AE Wakeling

CG Schulze

D Kung

E Wayne

Hye-Suk Han

IL Shih

Joo Young Lee

K Mimatsu

Ki Hyeong Lee

LM Ho

LY Kernagis

M Maemondo

M Matsuura

Ok-Jun Lee

R Coriat

Seung Taik Kim

Sung-Nam Lim

T Tsujimoto

TH Florin

TR Asmis

TS Mok

TW Flaig

Y Heng

Yong Hyeok Choi

Young Kwang Shim

BMC Cancer

English

PubMed

Springer - Publisher Connector

CASE REPORT Open Access
Pneumatosis intestinalis and portal venous gas
secondary to Gefitinib therapy for lung
adenocarcinoma
Joo Young Lee1, Hye-Suk Han1*, Sung-Nam Lim1, Young Kwang Shim1, Yong Hyeok Choi1, Ok-Jun Lee2,
Ki Hyeong Lee1 and Seung Taik Kim1
Abstract
Background: Pneumatosis intestinalis (PI), defined as the presence of gas in the bowel wall, and portal venous gas
(PVG) are relatively rare radiological findings. Although several chemotherapeutic agents and anti-vascular
endothelial growth factor agents are reported to be associated with PI and PVG, an association with anti-epidermal
growth factor receptor (EGFR) agents has not been described previously.
Case presentation: The present report describes a case of PI and PVG secondary to treatment with an EGFR
tyrosine kinase inhibitor. A 66-year-old woman who had been diagnosed with metastatic lung adenocarcinoma
presented with nausea, vomiting and abdominal distension after commencing gefitinib. A computed tomography
(CT) scan of the abdomen revealed PI extending from the ascending colon to the rectum, hepatic PVG, and
infarction of the liver. Gefitinib therapy was discontinued immediately and the patient was managed
conservatively. A follow-up CT scan 2 weeks later revealed that the PI and hepatic PVG had completely resolved.
Conclusion: This is the first report of PI and PVG caused by EGFR tyrosine kinase inhibitor. Although these
complications are extremely rare, clinicians should be aware of the risk of PI and PVG in patients undergoing
targeted molecular therapy.
Background
Recent advances in our understanding of the biology
and molecular mechanisms of cancer have led to the
introduction of molecular-targeted agents for the treat-
ment of non-small cell lung cancer (NSCLC). Gefitinib
is an orally active selective inhibitor of the epidermal
growth factor receptor (EGFR) tyrosine kinase, an
enzyme that regulates the intracellular signaling path-
ways implicated in the proliferation and survival of can-
cer cells [1]. Somatic mutations in the region of EGFR
that encodes the tyrosine kinase domain of the receptor
have been identified in patients with NSCLC and many
studies report that NSCLC patients who carry these
mutations are highly responsive to gefitinib [2,3].
In general, targeted molecular therapies such as gefiti-
nib have good toxicity profiles. However, some patients
develop specific and severe toxicities, since these mole-
cular targets are also expressed in normal cells.
Although gefitinib is generally well tolerated, its most
commonly reported side effects are of the gastrointest-
inal tract (diarrhea, nausea and vomiting) and skin
(rash, acne, dry skin and pruritus). Severe gastrointest-
inal toxicity secondary to gefitinib is uncommon, and
only 1% of patients treated with gefitinib develop grade
3 or 4 diarrhea [3].
The present report describes the development of
pneumatosis intestinalis (PI) and portal venous gas
(PVG) in a patient with metastatic lung adenocarcinoma
who had received gefitinib therapy.
Case presentation
A 66-year-old woman was diagnosed with lung adeno-
carcinoma with malignant pleural effusion in December
2009. A computed tomography (CT) scan of the chest
* Correspondence: sook3529@hanmail.net
1Department of Internal Medicine College of Medicine, Chungbuk National
University, 410 Seongbong-ro, Heungduk-Gu, Cheongju 361-711, South
Korea
Full list of author information is available at the end of the article
Lee et al. BMC Cancer 2012, 12:87
http://www.biomedcentral.com/1471-2407/12/87
© 2012 Lee et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
at diagnosis revealed a mass in the right middle lobe
and a right-sided pleural effusion. Histological examina-
tion of a cell block from the pleural effusion following
hematoxylin and eosin staining confirmed a diagnosis of
metastatic lung adenocarcinoma. Immunohistochemical
staining showed that the tumor cells were positive for
cytokeratin 7 (1:600; NeoMarkers, California, USA) and
thyroid transcription factor-1 (1:300; Leica, Newcastle-
upon-Tyne, UK), but negative for cytokeratin 20 (1:200;
Leica) (Figure 1). The patient received six cycles of pal-
liative chemotherapy, consisting of gemcitabine and cis-
platin, which resulted in a partial response. In
November, 2010, the patient developed anorexia and
abdominal distension. A CT scan of the chest revealed
that the disease had progressed. Moreover, a CT scan of
the abdomen revealed mild ascites, omental dirty fat
infiltration, and lymph node enlargement in the porta
hepatis, peripancreatic, interaortocaval and paraaortic
areas. Histological examination of a cell block from the
