Adult Pulmonary Blastoma: A Case Report with Spectrum of Rare Manifestations
Mayur PARKHI1, Nishtha AHUJA1, Divyesh KUMAR2, Rajender Kumar BASHER3, Navneet SINGH4, Harkant SINGH5, Amanjit BAL1
1Departments of Histopathology, Post Graduate Institute of Medical Education & Research (PGIMER), CHANDIGARH, INDIA
2Departments of Radiotherapy and Oncology, Post Graduate Institute of Medical Education & Research (PGIMER), CHANDIGARH, INDI
3Departments of Nuclear Medicine, Post Graduate Institute of Medical Education & Research (PGIMER), CHANDIGARH, INDIA
4Departments of Pulmonary Medicine, Post Graduate Institute of Medical Education & Research (PGIMER), CHANDIGARH, INDIA
5Departments of Cardiovascular and Thoracic Surgery, Post Graduate Institute of Medical Education & Research (PGIMER), CHANDIGARH, INDIA
Keywords: Pulmonary blastoma, Non-smoker, Immunohistochemistry, Next generation sequencing, MYCN, ATM
Pulmonary blastoma (PB) is an exceedingly rare and aggressive malignant lung neoplasm that has distinct biphasic morphology. In this report,
we document rare manifestations and molecular alterations in PB.
A 59-year-old non-smoker female, presented with cough and hemoptysis for 4 months. The high-resolution computed tomography chest
scan showed a 3.5x2.7 cm mass in the basal segment of the left lung. Positron emission tomography and computed tomography revealed a
fluorodeoxyglucose avid lobulated mass in the superior segment of the lower lobe of the left lung. On core biopsy, the diagnosis of pleomorphic
carcinoma in a background of adenocarcinoma was made. A definite diagnosis of pulmonary blastoma was established on the left lung lobectomy
specimen based on morphological and immunohistochemical findings. Post-surgical biopsy from the scalp swelling showed metastatic deposits.
On Next Generation Sequencing (NGS), in addition to conventional CTNNB1 gene mutation, new pathogenic MYCN and ATM gene mutations
were detected. Post-chemotherapy, the patient was doing well after 10 months of close follow-up.
PB exhibited rare associations in the form of non-smoker status, scalp metastasis, and MYCN and ATM gene mutations on NGS in addition to
conventional CTNNB1 gene mutation. Large cohort studies are required to discover the incidence, significance and therapeutic implications of
these co-existing pathogenic molecular alterations in PB.
Pulmonary blastoma (PB) is an exceedingly unusual and
aggressive malignant neoplasm of the lung that accounts for
0.25% to 0.5% of all resected lung cancers 1
. It principally
consists of immature mesenchymal and epithelial elements
that structurally mimic the embryonic lung. In 1945, Barrett
and Bernard were the first ones to bring forward this entity;
and Bernard later called it ‘embryoma’ 2,3
. A decade later,
Spencer termed this neoplasm as pulmonary blastema
based on its histological resemblance to the fetal lung 4
Despite this embryonic derivation, it commonly affects the
adult population rather than childhood. As per the recent
2021 world health organization (WHO) classification
of thoracic tumours, this rare neoplasm along with
pleomorphic carcinoma and carcinosarcoma comes under
the broad category of sarcomatoid carcinomas 5
date, the most common genetic alteration is the missense
mutation in exon 3 of the CTNNB1 gene 6
. The survival
outcome in these patients is very poor due to the high rate
of tumour recurrence and distant metastasis, and about two-third of the patients succumb to the disease within 2
years of the diagnosis 7
. Herein, we present a non-smoker
female in her late adulthood diagnosed with PB showing
scalp metastasis and unique molecular alterations on nextgeneration
A 59-year-old female, a non-smoker, presented with complaints
of productive cough and hemoptysis for 4 months.
In association, loss of weight and appetite was also noted;
however, there was no history of fever, abdominal pain,
or distension. Fifteen years back, she was operated for
haemorrhoids. The high-resolution computed tomography
(HRCT) chest scan showed a 3.5x2.7 cm soft tissue mass
with smooth margins in the basal segment of the left lung.
