Paraneoplastic Syndromes in Children with Hodgkin Lymphoma

Oncology & Hematology Review, 2017;13(1):41–4 DOI: https://doi.org/10.17925/OHR.2017.13.01.41

Abstract:

Paraneoplastic 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.
Received: February 22, 2017 Accepted March 21, 2017
Correspondence: Angela Punnett, Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G 1X8, Canada. E: angela.punnett@sickkids.ca
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.

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.

Neurologic syndromes
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 opsoclonusmyoclonus 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 degeneration, and anti-NMDA antibody in anti-NMDA encephalitis.6,12 Although the pathophysiology remains unclear, it has been speculated that the expression of these onconeural proteins by the lymphoma triggers an immune response that is misdirected to the patient’s nervous system, resulting in the associated deficits.13

Limbic encephalitis The association of LE with HL is known as Ophelia syndrome.15 Typical features include personality changes, irritability, cognitive dysfunction, frank psychosis, generalized or complex partial seizures, and memory loss.6 There are no clear-cut diagnostic criteria for LE in children; in adults, the definition requires:
• subacute onset (up to 12 weeks) of seizures, short-term memory loss, confusion, and psychiatric symptoms;
• neuropathologic or neuroradiologic evidence of involvement of the medial temporal lobes and amygdala;
• exclusion of other possible etiologies of the limbic system; and
• demonstration of a cancer within 5 years of the diagnosis of the neurologic disorder or demonstration of an onconeural antibody.6,15

LE is an autoimmune process and the anti-mGLuR5 antibody is the associated onconeural antibody found in 60% of adult patients.6 The incidence in children is unknown. Because the autoimmune process in paraneoplastic LE is more commonly associated with neuronal dysfunction than neuronal death, LE in patients with HL typically has a better prognosis. Patients often have a full neurologic recovery with successful treatment of the tumor.12 Other attempted therapies have included early immunotherapy with intravenous immunoglobulin, steroids, and plasma exchange, and in more refractory cases, cyclophosphamide, and monoclonal anti-B cell antibodies. However, it should be noted that the treatment response in these cases is poor, especially in those patients with detectable onconeural antibodies.7,12,15

Paraneoplastic cerebellar degeneration PCD is the best characterized paraneoplastic neurologic syndrome in pediatric HL. The hallmark of PCD is a loss of Purkinje cells in the cerebellum, leading to subacute dysfunction. It presents with dizziness and vertigo, followed by truncal and limb ataxia, dysarthria, diplopia, and downbeating nystagmus. Imaging studies demonstrate evidence of cerebellar atrophy on magnetic resonance imaging (MRI) and hypometabolism on positron emission tomography (PET) scan. Lumbar puncture may reveal a cerebrospinal fluid (CSF) pleocytosis. In approximately 80% of adult and pediatric patients with HL, PCD precedes the oncologic diagnosis.6

PCD is an immune-mediated syndrome, sometimes associated with the anti-Tr antibody.16 Like other PNS in pediatric HL, the symptoms often resolve with standard therapy. Avramova et al. described an eight-year-old boy presenting with dysarthria and diplopia and subsequently diagnosed with HL. He had a complete resolution of symptoms with standard HL treatment.14 Immunotherapy has not been shown to be particularly effective in the treatment of the neurologic outcomes associated with PCD.14,17