ascites confirmed a diagnosis of metastatic adenocarci-
noma, and the immunohistochemical profile was consis-
tent with that obtained previously for the malignant
pleural effusion. To exclude the existence of another
primary site, esophagogastroduodenoscopy, colonoscopy
and positron emission tomography-CT scanning were
performed; no intra-abdominal primary site was identi-
fied. On the basis of these findings, a diagnosis of pri-
mary lung adenocarcinoma with peritoneal metastases
was assigned. The tumor tissue was analyzed for the
presence of an EGFR mutation using the PNAClamp™
EGFR Mutation Detection kit (PANAGENE, INC. Dae-
jeon, Korea). In the cell blocks from the pleural fluid
and the ascites, an L858R mutation in exon 21 was
detected. Gefitinib therapy was therefore commenced.
In January, 2011 the patient presented with a 7-day
history of progressively worsening nausea, vomiting,
diarrhea and abdominal distension. On examination, she
appeared non-toxic and was afebrile with stable vital
signs. Although abdominal distension with decreased
bowel sounds and generalized mild abdominal tender-
ness upon palpation were detected, no peritoneal signs
were present. Investigation of blood chemistry revealed
an alanine aminotransferase of 1435 IU/L, an aspartate
aminotransferase of 2178 IU/L, a total bilirubin of 0.85
mg/dL, a blood urea nitrogen of 36.1 mg/dL and a crea-
tinine of 1.38 mg/dL. A stool culture was negative. A
plain abdominal radiograph showed a dilated colon with
diffuse and extensive intraluminal air (Figure 2). A CT
scan of the chest and abdomen revealed that the size of
the mass in the right middle lobe, the volume of the
malignant pleural effusion, the volume of the ascites and
A
B
C
Figure 1 Pathological features of a cell block from the
malignant pleural effusion. Histological examination of the cell
block revealed metastatic adenocarcinoma (A, H&E × 400).
Immunohistochemistry showed that the tumor cells were positive
for (B) cytokeratin 7 and (C) thyroid transcription factor-1 (× 400).
Lee et al. BMC Cancer 2012, 12:87
http://www.biomedcentral.com/1471-2407/12/87
Page 2 of 5
the level of omental dirty fat infiltration had all mark-
edly decreased. However, PI extending from the
ascending colon to the rectum was detected in the
absence of pneumoperitoneum or other abnormalities
(Figure 3A). Moreover, a large volume of hepatic PVG
and a low-attenuation lesion in the right lobe of the
liver were observed. These findings were considered to
be suggestive of an infarction of the liver (Figure 3B).
Although the CT images were striking, surgical
exploration was not performed since the patient was
non-toxic and had mild symptoms. The patient was
not taking any medicine except gefitinib. Gefitinib
therapy was immediately discontinued and the patient
was managed conservatively with nasogastric-tube-drai-
nage and prophylactic antibiotics. Two weeks later, the
gastrointestinal symptoms improved and a reduction in
the levels of the liver enzymes was observed. A follow-
up CT scan at this time-point revealed that the PI and
HPVG had completely resolved.
Although gefitinib had led to a partial response, this
therapy was now considered to be contraindicated in
this patient. Pemetrexed was therefore commenced
instead as a third-line therapy. However, the malignant
pleural effusion and peritoneal carcinomatosis became
exacerbated, and the patient died of bacterial pneumonia
with sepsis 18 months after the initial diagnosis.
Figure 2 A plain abdominal radiograph. Abdominal X-ray showed a dilated colon and the presence of intraluminal air along the entire wall of
the colon (black arrows).
Lee et al. BMC Cancer 2012, 12:87
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Page 3 of 5
Conclusions
PI is defined as the presence of gas within the bowel
wall and represents a radiological finding rather than a
diagnosis [4]. Although it can occur as a primary dis-
ease, PI occurs more commonly secondary to other
causes which range from benign conditions to fulminant
disease [4,5]. Although the pathogenesis and etiology of
PI are not fully understood, its causes can be classified
into several conditions: life-threatening bowel necrosis,
such as necrotizing enterocolitis and bowel ischemia;
raised intra-abdominal pressure due to bowel obstruc-
tion, abdominal trauma, ileus, surgery and colonoscopy;
increased mucosal permeability associated with steroid
therapy, chemotherapy, connective tissue disease and
immunosuppressive therapy; respiratory conditions such
as chronic bronchitis, emphysema and asthma; trichlor-
oethylene exposure, ingestion of carbohydrate such as
lactose or sorbitol; and counter-perfusion super-satura-
tion [4-7]. However, in the present case, no mechanical
or bacterial factors, such as bacterial ischemia, bowel
obstruction, inflammatory bowel disease, obstructive
pulmonary disease or infectious colitis, were identified.
In addition, the intraluminal air extended continuously
from the ascending colon to the rectum, a pattern
which is incompatible with any vascular territory, and
