Primary central nervous system lymphoma natural history, complications, and prognosis: Difference between revisions

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==Overview==
==Overview==
If left untreated, primary central nervous system lymphoma may progress to develop [[elevated intracranial pressure]], ocular symptoms, focal neurological deficits, and neuropsychiatric problems.<ref name=SymptomsofprimaryCNSLymphoma1>Symptoms of primary CNS Lymphoma. Lymphomation 2016. http://www.lymphomation.org/type-cns.htm. Accessed on February 24, 2016</ref> Common complications of primary central nervous system lymphoma include [[relapse]], [[metastasis|extracranial or subcutaneous metastasis]], neuropsychiatric problems, and neurological toxicity.<ref name=SymptomsofprimaryCNSLymphoma1>Symptoms of primary CNS Lymphoma. Lymphomation 2016. http://www.lymphomation.org/type-cns.htm. Accessed on February 24, 2016</ref><ref name="AhmedRamanathan2014">{{cite journal|last1=Ahmed|first1=Zartaj|last2=Ramanathan|first2=Ramesh K.|last3=Ram|first3=Sunil|last4=Newell|first4=James|last5=Halepota|first5=Maqbool|title=Unusual Relapse of Primary Central Nervous System Lymphoma at Site of Lumbar Puncture|journal=Case Reports in Hematology|volume=2014|year=2014|pages=1–4|issn=2090-6560|doi=10.1155/2014/161952}}</ref><ref name="Yamanaka2013">{{cite journal|last1=Yamanaka|first1=Ryuya|title=Primary Central Nervous System Lymphoma − Recent Advance on Clinical Research|year=2013|doi=10.5772/52757}}</ref> The prognosis of primary central nervous system lymphoma is generally poor.<ref name="AhmedRamanathan2014">{{cite journal|last1=Ahmed|first1=Zartaj|last2=Ramanathan|first2=Ramesh K.|last3=Ram|first3=Sunil|last4=Newell|first4=James|last5=Halepota|first5=Maqbool|title=Unusual Relapse of Primary Central Nervous System Lymphoma at Site of Lumbar Puncture|journal=Case Reports in Hematology|volume=2014|year=2014|pages=1–4|issn=2090-6560|doi=10.1155/2014/161952}}</ref><ref name=prognosisofprimarycnslymphoma1>Prognosis of primary central nervous system lymphoma. Canadian cancer society 2016. http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/primary-cns-lymphoma/?region=on. Accessed on February 17, 2016</ref>
If left untreated, primary central nervous system lymphoma may progress to develop [[elevated intracranial pressure]], ocular symptoms, focal neurological deficits, and neuropsychiatric problems. Common complications of primary central nervous system lymphoma include [[relapse]], [[metastasis|extracranial or subcutaneous metastasis]], neuropsychiatric problems, and neurological toxicity. The prognosis of primary central nervous system lymphoma is generally poor.


==Natural History==
==Natural History==
*Primary central nervous system lymphoma is usually a fast-growing (aggressive) lymphoma.<ref name=prognosisofprimarycnslymphoma1>Prognosis of primary central nervous system lymphoma. Canadian cancer society 2016. http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/primary-cns-lymphoma/?region=on. Accessed on February 17, 2016</ref>
*Primary central nervous system lymphoma is usually an aggressive lymphoma.<ref name="prognosisofprimarycnslymphoma1">Prognosis of primary central nervous system lymphoma. Canadian cancer society 2016. http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/primary-cns-lymphoma/?region=on. Accessed on February 17, 2016</ref>
*Primary central nervous system lymphoma often recurs after treatment.
 
