Case Studies
Thyroid Cancer and T Lymphoblastic
Leukemia in Crohn Disease: A Case Report
and Literature Review
Lab Med Spring 2015;46:140-145
DOI: 10.1309/LMU4KMJDRM3AD6FQ
ABSTRACT
The effectiveness of the tumor necrosis–α (TNF-α) blockade has
changed the treatment of several chronic inflammatory diseases,
including inflammatory bowel disease; however, this treatment also
has disadvantages. The use of immunosuppressants in combination
with infliximab has been associated with greater risk of developing
malignant neoplasms. Herein, we report the case of a 33-year-old
ethnic Korean man with Crohn disease (CD) who developed papillary
thyroid carcinoma (PTC) and, subsequently, T-cell acute lymphoblastic
leukemia (ALL) after approximately 16.0 years of immunosuppressant
Abbreviations:
IBDs, inflammatory bowel diseases; CD, Crohn disease; UC, ulcerative
colitis; PTC, papillary thyroid carcinoma; ALL, acute lymphoblastic
leukemia; CDAI, Crohn’s Disease Activity Index; 6-MP, mercaptopurine;
TdT, terminal deoxynucleotidyl transferase; TNM, tumor size, nodes
involved, metastasis; FISH, fluorescent in situ hybridization; RT-PCR,
reverse transcription–polymerase chain reaction; VPDL, vincristine,
prednisolone, daunorubicin, and L-asparaginase; CT, computed
tomography; ROS, reactive oxygen species; TPMT, thiopurine
S-methyltransferase; AML, acute myeloid leukemia; TNF-α, tumor
necrosis factor–α
Departments of 1Internal Medicine and 2Laboratory Medicine, School of
Medicine, and 3Department of Medicine, Graduate School, Kyung Hee
University, Seoul, South Korea
*To whom correspondence should be addressed.
wkiki@naver.com
140 Lab Medicine
Spring 2015 | Volume 46, Number 2
therapy and 5.5 years of infliximab therapy. To our knowledge, this
is the first case described in the literature of 2 different malignant
neoplasms, 1 of hematologic origin and the other involving the solid
organs, in a patient with CD. Through a systematic literature review,
we found 28 cases of acute leukemia in adult patients with CD,
of whom 22 had myeloid leukemia and 6 had lymphoid leukemia.
Half of the patients with ALL underwent TNF-α–blocker therapy in
combination with thiopurines.
Keywords: acute leukemia, papillary thyroid carcinoma, Crohn
disease, infliximab, thiopurine, mercaptopurine
Inflammatory bowel disease (IBD), which results from an
aberrant immune system response to intestinal bacteria
in genetically susceptible individuals, is associated with
compromised quality of life and shorter life expectancy.1
Crohn disease (CD) and ulcerative colitis (UC) are the 2
most common causes of IBD.2 In light of the relapsing
inflammatory nature of this disease, a large number
of patients with IBD are subjected to treatment with
immunomodulators or biologic agents, in addition to
corticosteroids, for an extended period. 2 This multimodal
approach is associated with a significantly altered immune
system in patients and, subsequently, a slightly increased
risk of developing malignant neoplasms.3,4 Herein, we
report a case of a 33-year-old ethnic Korean man with
CD who developed papillary thyroid carcinoma (PTC)
and, subsequently, T-cell acute lymphoblastic leukemia
(ALL) after approximately 16 years of immunosuppressant
therapy and 5.5 years of infliximab therapy. To our
knowledge, this is the first CD case associated with ALL
and PTC. We also provide a concise review from the
literature of acute leukemia cases in adult patients (aged
≥16 years) with CD.5-25
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Ja Min Byun, MD,1,3 Sun Kyung Baek, MD, PhD,1 Hwi-Joong Yoon, MD, PhD,1
Si-Young Kim, MD, PhD,1 Chi Hoon Maeng, MD, PhD,1 Tae Sung Park, MD, PhD,2
Hyo-Jong Kim, MD, PhD,1 Yun Young Choi, MD,1 Yu Jin Um, MD1
Case Studies
A
B
Image 1
Pathologic images of thyroid specimen from the patient, a
33-year-old ethnic Korean man. Pathologic TNM (tumor size,
nodes involved, metastasis) staging of the disease of the patient
at the time of specimen harvest was pT3N1M0. A, Thyroid cells
showing papillary carcinoma (arrows; hematoxylin-eosin staining, original magnification ×40). B, Immunohistochemical staining
of papillary carcinoma showing expression of CK19 (arrows). C,
Immunohistochemical staining of papillary carcinoma showing
expression of galectin-3 (arrows).
