Carcinoids are malignant neuroendocrine tumors consisting of a spectrum of neoplasms from low-grade typical carcinoid to high-grade small cell carcinoma. We report a case of atypical thymic carcinoid that responded to neoadjuvant therapy with octreotide and sunitinib, an oral multikinase inhibitor. After 3 weeks of treatment, tumor size significantly decreased to allow for a safe surgical resection with clear margins. We believe that further study of sunitinib and octreotide with the neoadjuvant intent of preparing tumors for resection is warranted as a strategy to improve curative management of neuroendocrine tumors

Dham, Anu

Dudek, Arkadiusz Z.

Truskinovsky, Alexander M.

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Thymic Carcinoid Responds to Neoadjuvant Therapy with Sunitinib and Octreotide: A Case Report 

CASE REPORT
Thymic Carcinoid Responds to Neoadjuvant Therapy with
Sunitinib and Octreotide: A Case Report
Anu Dham, MD,* Alexander M. Truskinovsky, MD,† and Arkadiusz Z. Dudek, MD, PhD*
Carcinoids are malignant neuroendocrine tumors consisting of a
spectrum of neoplasms from low-grade typical carcinoid to high-
grade small cell carcinoma. We report a case of atypical thymic
carcinoid that responded to neoadjuvant therapy with octreotide and
sunitinib, an oral multikinase inhibitor. After 3 weeks of treatment,
tumor size significantly decreased to allow for a safe surgical
resection with clear margins. We believe that further study of
sunitinib and octreotide with the neoadjuvant intent of preparing
tumors for resection is warranted as a strategy to improve curative
management of neuroendocrine tumors.
Key Words: Carcinoids, Neoadjuvant therapy, Octreotide,
Sunitinib, Somatostatin receptor, Vascular endothelial, Growth fac-
tor receptor, Platelet-derived growth factor receptor.
(J Thorac Oncol. 2008;3: 94–97)
Carcinoids are a rare type of neuroendocrine tumor that arefrequently inoperable due to anatomic location or num-
ber of metastases. Chemotherapy is associated with limited
response rates and significant toxicities.1,2 Carcinoids tumors
overexpress somatostatin receptor, and somatostatin ana-
logues are commonly used in the diagnosis and treatment of
carcinoids, in which they have shown benefit in improving
tumor localization and increasing tumor control.3 Similarly,
carcinoids may be susceptible to neoadjuvant therapy targeting
several other receptors overexpressed in these tumors, including
vascular endothelial growth factor receptor (VEGFR)4 and
platelet-derived growth factor receptor (PDGFR).5 Here, we
describe the rapid shrinkage of a thymic carcinoid following
neoadjuvant therapy with the somatostatin analogue oct-
reotide and the receptor tyrosine kinase inhibitor sunitinib.
CLINICAL SUMMARY
A 40-year-old man presented with a 6-month history of
exertional dyspnea and fatigue. His symptoms subsequently
progressed into dysphagia. Past medical history was not
significant for weight loss, night sweats, fevers, facial flush-
ing, or diarrhea. The patient reported mild asthma, use of
chewing tobacco, and occasional use of alcohol. He had
undergone operations on his knee and wrist. His family
history revealed paternal diabetes and rheumatoid arthritis.
His physical examination revealed no signs of adenopathy or
organomegaly.
Chest radiogram revealed a large anterior mediastinal
mass. Positron emission tomography and computerized to-
mography (PET/CT) scan confirmed the location of a lobu-
lated, heterogenous, soft-tissue mass (8.3  5.0 cm) with
lymphadenopathy extending into the right hilar region and
compressing the right mainstem bronchus (Figure 1). The
standardized uptake value (SUV) was 12.7. The mass also
abutted the right anterior pericardium, and a 1.4 cm right
cardiophrenic lymph node (SUV 5.3) was observed. Patchy
nodular opacities were also seen in both lungs. The original
percutaneous needle biopsy of the mediastinal mass showed
solid sheets of small, monotonous neoplastic cells separated
by hyalinized fibrous septa. The tumor had prominent areas
of crush artifact. The cells contained scant cytoplasm and
small, hyperchromatic nuclei with finely dispersed chromatin.
No conspicuous mitotic activity was identified (Figure 2).
Immunostains performed at the referring institution demon-
strated that the tumor had a neuroendocrine immunopheno-
type. The tumor showed positive immunostaining for CD117
(c-kit), but not for epidermal growth factor receptors. Based
on the low mitotic activity, lack of necrosis, and a low Ki67
(proliferative) index of the tumor, a diagnosis of typical
carcinoid tumor was rendered.
As part of staging, the patient underwent drainage of
