Hodgkin's lymphoma pathophysiology: Difference between revisions

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On gross pathology, white-grey, uniform, and enlarged [[lymph nodes]] are characteristic findings of Hodgkin's lymphoma. On microscopic histopathological analysis, [[Reed-Sternberg cells]], reactive cell infiltrate, and complete or partial effacement of the lymph node architecture are characteristic findings of Hodgkin's lymphoma.
On gross pathology, white-grey, uniform, and enlarged [[lymph nodes]] are characteristic findings of Hodgkin's lymphoma. On microscopic histopathological analysis, [[Reed-Sternberg cells]], reactive cell infiltrate, and complete or partial effacement of the lymph node architecture are characteristic findings of Hodgkin's lymphoma.
==Pathophysiology==
==Pathophysiology==
Hodgkin's lymphoma, is a type of [[lymphoma]], in which [[cancer]] originates from a specific type of [[white blood cell]]s called [[lymphocyte]]s.<ref>{{cite book|title=Scientific Style and Format: The CBE Manual for Authors, Editors, and Publishers|url=https://books.google.com/books?id=PoFJ-OhE63UC&pg=PA97|year=1994|publisher=Cambridge University Press|isbn=978-0-521-47154-1|pages=97–}}</ref><ref name=Lozano_2012>{{cite journal  |vauthors=Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, etal | title = Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. | journal = Lancet | volume = 380 | issue = 9859 | pages = 2095–128 | date = Dec 15, 2012 | oclc = 23245604 | doi = 10.1016/S0140-6736(12)61728-0 }}</ref>
*Hodgkin's lymphoma, is a type of [[lymphoma]], in which [[cancer]] originates from a specific type of [[white blood cell]]s called [[lymphocyte]]s.<ref>{{cite book|title=Scientific Style and Format: The CBE Manual for Authors, Editors, and Publishers|url=https://books.google.com/books?id=PoFJ-OhE63UC&pg=PA97|year=1994|publisher=Cambridge University Press|isbn=978-0-521-47154-1|pages=97–}}</ref><ref name=Lozano_2012>{{cite journal  |vauthors=Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, etal | title = Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. | journal = Lancet | volume = 380 | issue = 9859 | pages = 2095–128 | date = Dec 15, 2012 | oclc = 23245604 | doi = 10.1016/S0140-6736(12)61728-0 }}</ref>
* The main pathological feature of Hogkin's lymphoma is the Reed-Sternberg cells which is created mainly due to activation of the nuclear factor kappa B (NF-kB) transcription factor-signaling pathway. The improper activation of the (NF-kB) system proteins is correlated with many neoplasms.<ref name="pmid15164877">{{cite journal| author=Shishodia S, Aggarwal BB| title=Nuclear factor-kappaB activation mediates cellular transformation, proliferation, invasion angiogenesis and metastasis of cancer. | journal=Cancer Treat Res | year= 2004 | volume= 119 | issue=  | pages= 139-73 | pmid=15164877 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15164877  }}</ref><ref name="pmid8639794">{{cite journal| author=Bargou RC, Leng C, Krappmann D, Emmerich F, Mapara MY, Bommert K et al.| title=High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells. | journal=Blood | year= 1996 | volume= 87 | issue= 10 | pages= 4340-7 | pmid=8639794 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8639794  }}</ref>
* NF-kB is degraded normally by "I kappa B (IkB)" family in order to prevent the unwanted stimulation and neoplasm formation. However, there are specific cellular proteins which lead to inactivation of the (IkB). So, by inactivating the (IkB), the NF-kB transcription factors will not be degraded and leads to gene transcriptions activation.<ref name="pmid15164877" />
* In Hodgkin's lymphoma, there are elevated levels of the NF-kB proteins especially c-REL and REL-A.<ref name="pmid9597130">{{cite journal| author=Ghosh S, May MJ, Kopp EB| title=NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. | journal=Annu Rev Immunol | year= 1998 | volume= 16 | issue=  | pages= 225-60 | pmid=9597130 | doi=10.1146/annurev.immunol.16.1.225 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9597130  }}</ref>
* Unstopped activation of (NF-kB):
** Active (NF-kB) will lead to consistent gene activation and eventually no apoptosis takes place. Moreover, uninhibited proliferation of Reed-Sterburg cells.
** Activation of (NF-kB) occurs due to the following causes:<ref name="pmid11830490">{{cite journal| author=Joos S, Menz CK, Wrobel G, Siebert R, Gesk S, Ohl S et al.| title=Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2. | journal=Blood | year= 2002 | volume= 99 | issue= 4 | pages= 1381-7 | pmid=11830490 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11830490  }}</ref><ref name="pmid27496304">{{cite journal| author=Mathas S, Hartmann S, Küppers R| title=Hodgkin lymphoma: Pathology and biology. | journal=Semin Hematol | year= 2016 | volume= 53 | issue= 3 | pages= 139-47 | pmid=27496304 | doi=10.1053/j.seminhematol.2016.05.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27496304  }}</ref>
*** Loss of function Mutation of the IkB protein which is responsible for inhibiting NF-kB
*** Alteration in the NF-kB itself protecting it from inhibition by IkB
*** Gain of function mutation of the ''MAP3K14'' gene which is an activator of NF-kB
** NF-kB leads to activation of many genes which appear to be related to HL. Some examples of the genes expressed in HL include the following:<ref name="pmid11238088">{{cite journal| author=Buri C, Körner M, Schärli P, Cefai D, Uguccioni M, Mueller C et al.| title=CC chemokines and the receptors CCR3 and CCR5 are differentially expressed in the nonneoplastic leukocytic infiltrates of Hodgkin disease. | journal=Blood | year= 2001 | volume= 97 | issue= 6 | pages= 1543-8 | pmid=11238088 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11238088  }}</ref>
*** (ICAM-1) gene
*** GM-CSF gene
*** IL-6 gene
*** IKBA gene
* Besides NF-kB signaling pathway, Hodgkin's lymphoma can be caused by mutations in JAK-STAT pathway. Alterations in JAK tyrosine kinases signaling lead to high levels of activated STAT pathway which is considered an observed feature in some cases of HL.<ref name="pmid28082443">{{cite journal| author=Zahn M, Marienfeld R, Melzner I, Heinrich J, Renner B, Wegener S et al.| title=A novel PTPN1 splice variant upregulates JAK/STAT activity in classical Hodgkin lymphoma cells. | journal=Blood | year= 2017 | volume= 129 | issue= 11 | pages= 1480-1490 | pmid=28082443 | doi=10.1182/blood-2016-06-720516 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28082443  }}</ref>
* 
*
 
