14.2% and 24.4% in both components of biphasic PCs; 12.2% and 14.2% in the sarcoma component
of biphasic PCs; 0% and 8.1% in the carcinoma component of biphasic PCs; 22.2% and 33.3% in monophasic PCs; 0% and 22.2% in both
components of CSs; and 0% and 22.2% in the sarcoma component of CSs.
Conclusion: These findings demonstrate a loss of expression of SMARCA4 and SMARCA2 in pulmonary sarcomatoid carcinomas. Loss
of the SMARCA complex may be caused by the heterogeneous morphological profile of sarcomatoid carcinomas, independent of tumor
Sarcomatoid carcinomas of the lung are a group of
aggressive organotrophic tumors containing heterologous
elements. This group includes pleomorphic carcinomas
(PCs), carcinosarcomas (CSs), and pulmonary blastomas
(PBs) with sarcoma and carcinoma components. These
tumors typically exhibit high epithelial-mesenchymal
transformation abilities. Because of their diversity and
heterogeneity, their biological behavior generally includes
nodal lymph node involvement and distant metastasis.
The Switch/Sucrose Nonfermenting (SWI/SNF) complex is
a family of proteins involved in chromatin remodeling 1.
A subunit of the complex, SMARCA4 (BRG1), is encoded
in the 19p13.2 chromosome region and is involved in
the ATP-dependent transcriptional regulation process.
SMARCA2 (BRM) is the other major catalytic subunit of
the SWI/SNF family. The SWI/SNF protein complex is active in the initiation, progression, and differentiation
of neoplasms. It is active in the pathogenetic pathway of
complex, undifferentiated, and aggressive pediatric tumors
with a rhabdoid phenotype, malignant rhabdoid tumors
of the kidney, extrarenal soft tissue tumors, and visceral
organ tumors 2-4. In addition, specific neoplasms in the
gastrointestinal, pancreatic, sinonasal, and genitourinary
systems are characterized by a loss of subunits 2.
Yoshida et al. suggest thoracic undifferentiated sarcoma
and carcinomas with rounded or epithelioid histology
and loss of SMARCA as a separate group of tumors 5.
These are highly aggressive tumors. On the other hand,
the SMARCA4 alteration rate is 2.7-10% in common
carcinomas of the lung such as adenocarcinoma, small
cell carcinoma, squamous cell carcinoma, non-small cell
carcinoma, and large cell neuroendocrine carcinoma
6. Loss of the complex is an important finding in both
poorly differentiated/undifferentiated carcinomas and undifferentiated sarcomas of the thorax. However, data
on the SMARCA profile and phenotypic features in lung
sarcomatoid carcinomas are quite limited.
Our study investigated the morphological features of
sarcomatoid carcinomas of the lung. We evaluated the
loss of SMARC4A and SMARCA2 in this heterogeneous
tumor group. The relationship of protein loss with tumor
components and histopathological prognostic factors
was examined. Our aim was to determine the features of
SMARCA4 and SMARCA2 deficiency in lung sarcomatoid
In the present study, we searched for patients diagnosed
with PCs, CSs, or PBs who underwent anatomic lung
tumor resection between January 1, 2010, and December
31, 2019. The cases identified were re-evaluated according
to the sarcomatoid carcinoma criteria of the World
Health Organization Lung Tumor Classification. Surgical
nonanatomical resections, sarcomatoid carcinoma
metastases of extrapulmonary organs, and cases for which
specimens could not be obtained were excluded. Age, sex,
histological tumor type, surgical resection type, tumor
histological component, largest tumor diameter, and lymph
node metastasis status were investigated. Ethics committee
approval was obtained for the study (2258/2020).
For each case, we selected formalin-fixed paraffinembedded
tumor blocks containing carcinoma and
sarcoma components. Tissue samples were taken from
one or two paraffin blocks for each case. These samples
were mapped and new paraffin blocks were prepared, each
containing 14 tissues. Three-micron sections were taken
from the blocks. Pancytokeratin by immunohistochemistry
(CAM5.2; Master Diagnostica, Dubai, UAE), TTF-
1(8G7G3/; Santa Cruz Biotechnology, Dallas, TX, USA),
P40 (ZR8; Master Diagnostica), E-cadherin (BS38; Master
Diagnostica), SMARCA4 antibodies (orb513921; Abcam,
Cambridge, UK), SMARCA2 antibodies (orb575109;
Abcam), and Ki-67 (SP6; Master Diagnostica) were applied.