*The clinical course is rapidly fatal; these patients usually present with signs of elevated intracranial pressure, [[nausea]], [[papilledema]], [[vomiting]], and neuropsychiatric symptoms.<ref name="ManentiDi Giuliano2013">{{cite journal|last1=Manenti|first1=G.|last2=Di Giuliano|first2=F.|last3=Bindi|first3=A.|last4=Liberto|first4=V.|last5=Funel|first5=V.|last6=Garaci|first6=F. G.|last7=Floris|first7=R.|last8=Simonetti|first8=G.|title=A Case of Primary T-Cell Central Nervous System Lymphoma: MR Imaging and MR Spectroscopy Assessment|journal=Case Reports in Radiology|volume=2013|year=2013|pages=1–5|issn=2090-6862|doi=10.1155/2013/916348}}</ref>
*The clinical course is rapidly fatal; these patients usually present with signs of elevated intracranial pressure, [[nausea]], [[papilledema]], [[vomiting]], and neuropsychiatric symptoms.<ref name="ManentiDi Giuliano2013">{{cite journal|last1=Manenti|first1=G.|last2=Di Giuliano|first2=F.|last3=Bindi|first3=A.|last4=Liberto|first4=V.|last5=Funel|first5=V.|last6=Garaci|first6=F. G.|last7=Floris|first7=R.|last8=Simonetti|first8=G.|title=A Case of Primary T-Cell Central Nervous System Lymphoma: MR Imaging and MR Spectroscopy Assessment|journal=Case Reports in Radiology|volume=2013|year=2013|pages=1–5|issn=2090-6862|doi=10.1155/2013/916348}}</ref>