Computed tomography (CT) and positron emission tomography
and computed tomography (PET-CT) scan of
the whole body revealed a fluorodeoxyglucose (FDG) avid
lobulated soft tissue mass in the superior segment of the lower lobe of the left lung (Figure 1A,B
). In addition, FDG
avid necrotic enlarged left hilar lymph node and FDG avid
circumferential wall thickening involving the rectum and
anal canal, and the perilesional mesorectal and presacral
lymph nodes were also noted. Considering the imaging
findings, lower gastrointestinal (GI) bleeding was evaluated
first with suspected primary or metastatic rectal malignancy.
However, lower GI endoscopy guided biopsy did
not reveal any evidence of malignancy. Thus, we received
the following samples in a sequential manner: core left lung
biopsy and left lower lobectomy specimen.
Click Here to Zoom
|Figure 1: A,B) An intensely FDG avid lobulated soft tissue lesion (white arrow) in the superior segment of the left lung lower lobe with
an FDG avid enlarged left hilar lymph node (black arrow) on the trans-axial CT and fused PET-CT imaging. C) The epithelial component
displays complex acinar and glandular growth pattern with moderately pleomorphic nuclei (H&E; x200). D) The mesenchymal
component appeared oval-to-spindle shaped, and displayed a mild degree of pleomorphism, hyperchromatic nuclei, and inconspicuous
nucleoli (H&E; x200).
The biopsy from the left lung mass revealed a cellular tumour
with mainly epithelial (~90%) and some mesenchymal
(~10%) component. The epithelial component showed
complex acinar and glandular growth patterns (Figure
1C). The tumour cells were moderately pleomorphic with
round nuclei, dispersed chromatin, inconspicuous nucleoli
and moderate eosinophilic cytoplasm. The mesenchymal component appeared oval-to-spindle shaped, and displayed
a mild degree of pleomorphism, hyperchromatic nuclei,
and inconspicuous nucleoli (Figure 1D). Areas of necrosis
were also noted. The diagnosis of pleomorphic carcinoma
against the background of adenocarcinoma was suggested.
One month later, the left lower lobectomy specimen
measuring 14x6x2.5 cm was received. On serial slicing,
a solitary, ill-defined, grey-white, firm tumor mass was
seen measuring 5x3x3 cm (Figure 2A). The tumor was not
infiltrating the hilar vessels and lobar bronchus. The rest of
the lung parenchyma was sub-crepitant to feel. One hilar
lymph node measuring 0.5 cm in diameter was grossly
involved by tumor. Lymph nodes (station 3, 4, 5, 6, 7, 8,
9, 10) were also submitted along with the main specimen.
Microscopically, the tumor had biphasic morphology that
contained malignant epithelial and primitive mesenchymal
components. Both these components were mainly discrete
but intermingled with each other in some areas. The
epithelial cells were arranged predominantly as elongated glands and few discrete foci of solid sheet and cribriform
growth patterns (Figure 2B). The glands displayed nuclear
pseudo-stratification and overcrowding with subnuclear
vacuolation. The mild to moderately pleomorphic tumor
cells had round to oval nuclei, vesicular to dispersed
chromatin, inconspicuous to small distinct nucleoli, and
moderate clear to eosinophilic cytoplasm. Mitotic activity was intermediate to high (8-12/10 high power fields).
Squamous morules were also identified. The primitive
mesenchymal cells were highly cellular and moderately
pleomorphic (Figure 2C). The nuclei were oval-to-spindle
with clear to dispersed chromatin, inconspicuous nucleoli,
and scant cytoplasm. Mitoses was atypical and brisk (>15
per 10 high power fields). Areas of necrosis and hemorrhage were also noted but no heterologous elements were seen.
Lymphovascular emboli and visceral pleural invasion was
present (Figure 2D). No spread through air space was
noted. On immunohistochemistry (IHC), the epithelial
component showed membranous and nuclear expression
for pan-cytokeratin (Dako, clone MNF116, dilution 1:100)
and TTF-1 (Cell Marque, clone 8G7G3/1, dilution 1:300),
respectively (Figure 2E). The cytoplasmic and nuclear
expression of beta-catenin (Cell Marque, clone 14, dilution
1:100) was noted in glandular component (Figure 2F).
Chromogranin (Dako, clone DAK-A3, dilution 1:100)
and synaptophysin (Cell Marque, polyclonal, dilution
1:150) were negative and the ki-67 (Cell Marque, clone
SP6, dilution 1:300) proliferating index was around 80%.