Case Report
A 33-year old ethnic Korean man was referred to our
hematology department for evaluation of leukocytosis,
anemia, and thrombocytopenia. He had been diagnosed
with Crohn disease in May 1998 at the Department of
Gastroenterology at the Kyung Hee University School of
Medicine in Seoul, South Korea. At the time of diagnosis,
his CD was classified as A2-L1-B1p according to the
Montreal Classification and his Crohn Disease Activity
Index (CDAI) score was 349 points. He had no selfreported history of alcohol consumption or cigarette
smoking. The patient underwent right hemicolectomy
due to fistula-tract abscess formation that had occurred
within the same month. Since that time, for the past
10 years, he had taken mercaptopurine (6-MP), 75 mg/
day, and mesalazine (dose varying from 1.5 g/day to
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3.0 g/day, based on his condition). In May 2008, the
failure of mercaptopurine and mesalazine to improve
his symptoms led to the initiation of infliximab therapy,
5 mg/kg body weight every 8 weeks. His height was
167cm, weight 62.4 kg and his body mass index was
22.4 kg/m2. At the time of infliximab initiation, the CDAI
score of the patient was 387 points. With the use of
infliximab, stable remission of CD was achieved; the
CDAI score of the patient had dropped to less than 150.
In September 2013, approximately 5.5 years after the
initiation of therapy and after the 36th infliximab infusion
dose, his treating physician found a thyroid nodule
incidentally during an annual medical check-up. A fine
needle aspiration was performed; the results showed
papillary thyroid carcinoma. The patient underwent
total thyroidectomy with bilateral neck dissection.
The pathologic staging according to the TNM (tumor
size, nodes involved, metastasis) staging system was
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141
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C
Case Studies
A
B
Bone marrow aspiration smears (Wright-Giesma staining, original magnification ×1000) from the patient, a 33-year-old ethnic Korean
man. Blasts are characterized by abundant cytoplasm, scattered fine granules, and vacuoles. A, Initial smear, with blast count at 81.6%.
B, Follow-up smear, with blast count at 63.8%.
pT3N1M0 (Image 1A, 1B, and 1C). The leukocyte count
of the patient at the time he underwent his operation
was 6.38 × 10 9/L (reference range, 4.0-10.0 × 10 9/L),
with 29% neutrophils. His hemoglobin level was 13.1 g/
dL (reference range, 13-17 g/dL) and his platelet count
was 235 × 10 9/L (reference range, 150-350 × 10 9/L). Also,
the patient reported feeling reasonably well and did not
report any physical discomfort.
Approximately 2.5 months after the operation, in
December 2013, the patient reported a reduced sense
of well-being, increased myalgia, fatigue, febrile sense,
and upper respiratory tract symptoms. At this time, his
leukocyte count was 316.7 × 109/L with 79% blasts, his
hemoglobin level was 6.2 g/dL, and his platelet count was
46 × 109/L. Results of bone marrow biopsy and aspiration
showed marked infiltration of blasts (81.6%; Image 2A).
Immunophenotyping results were positive for CD2, CD13,
CD7, CD34, CD45, and CD3. Immunophenotyping results
were negative for CD10, CD19, terminal deoxynucleotidyl
transferase (TdT), CD33, CD79a, CD14 and anti-MPO.