All staining was performed on a Ventana fully automated
immunohistochemistry device (Roche Diagnostics,
Basel, Switzerland). We used the universal kit Ventana
BenchMark XT and BenchMark ULTRA instruments
For immunohistochemical evaluation, pancytokeratin
staining was categorized as diffuse, focal, or absent
(+2/+1/-); TTF-1 as diffuse, focal, or absent (+2/+1/-);
P40 as 50% or more, less than 50%, or absent (+2/+1/-); E-cadherin as diffuse, focal, or absent (+2/+1/-); and Ki-
67 nuclear staining as over 50%, 10-50%, or less than 10%
(2/1/0). SMARCA4 and SMARCA2 were evaluated as ‘1’ if
there was any positive nuclear expression and ‘0’ if none.
For pancytokeratin, TTF-1, and E-cadherin, we considered
the results positive if diffuse or focal staining was present.
For P40, staining of 50% or more was considered positive.
Data were analyzed using descriptive statistics. An analysis
was carried out using the SPSS 25 package program.
Relationships between two categorical variables were
examined with the chi-square test. The Yates correction
and p-values were used when appropriate. In the study, the
The p-value was considered significant if it was found to be
less than 0.05.
A total of 70 sarcomatoid carcinoma cases were identified.
One case was excluded because specimens could not be
obtained. A total of 131 samples were taken from formalinfixed,
paraffin-embedded blocks for the remaining 69 cases.
The age range of the cases was 34–76, the mean age was
60.8 years, and the median age was 61 years. The complete
demographic characteristics, type of surgical intervention,
largest tumor size, and lymph node metastasis status are
shown in Table I
. The tumor diameter range was 2.1–18 cm.
Of the 58 PCs cases, 49 (84.4%) were biphasic and 9
(15.5%) were monophasic. The carcinoma and sarcoma
components of biphasic cases were evaluated (Figure 1).
Their distribution was as follows: 46.9% adenocarcinoma,
20.4% squamous cell carcinoma, and 32.6% large cell
carcinoma. Overall, 87.7% of the sarcoma components of
the PCs were spindle cells and 12.2% giant cells.
Of the remaining nine monophasic PCs, five were pure
spindle cells and four were pure giant cells.
Click Here to Zoom
|Figure 1: Distribution of biphasic pleomorphic carcinomas with carcinoma and sarcoma components.
Among the CS cases, we observed 66.6% squamous cell
carcinomas, 22.2% adenocarcinomas, and 11.1% large
cell carcinomas. The dominant type among the sarcoma
components was chondrosarcoma (55%) (Table II).
Our immunohistochemical results for the sarcomatoid
carcinoma cases are shown in Table III.
The distribution of SMARCA4 and SMARCA2 loss in the
tumor components of sarcomatoid carcinomas is shown in
Table IV. SMARCA2 loss was greater than SMARCA4 loss.
The highest loss was detected in PCs (Figure 2).
Click Here to Zoom
|Figure 2: A) Spindle cell and squamous cell pleomorphic
carcinomas, B) Expression of pancytokeratin. Squamous cell
carcinoma component-positive, spindle cell componentnegative,
C) SMARCA4 appears to be preserved in the squamous
component and missing from the spindle component.
The loss in CSs was 22.2–33.3% (Figure 3).
Click Here to Zoom
|Figure 3: A) Carcinosarcoma with a chondrosarcoma component,
B) Preserved SMARCA4 expression in a carcinosarcoma,
C) Preserved SMARCA2 expression in a carcinosarcoma.
No loss was observed in two cases with PB (Figure 4).
A total of 12 (20.6%) cases showing a loss of both SMARCA4
and SMARCA2 were identified; 11 (18.9%) showed a loss
of the same component. One showed a loss in a different
component. All of these tumors were biphasic PCs.