==Complications==
==Complications==
Common complications of primary central nervous system lymphoma include:<ref name=SymptomsofprimaryCNSLymphoma1>Symptoms of primary CNS Lymphoma. Lymphomation 2016. http://www.lymphomation.org/type-cns.htm. Accessed on February 24, 2016</ref><ref name="AhmedRamanathan2014">{{cite journal|last1=Ahmed|first1=Zartaj|last2=Ramanathan|first2=Ramesh K.|last3=Ram|first3=Sunil|last4=Newell|first4=James|last5=Halepota|first5=Maqbool|title=Unusual Relapse of Primary Central Nervous System Lymphoma at Site of Lumbar Puncture|journal=Case Reports in Hematology|volume=2014|year=2014|pages=1–4|issn=2090-6560|doi=10.1155/2014/161952}}</ref><ref name="Yamanaka2013">{{cite journal|last1=Yamanaka|first1=Ryuya|title=Primary Central Nervous System Lymphoma − Recent Advance on Clinical Research|year=2013|doi=10.5772/52757}}</ref>
Common complications of primary central nervous system lymphoma include:<ref name="SymptomsofprimaryCNSLymphoma1">Symptoms of primary CNS Lymphoma. Lymphomation 2016. http://www.lymphomation.org/type-cns.htm. Accessed on February 24, 2016</ref><ref name="AhmedRamanathan2014">{{cite journal|last1=Ahmed|first1=Zartaj|last2=Ramanathan|first2=Ramesh K.|last3=Ram|first3=Sunil|last4=Newell|first4=James|last5=Halepota|first5=Maqbool|title=Unusual Relapse of Primary Central Nervous System Lymphoma at Site of Lumbar Puncture|journal=Case Reports in Hematology|volume=2014|year=2014|pages=1–4|issn=2090-6560|doi=10.1155/2014/161952}}</ref><ref name="Yamanaka2013">{{cite journal|last1=Yamanaka|first1=Ryuya|title=Primary Central Nervous System Lymphoma − Recent Advance on Clinical Research|year=2013|doi=10.5772/52757}}</ref>
*[[Relapse]]
*[[Relapse]]
*[[metastasis|Extracranial or subcutaneous metastasis]]
*[[metastasis|Extracranial or subcutaneous metastasis]]
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===Neurological Toxicity===
===Neurological Toxicity===
*As survival of patients with primary central nervous system lymphoma becoming long, the quality o life and mental function is now very important.<ref name="Yamanaka2013">{{cite journal|last1=Yamanaka|first1=Ryuya|title=Primary Central Nervous System Lymphoma − Recent Advance on Clinical Research|year=2013|doi=10.5772/52757}}</ref>
*As survival of [[Patient|patients]] with primary central nervous system lymphoma becoming long, the quality o life and [[mental]] function is now very important.<ref name="Yamanaka2013">{{cite journal|last1=Yamanaka|first1=Ryuya|title=Primary Central Nervous System Lymphoma − Recent Advance on Clinical Research|year=2013|doi=10.5772/52757}}</ref>
*[[Neurotoxicity]] typically is associated with significant cognitive, motor and autonomic dysfunction, and has a negative impact on quality of life.  
*[[Neurotoxicity]] typically is associated with significant cognitive, motor and [[autonomic dysfunction]], and has a negative impact on quality of life.  
*Delayed neurologic toxicity is a serious complication, especially occurring in patients older than 60 years.
*Delayed [[Neurology|neurologic]] [[toxicity]] is a serious [[Complication (medicine)|complication]], especially occurring in [[Patient|patients]] older than 60 years.
*[[Methotrexate|Methotrexate (MTX)]] is a known neurotoxin and has the potential of producing '''leukoencephalopathy''' as well as other types of neurotoxicities, such as microangiopathy. MTX is a folate antagonist inhibiting nucleic acid and methioine synthesis. [[Methionine]] is necessary for CNS myelination. The presence of a risk haplotype defined by polymorphisms influencing methionine metabolism referred a relative risk for CNS white matter changes. MTX in combination with [[radiation|whole brain radiotherapy (WBRT)]] relates to its potential for causing delayed leukoencephalopathy.<ref name="Yamanaka2013">{{cite journal|last1=Yamanaka|first1=Ryuya|title=Primary Central Nervous System Lymphoma − Recent Advance on Clinical Research|year=2013|doi=10.5772/52757}}</ref>
*[[Methotrexate|Methotrexate (MTX)]] is a known [[neurotoxin]] and has the potential of producing [[leukoencephalopathy]] as well as other types of neurotoxicities, such as [[microangiopathy]]. [[Methotrexate|MTX]] is a [[Folic Acid|folate]] [[antagonist]] inhibiting [[nucleic acid]] and methioine [[synthesis]]. [[Methionine]] is necessary for [[CNS]] [[myelination]]. The presence of a risk [[haplotype]] defined by [[polymorphisms]] influencing [[methionine]] [[metabolism]] referred a relative risk for [[CNS]] white [[matter]] changes. [[Methotrexate|MTX]] in combination with [[radiation|whole brain radiotherapy (WBRT)]] relates to its potential for causing delayed [[leukoencephalopathy]].<ref name="Yamanaka2013">{{cite journal|last1=Yamanaka|first1=Ryuya|title=Primary Central Nervous System Lymphoma − Recent Advance on Clinical Research|year=2013|doi=10.5772/52757}}</ref>
*Radiation therapy prior to MTX administration increase the risk of leukoencephalopathy. While intrathecal, intravenous MTX, and WBRT have the potential for producing leukoencephalopathy independently, when two or three of them are combined the risk will increase.
*[[Radiation therapy]] prior to [[Methotrexate|MTX]] administration increase the risk of leukoencephalopathy. While intrathecal, [[intravenous]] [[Methotrexate|MTX]], and WBRT have the potential for producing [[leukoencephalopathy]] independently, when two or three of them are combined the risk will increase.
*Nguyen et al. reported late treatment-associated neurotoxicity in 15% of patients and was significantly associated with total radiation doses greater than 36 Gy.
*Nguyen et al. reported late treatment-associated [[neurotoxicity]] in 15% of [[Patient|patients]] and was significantly associated with total radiation doses greater than 36 Gy.
*O`Brien et al. reported 30% of [[neurotoxicity]] risk who were treated with [[Methotrexate|MTX]] (1g/m2) followed by WBRT.<ref name="Yamanaka2013">{{cite journal|last1=Yamanaka|first1=Ryuya|title=Primary Central Nervous System Lymphoma − Recent Advance on Clinical Research|year=2013|doi=10.5772/52757}}</ref>
*Correa et al. reported the [[neuropsychological]] evaluation of 28 [[Patient|patients]]. These were of sufficient severity to reduce quality of life in half of the patient sample. [[Patient|Patients]] treated with WBRT +/- [[chemotherapy]] revealed more pronounced cognitive impairement, particularly in the memory and [[attention]]/executive domain. Extent of white matter [[disease]] correlated with attention/executive, [[memory]], and language impairment. Primary CNS lymphoma survivors treated with WBRT +/- [[chemotherapy]] displayed more pronounced [[Cognition|cognitive]] [[Dysfunctional|dysfunction]] than [[Patient|patients]] treated with [[Methotrexate|MTX]]-based [[chemotherapy]] alone.
*Delayed [[neurotoxicity]] may present as a rapidly progressive subcortical [[dementia]] characterized by psychomotor slowing, executive and memory [[dysfunction]], behavioral changes, [[gait ataxia]], and [[incontinence]]. [[Imaging]] findings may reveal diffuse white matter [[disease]] and cortical-subcortical atrophy.<ref name="Yamanaka2013">{{cite journal|last1=Yamanaka|first1=Ryuya|title=Primary Central Nervous System Lymphoma − Recent Advance on Clinical Research|year=2013|doi=10.5772/52757}}</ref>


