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2019, Volume 35, Number 1, Page(s) 074-078
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DOI: 10.5146/tjpath.2016.01368 |
Hodgkin Lymphoma in a Case of Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors |
Smeeta GAJENDRA, Archana SHARMA, Rashi SHARMA, Sunil Kumar GUPTA, Nitin SOOD, Ritesh SACHDEV |
Department of Pathology & Laboratory Medicine, Medanta the Medicity, GURGAON, INDIA |
Keywords: Hodgkin lymphoma, Imatinib, Chronic myeloid leukemia |
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Chronic myeloid leukemia (CML) is characterized by increased and unregulated proliferation of granulocytic lineage in the bone marrow and
presence of these immature myeloid cells in the peripheral blood with presence of Philadelphia (Ph) chromosome. Tyrosine kinase inhibitors
are the most important drugs in the CML therapy and provide long disease-free survival. Due to the increased survival of CML patients with
continual administration of these drugs, the chance of development of secondary malignancies may increase. The most common secondary
malignancies are prostate, colorectal and lung cancer, non-Hodgkin lymphoma, malignant melanoma, non-melanoma skin tumors and breast
cancer. Herein, we are describing a rare case of Hodgkin lymphoma in a patient of CML after ten year of primary disease presentation. Hodgkin
lymphoma in a known case of CML is very rare and further studies are also needed to know the pathogenic relationship between the two entities
and to assess the risk of secondary Hodgkin lymphoma in CML patients treated with tyrosine kinase inhibitors. CML itself is a risk factor for
development of solid cancers and hematologic malignancies. In addition, patients on chemotherapy are immune-compromised and may be at
greater risk of neoplasm driven by infectious agents such as Epstein-Barr virus. |
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Chronic myeloid leukemia (CML) is characterized by
increased and unregulated proliferation of granulocytic
lineage in the bone marrow and presence of these immature
myeloid cells in the peripheral blood. The cytogenetic
marker of CML is Philadelphia (Ph) chromosome (present
in granulocytes, monocyte-macrophages, erythroblasts,
megakaryocytes, B-lymphocytes) generated by translocation
between the long arm of chromosome 9 and 22
designated as t(9;22)(q34;q11) 1. Various therapeutic
approaches for CML patients are available as tyrosine
kinase inhibitors (TKI) which target against a set of
tyrosine kinase proteins: first generation TKI (Imatinib
mesylate) and second generation TKI (in case of Imatinib
resistance: Nilotinib, Dasatinib, Bosutinib), allogeneic stem
cell transplantation and other therapeutic options such
as Interferon alpha 2. These agents have a remarkable
efficacy in treating CML patients and provide long diseasefree
survival. Due to the increased survival of these patients
with continual administration of these drugs, the chance of
development of secondary malignancies may increase. An
increased incidence of second neoplasms of stomach, skin,
urogenital tract as well as lymphoid leukemias has been
documented in the literature 3. Herein, we are describing
a rare case of Hodgkin lymphoma in a patient of CML ten
years after primary disease presentation. |
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Abstract
Introduction
Case Presentation
Disscussion
References
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A 50-year-old male had been diagnosed as CML 10
years previously. The peripheral blood smear showed
hyperleucocytosis with neutrophil and myelocyte peak
and basophilia (Figure 1A). The Quantitative Real time
polymerase chain reaction (RT-PCR) for BCR-ABL was
91.0% at the time of diagnosis. He was started on Imatinib
400 mg daily. After one month of therapy, he achieved
complete hematologic response. Cytogenetic remission
was noted at the 6th month of the therapy. In December
2013, he stopped chemotherapy till April 2014 when again
he was started on Imatinib. In August 2014, the BCRABL
was found to be 27.38%. Chromosomal analysis
revealed 46XY; t(9;10;22)(q34;p11.2;q11.2) (11)/46, XY
(9). Mutation analysis showed E255V mutation in 100% of
cells. In view of the additional chromosomal abnormalities
and E255V mutation, he was started on dasatinib. In March
2015, he presented to our institution with the complaint
of fever. Contrast enhanced Computed Tomography
(CECT) of chest showed right-sided pleural effusion
with mediastinal and hilar lymphadenopathies. CECT
abdomen showed para-aortic, aorto-caval and retro-caval
lymphadenopathies. Bronchoscopy was performed and
the cytology was negative for malignancy or granulomas.
The patient was started on anti-tubercular drugs for
2 months on clinical suspicion with no improvement in symptoms. Positron emission tomography (PET)/
CECT scan showed enlarged hypermetabolic cervical,
mediastinal, hilar, mesenteric, retroperitoneal and
abdomino-pelvic lymphadenopathies above and below
the diaphragm with hypermetabolic splenic involvement.