the pericardial fluid along with pericardial biopsy to rule out
malignant invasion. No malignant cells were seen in the
pericardium, pericardial nodule, or pericardial fluid. Oc-
treoScan imaging showed a large focus of increased tracer
uptake in the chest corresponding to the mediastinal mass
noted on PET/CT. Normal uptake in liver, spleen, gallblad-
der, and kidneys was observed. No other focus of abnormal
tracer uptake was noted.
The tumor was considered unresectable at the time of
diagnosis because of extensive invasion into the mediasti-
num. The patient was started on sunitinib 50 mg per day for
4 weeks with 2 weeks off and 30 mg of depot formulation of
octreotide once every 4 weeks. No treatment-related toxicity
was observed. The patient reported resolution of chest pain,
pressure and dysphagia. Three weeks after initiation of ther-
From the *Division of Hematology, Oncology, and Transplantation, and
†Department of Laboratory Medicine and Pathology, University of
Minnesota Medical School, Minneapolis, Minnesota.
Disclosure: The authors declare no conflict of interest.
Address for correspondence: Arkadiusz Dudek, MD, PhD, Division of
Hematology, Oncology, and Transplantation, MMC 480, 420 Delaware
Street SE, Minneapolis, MN 55455. E-mail: dudek002@umn.edu
Copyright © 2007 by the International Association for the Study of Lung
Cancer
ISSN: 1556-0864/08/0301-0094
Journal of Thoracic Oncology • Volume 3, Number 1, January 200894
apy, PET/CT scan revealed that the mass had decreased in
size to 7.7  4.5 cm (Figure 3). Pericardial thickening
adjacent to the mass was observed. The right cardiophrenic
lymph node had also decreased in size to 1.3 cm. The patient
underwent right pneumonectomy, and the tumor was re-
moved with clean margins. The surgical resection specimen
of the right lung showed a firm white tumor measuring 8.5 
6.2 3.6 cm, which was invading the upper lobe of the lung.
The tumor invaded the pericardium, the visceral pleura and
the azygous vein. The histopathological findings indicated
extensive necrosis and hyalinization of the tumor. Only
approximately 30 to 35% of the neoplasm was viable. The
viable tumor cells were arranged in nests and solid sheets.
They had a moderate amount of cytoplasm, which was more
prominent than the cytoplasm of the neoplastic cells in the
needle biopsy. The tumor nuclei had finely granular chroma-
FIGURE 2. Needle biopsy specimen of the mediastinal
mass. (Hematoxylin and eosin, original magnification 400.)
FIGURE 4. Tumor in the resection specimen of the right
lung. Arrows mark mitotic figures. (Hematoxylin and eosin,
original magnification 400.)
FIGURE 1. Lobulated, heterogenous, mediastinal, soft-tis-
sue mass (8.3  5.0 cm) with right hilar lymphadenopathy.
Mass was measured at the level of branching of the main
pulmonary artery.
FIGURE 3. Decrease in size of anterior mediastinal mass
(7.7  4.5) after 3 weeks of sunitinib and octreotide ther-
apy. Mass was measured at the level of branching of the
main pulmonary artery.
Journal of Thoracic Oncology • Volume 3, Number 1, January 2008 Dham et al.
Copyright © 2007 by the International Association for the Study of Lung Cancer 95
tin and showed focal molding. The mitotic activity was more
prominent than in the needle biopsy specimen (Figure 4). The
tumor showed strong, diffuse positive immunostaining for
synaptophysin (Figure 5) and weak positive immunostaining
for chromogranin. The Ki67 index of the tumor was moder-
ately increased (Figure 6). The surgical margins were nega-
tive for tumor. There was metastatic tumor in five of eleven
mediastinal and hilar lymph nodes.
Based on the findings in the resection specimen, includ-
ing prominent mitotic activity and increased Ki67 index, a
diagnosis of neuroendocrine neoplasm, grade 2, of interme-
diate differentiation (atypical carcinoid) was made.
No evidence of disease recurrence was evident 12
months after the operation.
DISCUSSION
Thymic carcinoid tumors have higher rate of metastatic
disease in comparison to carcinoids in other locations. In
addition, this disease usually presents when the tumor is very
large, and surgical resection is associated with low postoper-
ative survival rates.6 Indeed, our patient was evaluated as
inoperable due to tumor invasion into the mediastinum, and a
neoadjuvant strategy was pursued with the aim of eliciting a
tumor response and thereby improving the chances of cura-
tive resection.
The differences in the morphologic and immunohisto-
chemical features between the tumor in the biopsy and in the
resection specimen were due to poor preservation and crush