References:
1. Pelosof LC, Gerber DE, Paraneoplastic syndromes: an approach to diagnosis and treatment, Mayo Clin Proc, 2010;85:838–54.
2. Sanin WB, Bolivar YR, Carvajal JJ, et al., Polyangiitis with granulomatosis as a paraneoplastic syndrome of B-cell lymphoma of the lacrimal gland, Case Rep Hematol, 2014;2014(713048).
3. Erlij D, Calderon B, Rivera A, et al., Polyarthritis and membranoproliferative glomerulonephritis as paraneoplastic manifestation of Hodgkin’s lymphoma: a case report and literature review, Rheumatol Clin, 2016;12:282–4.
4. Statistics SC, SEER Cancer Statistics Review, 1975–2013, 2015. Available at: http://seer.cancer.gov/csr/1975_2013 (accessed May 5, 2017)
5. Ballonoff A, Kavanagh B, Nash R, et al., Hodgkin lymphomarelated vanishing bile duct syndrome and idiopathic cholestasis: statistical analysis of all published cases and literature review, Acta Oncol, 2008;47:962–70.
6. Graus F, Arino H, Dalmau J, Paraneoplastic neurologic syndromes in Hodgkin and non-Hodgkin lymphoma, Blood, 2014;123:3230–8.
7. Hagler KT, Lynch JW, Paraneoplastic manifestations of lymphoma, Clin Lymphoma, 2004;5:29–36.
8. Abedi SH, Ghassami M, Molaei M, et al., Secondary sclerosing cholangitis and Hodgkin’s lymphoma, Clin Med Insights Case Rep, 2015;8:83–7.
9. Gong J, Lim SW, Alopecia areata as a paraneoplastic syndrome of Hodgkin’s lymphoma: a case report, Mol Clin Oncol, 2014;2:596–98.
10. Racanelli V, Prete M, Minoia C, et al., Rheumatic disorders as paraneoplastic syndromes, Autoimmun Rev, 2008;7:352–8.
11. Sfrijan, D, Tieranu I, Popa L, et al., Nephrotic syndrome, paraneoplastic syndrome associated to Hodgkin lymphoma, Maedica, 2016;11:64–7.
12. Alavi S, Paraneoplastic neurologic syndromes in children: a review article, Iran J Child Neurol, 2013;7:6–14.
13. Graus F, Delattre JY, Antoine JC, et al., Recommended diagnostic criteria for paraneoplastic neurologic syndromes, J Neurol Neurosurg Psychiatry, 2004;75:1135–40.
14. Avramova BE, Hristova T, Yordanova M, et al., Cerebellar degeneration as a rare paraneoplastic syndrome in a child with Hodgkin lymphoma, J Pediatr Hematol Oncol, 2016;38:470–2.
15. Juneja, M, Kaur S, Mishra D, and Jain S, Ophelia syndrome: Hodgkin lymphoma with limbic encephalitis, Indian Pediatr, 2015;52:335–6.
16. Srinivasan A, Satish G, Scott JX, et al., Two uncommon paraneoplastic neurologic syndromes in a child with Hodgkin lymphoma, J Pediatr Hematol Oncol, 2016;38:473–5.
17. Dalmau J and Rosenfeld MR, Paraneoplastic syndromes of the CNS, Lancet Neurol, 2008;7:327–40.
18. Aulicka S, Horak O, Mrazova L, et al., Malignant catatonia due to anti-NMDA-receptor encephalitis in a 15-year-old girl: case report and summary of current knowledge, Neuropsychiatry, 2016;6:136–41.
19. Dalmau J, Gleichman AJ, Hughes EG, et al., Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies, Lancet Neurol, 2008;7:1091–9.
20. Zandi MS, Irani SR, Follows G, et al., Limbic encephalitis associated with antibodies to the NMDA receptor in Hodgkin lymphoma, Neurology, 2009;73:2039–40.
21. Benjamin SB, Castell DO, Achalasia and Hodgkin’s disease: a chance association?, J Clin Gastroenterol, 1981;3:175–8.
22. Ertem M, Uysal Z, Yavuz G, Gozdasoglu S, Immune thrombocytopenia and hemolytic anemia as a presenting manifestation of Hodgkin disease, Pediatr Hematol Oncol, 2000;17:181–5.
23. Marino S, Di Cataldo A, Magro G, et al., A difficult diagnosis of Hodgkin lymphoma due to immune thrombocytopenia, Clin Case Rep, 2015;3:179–82.
24. Farruggia P, Trizzino A, Maringhini S, et al., Hodgkin lymphoma and nephrotic syndrome in childhood, Indian J Pediatr, 2010;77:1147–9.
25. Eliakim R, Vertman E, Shinhar E, Syndrome of inappropriate secretion of antidiuretic hormone in Hodgkin’s disease, Am J Med Sci, 1986;291:126–7.
26. Mittra ES, Davidzon G, Case 207: Hodgkin lymphoma with paraneoplastic hypercalcemic pancreatitis, Radiology, 2014;272:296–300.
27. Barber NA, Bierman PJ, Recognizing unusual manifestations of Hodgkin lymphoma, Curr Hematol Malig Rep, 2012;7:186–92.
28. Atalay H, Boyuk B, Ates M, et al., Idiopathic intrahepatic cholestasis as an unusual presentation of Hodgkin’s disease, Case Rep Hematol, 2015;2015:1–3.
29. Bouroncle BA, Old JW, Vazques AG, Pathogenesis of jaundice in Hodgkin’s disease, Arch Intern Med, 1962;110:872–83.
30. Scalabrini DR, Caravelli D, Schianca FC, et al., Complete remission of paraneoplastic vanishing bile duct syndrome after successful treatment of Hodgkin’s lymphoma: a case report and review of the literature, BMC Res Notes, 2014;7:1–6.
31. Wong KM, Chang CS, Wu CC, Yin HL, Hodgkin’s lymphoma-related vanishing bile duct syndrome: a case report and literature review, Kaohsiung J Med Sci, 2013;29:636–41.
32. Shay M, Braester A, Cohen I, Dermatomyositis as presenting symtom of Hodgkin’s disease, Ann Hematol, 1991;63:116–8.
33. Weisshaar E, Weiss M, Mettang T, et al., Paraneoplastic itch: an expert position statement from the Special Interest Group (SIG) of the International Forum on the Study of Itch (IFSI), Acta Derm Venereol, 2015;95:261–5.
34. Yosipovitch G, Chronic pruritis: a paraneoplastic sign, Demarol Ther, 2010;23(6):590–6.
35. Gobbi PG, Attardo-Parrinello G, Lattanzio G, et al., Severe pruritis should be a B-symptom in Hodgkin’s disease, Cancer, 1983;51:1934–6.
36. Bartus CL, Parker SR, Hodgkin lymphoma presenting as generalized pruritis in an adolescent, Cutis, 2011;87:169–72.
37. Shelnitz LS, Paller AS, Hodgkin’s disease manifesting as prurigo nodularis, Pediatr Dermatol, 1990;7:136–9. 38. Rubenstein M, Duvic M, Cutaneous manifestations of Hodgkin’s disease, Int J Dermatol, 2006;45:251–6.
Keywords: Paraneoplastic syndrome, Hodgkin lymphoma, paraneoplastic neurological syndrome, pediatrics, malignancy, vanishing bile duct, paraneoplastic and endocrine, paraneoplastic and kidney, paraneoplastic and hematologic