The hilar lymph node showed metastatic tumor deposits
with no extranodal extension; however, the remaining
station lymph nodes were uninvolved. Surgical margins
including bronchus, vascular and parenchymal were free.
The diagnosis of pulmonary blastoma, pT2bN1 (American Joint Committee on Cancer (AJCC) Staging Manual; Eighth
Edition) was rendered.
Click Here to Zoom
|Figure 2: A) On serial slicing, the left lower lobectomy specimen showing a solitary, ill-defined, grey-white, firm tumour mass.
B) The epithelial cells, arranged predominantly as elongated glands, show nuclear pseudo-stratification and overcrowding with subnuclear
vacuolation (H&E; x200). C) The primitive mesenchymal cells exhibit high cellularity, moderately pleomorphic nuclei, and brisk mitotic
figures (H&E; x200). D) Lymphovascular space emboli is seen (H&E; x20). E) Epithelial component expressing TTF-1 immunostain
(Peroxidase; x100). F) beta-catenin showing nuclear and cytoplasmic positivity in the epithelial cells (Peroxidase; x200).
Two months after lobectomy, the patient developed a
scalp lesion which showed an FDG avid uptake with lytic
destructive changes in the skull and minimal intracranial
extension on the coronal reformatted CT and PET-CT
images of the head (Figure 3A,B). A wide local excision
specimen measuring 6x4.5x1cm was sent. On serial
slicing, there was a partly demarcated grey-white and firm
mass measuring 5.2x4x0.7cm. Microscopically, the tumor
showed only mesenchymal component with primitive
cells arranged in variable-sized nodules and islands
(Figure 3C,D). No epithelial element was identified even
after thorough tumour tissue sampling. The morphology
and IHC findings were similar to lung mass. Along with
this specimen, there was a bone biopsy that also showed
infiltration by tumor. The diagnosis of metastatic PB was
Click Here to Zoom
|Figure 3: A,B) The coronal reformatted CT and PET-CT images of the head shows an FDG avid soft tissue mass in the scalp with lytic
destructive changes in the skull and minimal intracranial extension. C) The scalp metastasis contains only the mesenchymal element
in variable sized nodules and islands with similar morphology as primary lung tumor (H&E; x100). No epithelial element is identified.
D) Brisk mitotic activity is visible (H&E; x400).
Next Generation Sequencing
The DNA isolated from paraffin-fixed formalin-embedded
tissue was subjected for Next-Generation Sequencing and
it revealed mutations in the β-catenin (CTNNB1) gene
c.98C>G (ENST00000645 320.1) p.Ser33Cys/Exon 3 gain of
function mutation, MYCN gene c.131C>T (ENST00000281
043.4) p.Pro44Leu / Exon 2 gain of function mutation, and
ATM gene c.5631_5635deli nsA (ENST00000278 616.8)
p.Phe1877Leufs Ter39 / Exon 37 loss of function deletion.
Treatment and Follow-Up
The patient received one cycle each of neoadjuvant
and adjuvant chemotherapy before and after surgery,
respectively. The chemotherapy agents include pemetrexed,
carboplatin, and etoposide. In addition, the patient received
radiotherapy with 8 Gy per fraction for the scalp metastatic
site. The patient is alive till last 11 months of close followup;
but recently he was detected with metastasis in the
right paravertebral region and subcarinal lymph node on
positron emission tomography computed tomography
PB is one of the rare lung cancers that show biphasic
morphology containing fetal adenocarcinoma (low grade
or well-differentiated) and primitive mesenchymal stroma
. Pulmonary blastoma is considered as a separate entity
under the broad category of sarcomatoid carcinoma as
per the recent WHO classification of thoracic tumors
(fifth edition; 2021) 5
. Thus, it has the distinct biphasic
morphology, and aggressive behavior with a 5-year survival
rate of 16% 5,7
On computed tomography, the tumor appears wellcircumscribed
with varying contrast uptake and central
necrosis 8. The definite diagnosis comes from the
histopathological examination of the surgical specimens.