==Prognosis==
==Prognosis==
*The prognosis of primary central nervous system lymphoma is generally poor.<ref name=prognosisofprimarycnslymphoma1>Prognosis of primary central nervous system lymphoma. Canadian cancer society 2016. http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/primary-cns-lymphoma/?region=on. Accessed on February 17, 2016</ref><ref name="AhmedRamanathan2014">{{cite journal|last1=Ahmed|first1=Zartaj|last2=Ramanathan|first2=Ramesh K.|last3=Ram|first3=Sunil|last4=Newell|first4=James|last5=Halepota|first5=Maqbool|title=Unusual Relapse of Primary Central Nervous System Lymphoma at Site of Lumbar Puncture|journal=Case Reports in Hematology|volume=2014|year=2014|pages=1–4|issn=2090-6560|doi=10.1155/2014/161952}}</ref>
*The [[prognosis]] of primary central nervous system lymphoma is generally poor.<ref name="prognosisofprimarycnslymphoma1">Prognosis of primary central nervous system lymphoma. Canadian cancer society 2016. http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/primary-cns-lymphoma/?region=on. Accessed on February 17, 2016</ref><ref name="AhmedRamanathan2014">{{cite journal|last1=Ahmed|first1=Zartaj|last2=Ramanathan|first2=Ramesh K.|last3=Ram|first3=Sunil|last4=Newell|first4=James|last5=Halepota|first5=Maqbool|title=Unusual Relapse of Primary Central Nervous System Lymphoma at Site of Lumbar Puncture|journal=Case Reports in Hematology|volume=2014|year=2014|pages=1–4|issn=2090-6560|doi=10.1155/2014/161952}}</ref>
*Poor prognostic factors for primary central nervous system lymphoma include:<ref name=prognosisofprimarycnslymphoma1>Prognosis of primary central nervous system lymphoma. Canadian cancer society 2016. http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/primary-cns-lymphoma/?region=on. Accessed on February 17, 2016</ref><ref name=prognosticfactorsprimarycnslymphoma1w2sw>Prognsotic factors for primary CNS lymphoma. National cancer institute 2016. http://www.cancer.gov/types/lymphoma/hp/primary-cns-lymphoma-treatment-pdq. Accessed on February 19, 2016</ref>
*Poor [[Prognosis|prognostic]] factors for primary central nervous system lymphoma include:<ref name="prognosisofprimarycnslymphoma1">Prognosis of primary central nervous system lymphoma. Canadian cancer society 2016. http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/primary-cns-lymphoma/?region=on. Accessed on February 17, 2016</ref><ref name="prognosticfactorsprimarycnslymphoma1w2sw">Prognsotic factors for primary CNS lymphoma. National cancer institute 2016. http://www.cancer.gov/types/lymphoma/hp/primary-cns-lymphoma-treatment-pdq. Accessed on February 19, 2016</ref>
:*Elderly patient (>50 years)
 