Chromosome analysis revealed 46,XY,der(1)t(1;3)
(p?36.1;q21),-20,+mar[15]/46,XY[5]. Fluorescent in situ
hybridization (FISH) cytogenetic analysis results showed
D20S108(20q12)/MYBL2(20q13.12) gene deletion. We
performed HemaVision (DNA Diagnostics A/S, Risskov,
Denmark), a qualitative multiplex reverse transcription–
142 Lab Medicine
Spring 2015 | Volume 46, Number 2
polymerase chain reaction (RT-PCR) method that
allows rapid screening of 28 different translocations or
chromosomal rearrangements specific for particular
subtypes of leukemia; the results were negative. The final
diagnosis of T-cell ALL was established. We instituted
standard induction chemotherapy that consisted
of cyclophosphamide, vincristine, doxorubicin, and
dexamethasone. The patient then received subsequent
chemotherapy consisting of high-dose methotrexate and
cytarabine. We decided to continue infliximab treatment
for his CD.
However, follow-up bone marrow examination results for
the patient showed treatment-refractory leukemia, with a
blast count of 63.8% and persistent abnormalities present
in chromosome and cytogenetic analyses (Image 2B). We
decided to administer salvage chemotherapy, consisting of
vincristine, prednisolone, daunorubicin, and L-asparaginase
(VPDL). Before the second cycle of VPDL, the patient was
admitted to the hospital due to severe abdominal pain.
The abdomen computed tomography (CT) scan showed
multisegmental small-bowel obstruction due to fibrosis,
some of which was associated with a previous fistula.
The patient underwent laparoscopic adhesiolysis; the
procedure was successful. The second cycle of VPDL was
initiated 2 weeks after the procedure. However, the patient
subsequently died of pneumonia and cerebral hemorrhage.
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Image 2
Case Studies
Table 1. Cases of Acute Leukemia in Patients With Crohn Disease (CD)
No.
Sex/Age, y
Interval Since CD Diagnosis
Therapy for CD
Type of Leukemia
Outcome
Reference No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
M/17
M/18
M/28
F/21
F/21
F/22
M/31
M/32
M/33
M/36
F/37
M/38
M/40
M/41
M/43
M/43
M/47
F/53
F/54
M/56
F/62
F/63
F/63
M/64
F/65
F/67
F/71
M/78
3y
1y
18 y
3y
3y
1y
18 y
22 y
15 y
10 y
8y
2y
4y
9y
10 y
1 mo
2y
8y
4 mo
3 mo
20 y
5y
22 y
36 y
5y
44 y
12 y
11 y
Steroid, SAS
Steroid
Steroid, SAS
AZA
Steroid, SAS, 6-MP
SAS
Steroid, AZA
AZA, infliximab
SAS, 6-MP, infliximab
Steroid, SAS
Steroid, SAS
Steroid, SAS, AZA
SAS, AZA, infliximab, MTX
Steroid, SAS
SAS
Steroid, AZA
Steroid, SAS
Steroid, SAS
NA
Steroid
SAS, 6-MP
Steroid, SAS, 6-MP
Steroid, AZA, adalimumab
Steroid, SAS, 6-MP
SAS
Steroid
AZA
Steroid, SAS
ALL, T-cell
AML
ALL
AML
AML, M5a subtype
ALL
AML, M1 subtype
AML, M4 subtype
ALL, T-cell
AML
AML, M3 subtype
AML, M5a subtype
ALL, BCR/ABL+
AML
AML, M4 subtype
AML
AML, M4 subtype
AML, M4 subtype
AML
AML
AML
AML, M4 subtype
ALL
AML
AML, M4 subtype
AML
AML
AML, M3 subtype
Remission
Died
Died
Died
Remission
Remission
NA
Remission
Died
NA
Remission
NA
Remission
NA
NA
Remission
NA
Died
Remission
NA
NA
NA
Remission
Died
NA
Died
Died
Died
24
5
23
18
21
25
22
Present case
14
17
13
6
13
13
20
11
1
16
12
19
8
7
15
11
5
9
17
F, female; M, male; CD, Crohn disease; SAS, sulfasalazine; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; AZA, azathioprine; 6-MP, mercaptopurine; MTX,
methotrexate; NA, not available
Discussion
Most patients with CD are subjected to prolonged
exposure to multiple immunomodulators due to
the systemic nature of the illness and the naturally
progressive and destructive disease course. The use
of immunosuppressants in combination with infliximab
has been associated with greater risk of malignancy.26
Regarding tumor necrosis factor–α (TNF-α) blockers, it
has been shown27 that TNF-α inhibits the colony growth
of human leukemia progenitor cells in a dose-dependent
manner and suppresses various leukemic cell lines. It
also plays a pivotal role in cell-mediated immunity by
regulating cytokine production and, therefore, T-cell