Complete blood count showed hemoglobin of123g/L, total
leucocyte count of 3.73 x109/L, and platelets of 330x109/L.
Peripheral blood smear showed no abnormal cells. BCRABL
(RT-PCR) was 0.0%. Supraclavicular lymph node
biopsy showed atypical polymorphous infiltrate composed
of scattered large multilobulated Reed-Sternberg (RS) cells
in a reactive background which consists of lymphocytes,
plasma cells, histiocytes and eosinophils (Figure 1B). On
immunohistochemistry, these large cells were positive for
CD30 (Figure 1C), CD15 (Figure 1D), MUM-1, PAX5
(weak variable) and negative for MPO, leucocyte common antigen (CD45), CD3 and CD20; suggesting a diagnosis
of Classical Hodgkin Lymphoma. Fluorescence in situ
hybridisation method to detect Epstein-Barr virus (EBV)
DNA was negative. Bone marrow examination done for
staging showed infiltration by Reed-Sternberg cells (Figure
1E) which were CD30 positive (Figure 1F), compatible with
involvement by Hodgkin lymphoma. A final diagnosis
of stage IV Hodgkin lymphoma in a case of CML was
made. The patient was scheduled for ABVD (adriamycin,
bleomycin, vinblastine, dacarbazine)-based chemotherapy
for 6 cycles. After completion of 3 cycles of chemotherapy,
PET-CT was performed and revealed complete metabolic
and significant morphological regression of all the previous
nodal and extra-nodal disease, with no new metabolically
active lesion.
Click Here to Zoom |
Figure 1: A) Peripheral blood smear showing hyperleucocytosis with neutrophil and myelocyte peak and basophilia (Wright -Giemsa;
x200). B) Lymph node biopsy showing scattered large multilobulated Reed-Sternberg cells (H&E; x40). C) Reed-Sternberg cells are
positive for CD30 (CD30; x100). D) Reed-Sternberg cells are positive for CD15 (CD15; x100). E) Bone marrow biopsy showing infiltration
by Reed-Sternberg cells (H&E; x40). F) CD30 positive Reed-Sternberg cells (CD30; x100). |
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Abstract
Introduction
Case Presentation
Disscussion
References
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Factors that are thought to contribute to the coexistence
of hematological malignancies include host-specific characteristics,
environment, history of previous chemotherapy
and radiation or a possible common hematologic stem cell
4. Host-specific factors may include age, gender, race,
genetic make-up, and life style choices. In the literature,
there are multiple articles reviewing the association of
prior treatment of chemotherapy or radiation and the
development of second malignancy in the following
months, particularly in Imatinib-treated CML. However,
the incidence of secondary malignancies in CML patients
is controversial as described in the literature. Miranda et al.
analysed CML patients with secondary malignancies and
found that 67 secondary malignancies developed in 64 out
of 1525 CML patients in the chronic phase treated with TKI
(n = 61) and interferon-α only (n = 3). The most common
malignancies were prostate, colorectal and lung cancer,
non-Hodgkin lymphoma (NHL), malignant melanoma,
non-melanoma skin tumors and breast cancer 5. Roy
et al. reported 6 cases of secondary malignancies among
a French cohort of 189 CML patients treated with TKI
(Imatinib) following Interferon failure for the first time in
the literature in 2005. Out of six patients who developed a
second malignancy, three patients developed prostate cancer
and one patient each developed urinary bladder, colon and
unknown site, with a duration of 33 to 110 months from
CML diagnosis, and 8-36 months from the start of imatinib
therapy. All these six patients had received an interferonbased
regimen. The study suggested that the incidence of
secondary malignancy among those patients and especially
the incidence of prostate cancer was increased about four
times compared to the incidence expected in the normal
population 6. However, Pilot et al. published a data based
on an epidemiological analysis performed by Novartis
of second primary malignancies among 9518 patients in
their global database treated with imatinib, which did not
confirm the above observation. A second neoplasm was
detected in 110 patients, but it was shown that the numbers
of second cancers in clinical trials are similar to those
expected based on the rates in the general population. 7.