:*[[Old age|Elderly]] [[patient]] (>50 years)
:*Poor performance status of the individual (PS > 1 or Karnofsky PS < 70)
:*Poor performance status of the individual (PS > 1 or Karnofsky PS < 70)
:*AIDS-related primary central nervous system lymphoma
:*AIDS-related primary central nervous system lymphoma
:*Elevated serum level of [[LDH|lactate dehydrogenase]]
:*Elevated [[serum]] level of [[LDH|lactate dehydrogenase]]
:*Elevated [[cerebrospinal fluid protein]] concentration
:*Elevated [[cerebrospinal fluid protein]] [[concentration]]
:*Involvement of ''nonhemispheric areas'' of the brain ([[Ventricular system|periventricular]], [[basal ganglia]], [[brainstem]], and [[cerebellum]])
:*Involvement of ''nonhemispheric areas'' of the [[brain]] ([[Ventricular system|periventricular]], [[basal ganglia]], [[brainstem]], and [[cerebellum]])


===In Immunocompetent Patients===
===In Immunocompetent Patients===
*The initial response to [[radiotherapy]] is often excellent, and may result in a complete remission. However, the duration of response with [[radiotherapy]] alone remains short, with median survival after treatment with radiotherapy is 18 months.  
*The initial response to [[radiotherapy]] is often excellent, and may result in a complete remission. However, the duration of response with [[radiotherapy]] alone remains short, with median survival after treatment with radiotherapy is 18 months.  
*[[Methotrexate|Methotrexate-based chemotherapy]] markedly improves survival, with some studies showing median survival after methotrexate chemotherapy reaching 48 months.<ref name=prognosisofprimarycentralnervoussystemlymphoma1>Prognosis of primary central nervous system lymphoma. Wikipedia 2016. https://en.wikipedia.org/wiki/Primary_central_nervous_system_lymphoma. Accessed on February 18, 2016</ref>
*[[Methotrexate|Methotrexate-based chemotherapy]] markedly improves survival, with some studies showing median survival after [[methotrexate]] [[chemotherapy]] reaching 48 months.<ref name="prognosisofprimarycentralnervoussystemlymphoma1">Prognosis of primary central nervous system lymphoma. Wikipedia 2016. https://en.wikipedia.org/wiki/Primary_central_nervous_system_lymphoma. Accessed on February 18, 2016</ref>


===In AIDS patients===
===In AIDS patients===
*Patients with [[AIDS]] and primary central nervous system lymphoma have a median survival of only 4 months with [[radiotherapy]] alone. Untreated, median survival is only 2.5 months, sometimes due to concurrent opportunistic infections rather than the lymphoma itself.<ref name=prognosisofprimarycentralnervoussystemlymphoma1>Prognosis of primary central nervous system lymphoma. Wikipedia 2016. https://en.wikipedia.org/wiki/Primary_central_nervous_system_lymphoma. Accessed on February 18, 2016</ref>
*[[Patient|Patients]] with [[AIDS]] and primary central nervous system lymphoma have a median survival of only 4 months with [[radiotherapy]] alone. Untreated, median survival is only 2.5 months, sometimes due to concurrent [[Opportunistic infection|opportunistic infections]] rather than the [[lymphoma]] itself.<ref name="prognosisofprimarycentralnervoussystemlymphoma1">Prognosis of primary central nervous system lymphoma. Wikipedia 2016. https://en.wikipedia.org/wiki/Primary_central_nervous_system_lymphoma. Accessed on February 18, 2016</ref>
*Extended survival has been seen, however, in a subgroup of AIDS patients with [[CD4]] counts of more than 200 and no concurrent opportunistic infections, who can tolerate aggressive therapy consisting of either [[methotrexate|methotrexate monotherapy]] or [[vincristine]], procarbazine, or [[radiotherapy|whole brain radiotherapy]].
*Extended survival has been seen, however, in a subgroup of [[HIV AIDS|AIDS]] [[Patient|patients]] with [[CD4]] counts of more than 200 and no concurrent [[Opportunistic infection|opportunistic infections]], who can tolerate aggressive [[therapy]] consisting of either [[methotrexate|methotrexate monotherapy]] or [[vincristine]], [[procarbazine]] or [[radiotherapy|whole brain radiotherapy]].
*These patients have a median survival of 10–18 months. Of course, [[highly active antiretroviral therapy]] (HAART) is critical for prolonged survival in any [[AIDS]] patient, so compliance with HAART may play a role in survival in patients with concurrent AIDS and primary CNS lymphoma.<ref name=prognosisofprimarycentralnervoussystemlymphoma1>Prognosis of primary central nervous system lymphoma. Wikipedia 2016. https://en.wikipedia.org/wiki/Primary_central_nervous_system_lymphoma. Accessed on February 18, 2016</ref>
*These [[Patient|patients]] have a median survival of 10–18 months. Of course, [[highly active antiretroviral therapy]] (HAART) is critical for prolonged survival in any [[AIDS]] [[patient]], so [[compliance]] with HAART may play a role in survival in [[Patient|patients]] with concurrent [[HIV AIDS|AIDS]] and primary CNS lymphoma.<ref name="prognosisofprimarycentralnervoussystemlymphoma1">Prognosis of primary central nervous system lymphoma. Wikipedia 2016. https://en.wikipedia.org/wiki/Primary_central_nervous_system_lymphoma. Accessed on February 18, 2016</ref>