an ischemic cause was therefore unlikely. The intra-
abdominal metastases of lung adenocarcinoma showed a
marked improvement in response to gefitinib therapy.
However, the PI developed after the commencement of
gefitinib and gradually resolved following its disconti-
nuation. The patient was not taking any other medicines
that might have been the cause of PI. We therefore pre-
sume that gefitinib played a major role in the develop-
ment of PI in the present case.
Several chemotherapeutic agents have been reported
to be associated with PI, including cyclophosphamide,
methotrexate, vincristine, doxorubicin, daunorubicin,
cytarabine, fluorouracil, paclitaxel, docetaxel, etoposide,
irinotecan and cisplatin [8-10]. Since the intestinal
mucosa is highly proliferative, chemotherapy often
causes mucosal damage. Chemotherapeutic agents may
also interfere with the mucosal integrity of the intestinal
tract, resulting in extensive intramural air. However, PI
secondary to molecularly-targeted agents is very rare.
Recent reports describe the development of PI in
patients receiving anti-vascular endothelial growth factor
(VEGF) agents such as bevacizumab, sunitinib, and sora-
fenib [11-13]. VEGF inhibition can damage the micro-
vasculature of the intestinal wall and it is plausible that
a secondary insult to the intestine may lead to the devel-
opment of PI. EGFR tyrosine kinase inhibitors such as
gefitinib are associated with more gastrointestinal symp-
toms than other molecularly-targeted agents, partly as a
result of their oral formulation. Although the precise
pathophysiology of anti-EGFR agent-related gastrointest-
inal toxicity remains unclear, EGF is involved in the
maintenance of mucosal integrity [14]. EGF deficiency
secondary to anti-EGFR agents interferes with the
BA
Figure 3 Computed tomography (CT) image of the abdomen and pelvis. The CT scan shows extensive bubble-like pneumatosis intestinalis
along the entire colon (A, white arrows), branching lucencies indicating hepatic portal venous gas, and a low-attenuation lesion in the right
lobe of the liver, suggestive of infarction of the liver (B, black arrows).
Lee et al. BMC Cancer 2012, 12:87
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Page 4 of 5
mucosal integrity of the intestinal tract resulting in diar-
rhea, constipation, nausea and vomiting, and PI.
Furthermore, the patient described herein had a hepatic
PVG on CT scan of the abdomen. The finding of PI and
PVG during CT scanning usually indicates mesenteric
ischemia or infarction [15,16]. However, both findings are
also observed in a range of non-ischemic conditions.
Therefore, conservative therapy may be effective, although
immediate laparotomy is usually recommended in patients
presenting with PVG [17]. In the present case, non-inva-
sive management was indicated since the hepatic PVG
was secondary to gefitinib-induced gastrointestinal toxicity
rather than to bowel necrosis.
To our knowledge, the present report is the first to
identify gefitinib as a cause of PI and PVG, and thus
extends the literature concerning gefitinib-induced gas-
trointestinal toxicity. In conclusion, although PI and
PVG are extremely rare complications of targeted mole-
cular therapy, clinicians should be aware of the possibi-
lity of PI and PVG in patients receiving anti-EGFR
therapies. Further studies are warranted to analyze the
biological effects of targeted therapies on normal tissues
as well as on cancer cells.
Consent
Written informed consent for publication of this case
report and associated images could not be obtained
from the patient, but the patient’s son provided the
required consent.
Acknowledgements
This study was supported by the research grant of the Chungbuk National
University in 2011. Written consent was obtained from the patient’s son for
publication of the study.
Author details
1Department of Internal Medicine College of Medicine, Chungbuk National
University, 410 Seongbong-ro, Heungduk-Gu, Cheongju 361-711, South
Korea. 2Department of Pathology, College of Medicine, Chungbuk National
University, Cheongju, South Korea.
Authors’ contributions
LJY is the first author; HHS is the corresponding author of the manuscript.
LOJ provided pathologic evaluation. LSN and SYK collected the patient’s
data and provided figures. CYH, LKH and KST were involved in drafting and
revising the manuscript. The final version of the manuscript was seen and
approved by all authors.
Competing interests
The authors declare that they have no competing interests.
Received: 27 July 2011 Accepted: 10 March 2012
Published: 10 March 2012
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Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1471-2407/12/87/prepub
doi:10.1186/1471-2407-12-87
Cite this article as: Lee et al.: Pneumatosis intestinalis and portal venous
gas secondary to Gefitinib therapy for lung adenocarcinoma. BMC
Cancer 2012 12:87.
Lee et al. BMC Cancer 2012, 12:87
http://www.biomedcentral.com/1471-2407/12/87
Page 5 of 5