Verma et al. analysed patient cohorts from multiple phase I
and II trials at the MD Anderson Cancer Center, who were
treated with TKI for CML and other myeloproliferative
neoplasms and showed that the standardized incidence
ratio of second cancers was 0.60, suggesting that the risk
of secondary malignancies in patients treated with TKI was
lower than expected in the general population, which was
also in contrast to the observations by Roy et al, although the incidences of melanoma, endocrine tumors, kidney
cancers, and CLL were higher than expected. The risk of
secondary malignancies was lower than expected in the
general population 8. Similarly, Helbig et al. found that a
second malignancy developed in 8 patients (one case each
of malignancy of endometrium, testis, skin melanoma,
breast, bladder, prostate, large bowel and lung) out of 221
CML patients (3.6%) treated with Imatinib with a median
interval of 61 months (10-137 months). However, the risks
for second malignancy development as well as for related
death in CML patients were not statistically increased if
compared to age-adjusted population 9. There was no case
of Hodgkin lymphoma detected in the above studies. A few
other studies demonstrated a higher incidence of secondary
malignancy in CML patients. The incidence of second
malignancy in CML patients in the post-imatinib era was
significantly higher than the pre-Imatinib era (observed/
expected ratio of 1.48 versus 1.06) as demonstrated by
Shah et al. by a survey done on the SEER (Surveillance,
Epidemiology, and End Results) database. The highest
risk of tumor development was found to be within 1 to 11
months after Imatinib initiation. The most frequent site of
development of second malignancy was the digestive tract.
Hodgkin lymphoma cases were not specified in the study
10. In a study done by Gunnarsson et al. that crosslinked
the Swedish CML register to the Swedish Cancer registry, the
risk of second malignancies was higher in the CML cohort
from the imatinib era with a standardized incidence ratio of
1.52 and a median follow-up of 3·7 years (range 0-9·9years)
11. In the Czech Republic and Slovakia, a retrospective
analysis of 1038 CML patients treated with tyrosine kinase
inhibitors between 2000 and 2009 was conducted by
Voglova et al. A second malignancy was detected in 35
patients (3.37%) with median interval of 32 months from
the initiation of tyrosine kinase inhibitor therapy. The
study found that the age-standardized incidence rate of
all malignant tumors (except non melanoma skin cancers)
was 1.5 fold higher in CML patients treated with TKI than
in the normal population (6.76 / 1,000 person-years vs.
9.84 / 1,000 person-years), although the difference was
statistically insignificant 12. The very rare occurrence of
concurrent Hodgkin disease in a CML patient was reported
by Sharkunov et al. 13.
The pathophysiological or molecular mechanism of
development of Hodgkin lymphoma in CML patients
treated with Imatinib is largely unknown. However, CML
itself is a risk factor for development of solid cancers
and hematologic malignancies as the acquired BCR-ABL
translocation at the time of CML diagnosis and additional chromosomal abberations as a sign of clonal evolution
during the course of disease show the potential of genetic
instability in CML. Therefore, progenitors may already
have the capacity to enforce themselves as distinct cells
with enhanced malignancy resulting in solid cancers or
hematologic malignancies before or later in CML 14.
In addition, Imatinib has an immunoregulatory effect by
inhibiting T-cell activation and proliferation as well as by
diminishing the capacity of dendritic cells to elicit primary
T-cell responses 15. The exposure to Imatinib induces
centrosome and chromosome aberrations in cultures
of normal human dermal fibroblasts, Chinese hamster
embryonal and Indian muntjac fibroblasts in a significant,
dose-dependent and species-independent manner.
Those aberrant karyotypes emerging under Imatinib use
were irreversible after a prolonged culture omitting the
drug. Thus, these observations suggest that neoplastic,
chromosomally unstable clones may be developed de novo
from normal non-hematopoietic cells by Imatinib 16.
Genetic instability caused by centrosome defects has an
important influence in early steps of the development as well
as in the progression of many cancers 17-19. In addition,
the c-Abl tyrosine kinase was found to promote DNA
damage-induced apoptosis. The inhibition of apoptosis
associated by TKIs may also explain a proliferative potential
of those drugs 20. EBV has been etiologically associated
with a proportion of classical HL patients. EBV latent
membrane protein (LMP)-1 and/or EBV-encoded small
RNAs (EBERs) have been detected in 40% of classical HL
patients in economically developed countries 21. Patients
on chemotherapy are immunocompromised and may be at
greater risk of neoplasm driven by infectious agents such as
EBV and Hodgkin lymphoma.
Lymphadenopathy in a known case of CML may be due
to extra-medullary blast crisis or development of second
malignancy de novo or due to previous chemotherapy.
A correct diagnosis requires histopathology with
immunohistochemistry and molecular analysis. As
Hodgkin lymphoma in a known case of CML is very rare,
further studies are also needed to know the pathogenic
relationship between the two entities and to assess the risk
of Hodgkin lymphoma in CML patients treated with TKI.
CONFLICT OF INTERESTS
The authors declared no conflict of interest. |
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Abstract
Introduction
Case Presentation
Discussion
References
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Abstract
Introduction
Case Presentation
Discussion
References
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