response. More specifically, TNF-α promotes the killing of
tumor cells through apoptosis via interaction with deathdomain regions in tumor cells, by stimulating natural
killer cells, and by inducing CD 8 cytotoxic T-cells. TNF-α
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blockers should reverse these effects.6 The malignant
neoplasms most often associated with TNF-α inhibitors
are lymphomas and leukemias. However, the possibility
of prolonged exposure to thiopurines leading to genetic
instability and, ultimately, to cancer development is
grounded in more solid evidence. Thiopurine therapy
results in the incorporation of drug-derived thioguanine
nucleotides into DNA. Once thioguanine nucleotides
are incorporated into DNA, radiation leads to reactive
oxygen species (ROS) formation. These ROS can then
attack DNA and surrounding proteins and promote
mutagenesis.26 The thiopurine drugs are inactivated by
thiopurine S-methyltransferase (TPMT). The catabolic
enzyme activity of TPMT is genetically determined; low
TPMT activity is associated with higher risk of druginduced bone marrow toxicity as the unmetabolized drug
accumulates.28 In 2003, Smith et al29 reported therapyrelated leukemias that followed immunosuppressive
treatment with mercaptopurine and azathioprine. Other
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Case Studies
case reports7,30 have also described the possible link
between thiopurine therapy and acute leukemias, drawing
attention to the importance of thiopurine testing in the
management of IBD. Large-scale studies are required
to properly evaluate the clinical implication of genetic
evaluation, such as TPMT genotyping, in patients with
IBD.
CD is frequently associated with increased risk of
gastrointestinal malignancies, but not often with acute
leukemias. 2 Most reported cases of acute leukemia in
association with CD have described involvement by
acute myeloid leukemia (AML), only 5 cases with ALL in
patients older than 16 years have been reported.5-25 For
more complete characterization of CD in association
with acute leukemia, we conducted a literature review
using the PubMed database. We limited our search to
patients older than 16 years. Using the key phrases acute
leukemia and Crohn disease, we found a total of 27
cases, excluding the present case. Table 1 summarizes
the data from the reported cases. There were 16 men
and 12 women. Of the 28 patients, 22 had AML and 6
had ALL. The mean age at which hematologic disorder
developed was 44.4 years (median, 42 years; range, 17
to 78 years). The mean time elapsed from CD diagnosis
to leukemia detection was 10.5 years (median, 8 years;
range, 1 month to 44 years). Steroids and sulfasalazine
were the most widely used treatments for CD, as
reported by the authors. Other immunomodulators
included azathioprine in 8 cases, mercaptopurine in
5 cases, and methotrexate in only 1 case. Half of the
patients with ALL underwent TNF-α–blocker therapy in
combination with thiopurines. The data on prognosis
was available in only 18 patients. Of these 18 patients, 9
achieved remission and 9 died.
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Spring 2015 | Volume 46, Number 2
Acknowledgments
We thank all the residents of the Department of Internal
Medicine at Kyung Hee University Medical Hospital
for their help in the therapeutic management of this
patient. LM
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The development of papillary thyroid cancer deserves
equal attention. Considering that PTC was diagnosed
before ALL in our patient and that 3 months elapsed
from the first diagnosis to the second, the PTC seems
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To our knowledge, this is the first case of 2 different
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In conclusion, the relationship between these 3 relatively
uncommon diseases (CD, T-cell lineage ALL, and PTC)
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