Pneumatosis intestinalis and portal venous gas secondary to Gefitinib therapy for lung adenocarcinoma

Abstract
          
            Background
            Pneumatosis intestinalis (PI), defined as the presence of gas in the bowel wall, and portal venous gas (PVG) are relatively rare radiological findings. Although several chemotherapeutic agents and anti-vascular endothelial growth factor agents are reported to be associated with PI and PVG, an association with anti-epidermal growth factor receptor (EGFR) agents has not been described previously.
          
          
            Case presentation
            The present report describes a case of PI and PVG secondary to treatment with an EGFR tyrosine kinase inhibitor. A 66-year-old woman who had been diagnosed with metastatic lung adenocarcinoma presented with nausea, vomiting and abdominal distension after commencing gefitinib. A computed tomography (CT) scan of the abdomen revealed PI extending from the ascending colon to the rectum, hepatic PVG, and infarction of the liver. Gefitinib therapy was discontinued immediately and the patient was managed conservatively. A follow-up CT scan 2 weeks later revealed that the PI and hepatic PVG had completely resolved.
          
          
            Conclusion
            This is the first report of PI and PVG caused by EGFR tyrosine kinase inhibitor. Although these complications are extremely rare, clinicians should be aware of the risk of PI and PVG in patients undergoing targeted molecular therapy.
          </jats:sec

Crossref

Amano S: Pneumatosis cystoides intestinalis after fluorouracil chemotherapy for rectal cancer.

Chiba T: Therapeutic effects of rectal administration of basic fibroblast growth factor on experimental murine colitis. Gastroenterology

Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.

Goldwasser F: Pneumatosis intestinalis associated with treatment of cancer patients with the vascular growth factor receptor tyrosine kinase inhibitors sorafenib and sunitinib. Invest New Drugs

Hepatic portal venous gas. Imaging modalities and clinical significance. Acta Radiol

Hills BA: Does counterperfusion supersaturation cause gas cysts in pneumatosis cystoides coli, and can breathing heliox reduce them? Lancet

JE: Pneumatosis intestinalis in patients with ischemia: correlation of CT findings with viability of the bowel.

KH: ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res

KL: Pneumatosis coli after etoposide chemotherapy for breast cancer.

North-East Japan Study Group: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.

PD: Colonic pneumatosis and intestinal perforations with sunitinib treatment for renal cell carcinoma. Invest New Drugs

Pneumatosis cystoides intestinalis following alpha-glucosidase inhibitor treatment: a case report and review of the literature.

Pneumatosis intestinalis: a variant of bevacizumab related perforation possibly associated with chemotherapy related GI toxicity. Invest New Drugs

Rohrmann CA: Pneumatosis intestinalis: a review.

Saund MS: Pneumatosis intestinalis and portal venous gas without bowel ischemia in a patient treated with irinotecan and cisplatin. Dig Dis Sci

WM: Pneumatosis intestinalis in the adult: benign to life-threatening causes.

https://bmccancer.biomedcentral.com/track/pdf/10.1186/1471-2407-12-87?site=bmccancer.biomedcentral.com

Pneumatosis intestinalis and portal venous gas secondary to Gefitinib therapy for lung adenocarcinoma

Abstract

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