We explored prognostic histopathological parameters
and their relationship with histological type in SMARCAdeficient
tumors (Table V). There were no significant
differences in tumor diameter, lymph node metastasis
status, or tumor histology.
In our study, a loss of SMARCA4 and SMARCA2 in
pulmonary sarcomatoid carcinoma was found in 23.1% and
43.4% of cases, respectively. Deficient expression was high
in PCs, but not in PBs. The deficiency of the complex in lung
PCs varies from 36% to 41% (7). While subunit silencing
is seen in differentiated non-small cell lung carcinomas,
increased epithelial-mesenchymal transformation may be
responsible for the aggressive character of sarcomatoid
Sarcomatoid carcinomas are rare malignant pulmonary tumors
(8). They are heterogeneous neoplasms with different
variants and components with epithelial and non-epithelial
mesenchymal phenotypes. PCs were the most frequently
detected type of sarcomatoid carcinoma in our study. This
finding is consistent with the available data (9). However,
squamous cell carcinoma is the most common type of carcinosarcoma
and large cell carcinoma is the least common.
Chondrosarcoma was the most common type in the malignant
mesechymal component. In the pleomorphic carcinoma
study of A.W. et al., adenocarcinoma was detected most
frequently in both the dedifferentiated and sarcomatoid elements
(10). Chondrosarcoma was the most common type
in the malignant mesechymal component. The diversity of
subgroups in pleomorphic carcinoma may cause difficulties
in classifying these tumors. The difference in the loss of
SMARCA4 and SMARCA2 in these subgroups should be
investigated in larger studies.
A concomitant loss of SMARC subunits in different
tumors has been described. A loss of both SMARCA4
and SMARCA2 has been found in 10–26% of non-small
cell carcinomas (11-13). The mutual inactivation of only
SMARCA2-SMARB1 was detected in gastrointestinal
undifferentiated carcinomas with a rhabdoid phenotype
(14). Similarly, a loss of multiple SMARC subunits was
detected in PCs with biphasic components in the present
study. Concomitant inactivation has been reported to have
a negative effect on survival, independent of tumor stage
The SWI/SNF complex plays an important role in tumor
suppression and DNA repair by remodeling chromatin.
The most important subunits of the complex include
SMARCA4, SMARCA2, SMARCB1, ARID1A, ARID1B,
SMARCC2, SMARCE1, SMARCD1/2/3, BRD9, BCL7,
BCL11A/B, DPF2, and SS18 (15). Monoallelic or biallelic
SMARCA loss is often associated with tumor dedifferentiation
and/or rhabdoid morphology (16,17). A thoracic
SMARCA4-deficient undifferentiated tumor (also known
as a SMARCA4-deficient thoracic sarcoma) is a newly
identified SMARCA-deficient neoplasm with an ICD-O
code (6). The tumor is a high-grade malignancy with an
undifferentiated and/or rhabdoid phenotype. However,
inactivation is found in various tumors. Examples include
soft tissue tumors, head and neck tumors, endometroid
and gastrointestinal carcinomas, and particularly malignancies
with undifferentiated and rhabdoid morphologies
(14,16,18). Conversely, it has been suggested that the rhabdoid
phenotype may not be associated with SMARCA loss
in dedifferentiated or undifferentiated carcinomas (19).
Similarly, unit losses without a rhabdoid morphology have
been reported in a limited case series of lung carcinomas
(20). Thoracic tumors with rhabdoid features may not be
mandatory for SMARC deficiency.
Pulmonary sarcomatoid carcinomas are neoplasms with
a loss of SMARCA4 and SMARCA2 expression. A loss of
SMARC may result from the heterogeneous morphological
profile of sarcomatoid carcinomas, independent of histopathological
Authors would like to thank Kursat Nuri Baydili from the University
of Health Sciences, who helped with the statistical calculations of our
This study was financially supported as a Project (no: 2020/052) in
the Scientific Research Program of the University of Health Sciences,
Conflict of Interest
As the authors of our manuscript, we declare that there is no conflict
of interest regarding the publication of this paper
Concept: HNU, Design: HNU, Data collection or processing: HNU,
NU, Analysis or Interpretation: HNU, NU, NF, Literature search:
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