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Paraneoplastic Syndromes in Children with
Laura Betcherman 1 and Angela Punnett 1,2
1. University of Toronto, Ontario, Canada; 2. Division of Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada
P araneoplastic syndromes (PNS) refer to a phenomenon whereby certain malignancies manifest as symptoms not directly related to the
tumor itself. PNS has been described in association with Hodgkin lymphoma (HL) in adults and children and may affect a number of organ
systems. The pathophysiology is variable and in many cases is not well understood. Specific paraneoplastic antibodies have been isolated
in some syndromes, though are not required for the diagnosis. The two best described for HL are the anti-Tr and anti-mGluR5 antibodies identified
in some cases of limbic encephalitis and cerebellar degeneration respectively. A high index of suspicion for underlying malignancy is necessary
when recognizing these clinical syndromes to avoid a diagnostic delay. Successful treatment of the HL often reverses the manifestations of PNS
although organ function at diagnosis may limit therapeutic options. Some patients suffer devastating complications of their PNS.
Keywords Paraneoplastic syndrome, Hodgkin lymphoma,
paraneoplastic neurological syndrome,
pediatrics, malignancy, vanishing bile duct,
paraneoplastic and endocrine, paraneoplastic
and kidney, paraneoplastic and hematologic
Disclosure: Laura Betcherman and Angela Punnett
have nothing to declare in relation to this article.
This study involves a review of the literature and
did not involve any studies with human or animal
subjects performed by any of the authors. No funding
was received in the publication of this article.
Open Access: This article is published under the
Creative Commons Attribution Noncommercial License,
which permits any non-commercial use, distribution,
adaptation, and reproduction provided the original
author(s) and source are given appropriate credit.
Received: February 22, 2017
Accepted: March 21, 2017
Citation: Oncology & Hematology Review,
2017;13(1):41–4 Corresponding Author: Angela Punnett,
Hospital for Sick Children, 555 University Ave,
Toronto, ON, M5G 1X8, Canada.
The term paraneoplastic syndrome (PNS) was first described in the 1940s as the phenomenon that
certain cancers manifest as symptoms not directly related to the tumor itself. 1 Since then, there
have been a multitude of reports on PNS, which is observed in approximately 8–10% of all malignant
tumors. 1–3 PNS can affect any organ or tissue. It is generally due to ectopic hormone or cytokine
production, or may be related to autoimmune factors. In some cases, the syndromes may precede
the cancer diagnosis itself. 1
Lymphoma is the third most common malignancy in children following leukemias and malignancies
of the central nervous system. Hodgkin lymphoma (HL) occurs at a slightly higher incidence than
non-Hodgkin lymphoma (NHL) and is the most common malignancy among children 15–19 years of
age. 4 Almost all cases arise from germinal center B cells and are associated with an inflammatory
response and local disturbance of the normal function and regulation of the immune system. In
this context, certain autoimmune phenomena including PNS have been described in both adults
and children with HL. PNS in patients with HL can affect multiple organs including the neurologic,
hematologic, endocrine, renal, and hepatic systems. 5–7 In addition to the above, hepatic, dermatologic,
and rheumatologic manifestations have also been described in adults. 3,6,8–11 PNS in children with HL is
relatively rare, with few published case reports and case series in this population. This article will
review the state of knowledge of PNS in pediatric HL.
Paraneoplastic neurologic syndromes refer to signs and symptoms resulting from target organ damage
to any part of the nervous system that is not directly related to the malignant tumor or its metastases. 12
They may affect the central and peripheral nervous systems, the neuromuscular junction, and the
muscle itself, and may be associated with significant neurologic morbidity and mortality. Detailed
diagnostic criteria for these syndromes were defined by consensus of an international panel in 2004
taking into consideration the particular syndrome, timing, and clinical outcome in relation to cancer
diagnosis and therapy, and presence of onconeural antibodies. 13 The latter are supportive but not
required to make a diagnosis of a paraneoplastic neurologic syndrome.
The most commonly described neurologic syndromes in children with any type of malignancy include
opsoclonus-myoclonus syndrome, limbic encephalitis (LE), paraneoplastic cerebellar degeneration
(PCD), and anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis. 12–14 Although opsoclonus-
myoclonus syndrome is usually associated with neuroblastoma, the other three have been described
in pediatric HL and may be associated with onconeural antibodies—anti-metabotropic glutamate
receptor 5 (anti-mGluR5) in LE, the anti-Purkinje cell cytoplasmic antibody-Tr (anti-Tr) in cerebellar
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