==References==
==References==

Latest revision as of 16:17, 15 October 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

Overview

If left untreated, primary central nervous system lymphoma may progress to develop elevated intracranial pressure, ocular symptoms, focal neurological deficits, and neuropsychiatric problems. Common complications of primary central nervous system lymphoma include relapse, extracranial or subcutaneous metastasis, neuropsychiatric problems, and neurological toxicity. The prognosis of primary central nervous system lymphoma is generally poor.

Natural History

  • Primary central nervous system lymphoma is usually an aggressive lymphoma.[1]
  • The clinical course is rapidly fatal; these patients usually present with signs of elevated intracranial pressure, nausea, papilledema, vomiting, and neuropsychiatric symptoms.[2]

Complications

Common complications of primary central nervous system lymphoma include:[3][4][5]

  • Neurological toxicity

Neurological Toxicity

Prognosis

  • The prognosis of primary central nervous system lymphoma is generally poor.[1][4]
  • Poor prognostic factors for primary central nervous system lymphoma include:[1][6]

In Immunocompetent Patients

In AIDS patients

References

  1. ↑ 1.0 1.1 1.2 Prognosis of primary central nervous system lymphoma. Canadian cancer society 2016. http://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/types-of-nhl/primary-cns-lymphoma/?region=on. Accessed on February 17, 2016
  2. ↑ Manenti, G.; Di Giuliano, F.; Bindi, A.; Liberto, V.; Funel, V.; Garaci, F. G.; Floris, R.; Simonetti, G. (2013). "A Case of Primary T-Cell Central Nervous System Lymphoma: MR Imaging and MR Spectroscopy Assessment". Case Reports in Radiology. 2013: 1–5. doi:10.1155/2013/916348. ISSN 2090-6862.
  3. ↑ Symptoms of primary CNS Lymphoma. Lymphomation 2016. http://www.lymphomation.org/type-cns.htm. Accessed on February 24, 2016
  4. ↑ 4.0 4.1 Ahmed, Zartaj; Ramanathan, Ramesh K.; Ram, Sunil; Newell, James; Halepota, Maqbool (2014). "Unusual Relapse of Primary Central Nervous System Lymphoma at Site of Lumbar Puncture". Case Reports in Hematology. 2014: 1–4. doi:10.1155/2014/161952. ISSN 2090-6560.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Yamanaka, Ryuya (2013). "Primary Central Nervous System Lymphoma − Recent Advance on Clinical Research". doi:10.5772/52757.
  6. ↑ Prognsotic factors for primary CNS lymphoma. National cancer institute 2016. http://www.cancer.gov/types/lymphoma/hp/primary-cns-lymphoma-treatment-pdq. Accessed on February 19, 2016
  7. ↑ 7.0 7.1 7.2 Prognosis of primary central nervous system lymphoma. Wikipedia 2016. https://en.wikipedia.org/wiki/Primary_central_nervous_system_lymphoma. Accessed on February 18, 2016


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