The common differentials considered are WDFA,
carcinosarcoma, and pleomorphic carcinoma. These
differentials are important because PB has poor prognosis
compared to WDFA and better prognosis compared to
carcinosarcoma. There are limitations of diagnosing these
lesions on a core biopsy due to caveats like pure sampling
of either the epithelial or heterologous elements which
will create challenges for the pathologists that may affect
treatment decision. The tumor showing pure epithelial
component, absence of mesenchymal element and
consistent lack for TP53 mutation favor WDFA 9. The
possibility of carcinosarcoma can be kept when the tumor
contains high-grade fetal-type or clear cell adenocarcinoma with heterologous elements, lacks squamous morules,
membranous expression of beta-catenin and the molecular
features of blastoma 5. Pleomorphic carcinomas are
defined by the presence of non-small cell lung carcinoma
with at least 10% of the tumor area showing spindle cells
and/or giant cells 5. Considering these pathological
criteria, the diagnosis of pleomorphic carcinoma which we
made on core biopsy was later changed to PB on surgical
There is limited knowledge about the pathogenesis of PB.
Studies have shown strong correlation with the smoking
status. At molecular level, the most commonly associated
genetic alteration is a missense mutation in exon 3 of the
CTNNB1 gene which leads to WNT pathway activation
leading to nuclear localization of beta-catenin 6. However,
this mutation is not specific to PB cases and may be detected
in cases of WDFA and less often in PPB cases 5. Another
common mutation detected in PB is TP53 mutation which
may also be found in PPB but not in WDFA cases 10.
Besides these two mutations, the literature also showed
molecular alterations involving ROS1, EGFR, BRCA2,
ERBB4, ALK, MET, BRAF, RAF1, PTEN, and PIK3CA
genes 11,12. Additionally, the somatic DICER1 mutations
coupled with CTNNB1 mutations was identified in two cases
of adult-onset pulmonary blastoma 13. Thus, a potential
genetic link to pediatric pleuropulmonary blastoma was
indicated. Recently, MYCN mutation was detected in the
micro dissected mesenchymal component based on capturebased
targeted next generation sequencing method 14. In
the index case, we came across a pathogenic mutation in the
MYCN and ATM genes on NGS where the latter have not
been described in the literature as per our best knowledge.
Terra et al. (2016) analyzed 33 cases of pulmonary
sarcomatoid carcinoma for approximately 2800 mutations
in 50 oncogenes and tumor-suppressor genes on NGS 15.
They did not detect any case showing MYCN and ATM gene
mutation. Though the role of these mutations has not yet
been fully discovered in adult pulmonary blastoma but it
is known to be associated with poor prognosis and distant
metastasis in other malignancies (e.g., neuroblastoma, breast
cancer) 16,17. It is documented that the microRNA-421
mediates downregulation of ATM gene via overexpression
of MYCN transcriptional factor in neuroblastoma; however,
this relation in pulmonary blastoma needs to be discovered
through large cohort studies 18.
The PBs have the tendency of both local extensions into
adjacent structures and distant hematogenous spread. The
brain, bones, liver, breast, peritoneum and ovaries are the
common metastatic sites documented 8. Very few cases of PB with cutaneous spread, including the index case,
are reported 19. The treatment in the form of surgery,
and chemotherapy (neoadjuvant and adjuvant), and/or
radiotherapy are considered depending on the tumour
stage. Surgical resection (i.e., lobectomy) is mainly done as
most of the tumours are detected in the early stage. When
it comes to metastasis, there are no specific management
guidelines available 9.
In conclusion, pulmonary blastoma is an exceedingly rare
lung cancer that shows distinct biphasic morphology. The
definite diagnosis can be made on surgical specimens as
core biopsies have their limitations. In the index case, this
neoplasm exhibited rare associations in the form of nonsmoker
status, scalp metastasis (cutaneous spread), and
pathogenic molecular alterations in the MYCN and ATM
genes on NGS in addition to conventional CTNNB1 gene
mutation. In view of these co-existing pathogenic molecular
alterations, large cohort molecular studies are required
to discover the incidence, significance, and therapeutic
implications in pulmonary blastoma.
Conflict of Interest
The authors declare that there is no conflict of interest.
The authors have no funding or financial relationships to disclose.
Informed written consent was taken from the patient.
Concept: MP, DK, AB, Design: MP, AB, Data collection or processing:
MP, NA, DK, RKB, NS, HS, AB, Analysis or Interpretation: MP, DK,
RKB, NS, HS, AB, Literature search: MP, NA, AB, Writing: MP, NA,
Approval: MP, DK, RKB, NS, HS, AB.
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