==Associated Conditions==
==Associated Conditions==
Reports from countries like Honduras,<ref name="pmid8380725">{{cite journal| author=Ambinder RF, Browning PJ, Lorenzana I, Leventhal BG, Cosenza H, Mann RB et al.| title=Epstein-Barr virus and childhood Hodgkin's disease in Honduras and the United States. | journal=Blood | year= 1993 | volume= 81 | issue= 2 | pages= 462-7 | pmid=8380725 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8380725  }} </ref> China,<ref name="pmid8397160">{{cite journal| author=Zhou XG, Hamilton-Dutoit SJ, Yan QH, Pallesen G| title=The association between Epstein-Barr virus and Chinese Hodgkin's disease. | journal=Int J Cancer | year= 1993 | volume= 55 | issue= 3 | pages= 359-63 | pmid=8397160 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8397160  }} </ref> Mexico,<ref name="pmid7882287">{{cite journal| author=Zarate-Osorno A, Roman LN, Kingma DW, Meneses-Garcia A, Jaffe ES| title=Hodgkin's disease in Mexico. Prevalence of Epstein-Barr virus sequences and correlations with histologic subtype. | journal=Cancer | year= 1995 | volume= 75 | issue= 6 | pages= 1360-6 | pmid=7882287 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7882287  }} </ref> Peru,<ref name="pmid8380728">{{cite journal| author=Chang KL, Albújar PF, Chen YY, Johnson RM, Weiss LM| title=High prevalence of Epstein-Barr virus in the Reed-Sternberg cells of Hodgkin's disease occurring in Peru. | journal=Blood | year= 1993 | volume= 81 | issue= 2 | pages= 496-501 | pmid=8380728 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8380728  }} </ref> and Malaysia<ref name="pmid9088951">{{cite journal| author=Peh SC, Looi LM, Pallesen G| title=Epstein-Barr virus (EBV) and Hodgkin's disease in a multi-ethnic population in Malaysia. | journal=Histopathology | year= 1997 | volume= 30 | issue= 3 | pages= 227-33 | pmid=9088951 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9088951  }} </ref> suggest an association between [[EBV infection]] and Hodgkin's lymphoma, an association that is more evident in the pediatric population<ref name="pmid8389527">{{cite journal| author=Armstrong AA, Alexander FE, Paes RP, Morad NA, Gallagher A, Krajewski AS et al.| title=Association of Epstein-Barr virus with pediatric Hodgkin's disease. | journal=Am J Pathol | year= 1993 | volume= 142 | issue= 6 | pages= 1683-8 | pmid=8389527 | doi= | pmc=PMC1886981 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8389527  }} </ref> and in the subtype of [[mixed cellularity]].<ref name="pmid9110300">{{cite journal| author=Andriko JA, Aguilera NS, Nandedkar MA, Abbondanzo SL| title=Childhood Hodgkin's disease in the United States: an analysis of histologic subtypes and association with Epstein-Barr virus. | journal=Mod Pathol | year= 1997 | volume= 10 | issue= 4 | pages= 366-71 | pmid=9110300 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9110300  }} </ref>
Reports from countries like Honduras,<ref name="pmid8380725">{{cite journal| author=Ambinder RF, Browning PJ, Lorenzana I, Leventhal BG, Cosenza H, Mann RB et al.| title=Epstein-Barr virus and childhood Hodgkin's disease in Honduras and the United States. | journal=Blood | year= 1993 | volume= 81 | issue= 2 | pages= 462-7 | pmid=8380725 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8380725  }} </ref> China,<ref name="pmid8397160">{{cite journal| author=Zhou XG, Hamilton-Dutoit SJ, Yan QH, Pallesen G| title=The association between Epstein-Barr virus and Chinese Hodgkin's disease. | journal=Int J Cancer | year= 1993 | volume= 55 | issue= 3 | pages= 359-63 | pmid=8397160 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8397160  }} </ref> Mexico,<ref name="pmid7882287">{{cite journal| author=Zarate-Osorno A, Roman LN, Kingma DW, Meneses-Garcia A, Jaffe ES| title=Hodgkin's disease in Mexico. Prevalence of Epstein-Barr virus sequences and correlations with histologic subtype. | journal=Cancer | year= 1995 | volume= 75 | issue= 6 | pages= 1360-6 | pmid=7882287 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7882287  }} </ref> Peru,<ref name="pmid8380728">{{cite journal| author=Chang KL, Albújar PF, Chen YY, Johnson RM, Weiss LM| title=High prevalence of Epstein-Barr virus in the Reed-Sternberg cells of Hodgkin's disease occurring in Peru. | journal=Blood | year= 1993 | volume= 81 | issue= 2 | pages= 496-501 | pmid=8380728 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8380728  }} </ref> and Malaysia<ref name="pmid9088951">{{cite journal| author=Peh SC, Looi LM, Pallesen G| title=Epstein-Barr virus (EBV) and Hodgkin's disease in a multi-ethnic population in Malaysia. | journal=Histopathology | year= 1997 | volume= 30 | issue= 3 | pages= 227-33 | pmid=9088951 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9088951  }} </ref> suggest an association between [[EBV infection]] and Hodgkin's lymphoma, an association that is more evident in the pediatric population<ref name="pmid8389527">{{cite journal| author=Armstrong AA, Alexander FE, Paes RP, Morad NA, Gallagher A, Krajewski AS et al.| title=Association of Epstein-Barr virus with pediatric Hodgkin's disease. | journal=Am J Pathol | year= 1993 | volume= 142 | issue= 6 | pages= 1683-8 | pmid=8389527 | doi= | pmc=PMC1886981 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8389527  }} </ref> and in the subtype of [[mixed cellularity]].<ref name="pmid9110300">{{cite journal| author=Andriko JA, Aguilera NS, Nandedkar MA, Abbondanzo SL| title=Childhood Hodgkin's disease in the United States: an analysis of histologic subtypes and association with Epstein-Barr virus. | journal=Mod Pathol | year= 1997 | volume= 10 | issue= 4 | pages= 366-71 | pmid=9110300 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9110300  }} </ref>