artifact of the tissue in the biopsy specimen which precluded
accurate histopathological and immunohistochemical exami-
nation of the neoplasm. In addition, the neoplasm might have
been morphologically heterogeneous, and the biopsy might
have sampled a better-differentiated area. Final diagnosis was
therefore more consistent with atypical carcinoid.
Sunitinib is a potent antiangiogenic and antitumor
agent that inhibits signaling through multiple tyrosine kinase
receptors, including VEGFR, PDGFR, c-KIT, and FLT3. In
preclinical models, sunitinib has been shown to inhibit the
growth of small cell cancer cell lines, with dose-dependent
effects on cell proliferation and protein levels of stem cell
factor-stimulated KIT phosphotyrosine.7 Also, phospho-
PDGFR-beta levels expressed by tumor stroma and involved
in angiogenesis were greatly lowered by sunitinib.7 In human
trials, Kulke et al. have reported a lack of significant toxicity
associated with sunitinib therapy for patients with unresect-
able metastatic neuroendocrine tumors along with a high
percentage of stable disease.8 In our case, however, sunitinib
therapy was administered with the neoadjuvant intent of
increasing the feasibility of surgical resection.
In addition to sunitinib, our patient received octreotide
due to its proven antiangiogenic activity in vivo and in vitro.9
However, our patient experienced clinical and radiologic
responses within 3 weeks, well before one would expect a
response with octreotide alone. The median time of response
to somatostatin analogues is approximately 3 months.10 Our
patient’s rapid response to therapy indicates that the combi-
nation of sunitinib and octreotide or sunitinib alone was
responsible for tumor shrinkage. Further study of neoadju-
vant therapy with sunitinib and octreotide is warranted as a
strategy to improve curative management of pulmonary car-
cinoid tumors.
ACKNOWLEDGMENTS
The authors thank Michael Franklin for editorial
support.
FIGURE 5. Diffuse, strong positive immunostaining of the
tumor for synaptophysin. (Synaptophysin immunostain, orig-
inal magnification 200.)
FIGURE 6. Moderately increased Ki67 (proliferative) index
of the tumor in the resection specimen. (Ki67 immunostain,
original magnification 200.)
Thymic Carcinoid Responds to Sunitinib and Octreotide Journal of Thoracic Oncology • Volume 3, Number 1, January 2008
Copyright © 2007 by the International Association for the Study of Lung Cancer96
REFERENCES
1. Hage R, de la Rivie`re AB, Seldenrijk CA, et al. Update in pulmonary
carcinoid tumors. A review article. Ann Surg Oncol 2003;10:697–704.
2. Thomas CF Jr, Jett JR. Bronchial Carcinoid Tumors. [UpToDate Web
site] April 25, 2007. Available at: http://patients.uptodate.com/topic.
asp?filemisc_tum/7155. Accessed September 12, 2007.
3. Nilsson O, Ko¨lby L, Wa¨ngberg B, et al. Comparative studies on the
expression of somatostatin receptor subtypes, outcome of octreotide
scintigraphy and response to octreotide treatment in patients with car-
cinoid tumours. Br J Cancer 1998;77:632–637.
4. Terris B, Scoazec JY, Rubbia L, et al. Expression of vascular endothelial
growth factor in digestive neuroendocrine tumours. Histopathology
1998;32:133–138.
5. Chaudhry A, Funa K, Oberg K. Expression of growth factor peptides and
their receptors inneuroendocrine tumors of the digestive system. Acta
Oncol 1993;32:107–114.
6. Soga J, Yakuwa Y, Osaka M. Evaluation of 342 cases of mediastinal/
thymic carcinoids collected from literature: a comparative study between
typical carcinoids and atypical varieties. Ann Thorac Cardiovasc Surg
1999;5:285–292.
7. Abrams TJ, Lee LB, Murray LJ, et al. SU11248 inhibits KIT and
platelet-derived growth factor receptor beta in preclinical models of
human small cell lung cancer. Mol Cancer Ther 2003;2:471–478.
8. Kulke M, Lenz H, Meropol N, et al. A phase 2 study to evaluate the
efficacy and safety of SU11248 in patients (pts) with unresectable
neuroendocrine tumors (NETS). J Clin Oncol 2005;23:4008.
9. Dasgupta, P. Somatostatin analogues: multiple roles in cellular pro-
liferation, neoplasia, and angiogenesis. Pharmacol Ther 2004;102:
61–85.
10. Aparicio T, Ducreux M, Baudin E, et al. Antitumour activity of soma-
tostatin analogues in progressive metastatic neuroendocrine tumours.
Eur J Cancer 2001;37:1014–1019.
Journal of Thoracic Oncology • Volume 3, Number 1, January 2008 Dham et al.
Copyright © 2007 by the International Association for the Study of Lung Cancer 97


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Thymic Carcinoid Responds to Neoadjuvant Therapy with Sunitinib and Octreotide: A Case Report

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