Revision as of 19:03, 28 August 2018

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

Overview

On gross pathology, white-grey, uniform, and enlarged lymph nodes are characteristic findings of Hodgkin's lymphoma. On microscopic histopathological analysis, Reed-Sternberg cells, reactive cell infiltrate, and complete or partial effacement of the lymph node architecture are characteristic findings of Hodgkin's lymphoma.

Pathophysiology

  • Hodgkin's lymphoma, is a type of lymphoma, in which cancer originates from a specific type of white blood cells called lymphocytes.[1][2]
  • The main pathological feature of Hogkin's lymphoma is the Reed-Sternberg cells which is created mainly due to activation of the nuclear factor kappa B (NF-kB) transcription factor-signaling pathway. The improper activation of the (NF-kB) system proteins is correlated with many neoplasms.[3][4]
  • NF-kB is degraded normally by "I kappa B (IkB)" family in order to prevent the unwanted stimulation and neoplasm formation. However, there are specific cellular proteins which lead to inactivation of the (IkB). So, by inactivating the (IkB), the NF-kB transcription factors will not be degraded and leads to gene transcriptions activation.[3]
  • In Hodgkin's lymphoma, there are elevated levels of the NF-kB proteins especially c-REL and REL-A.[5]
  • Unstopped activation of (NF-kB):
    • Active (NF-kB) will lead to consistent gene activation and eventually no apoptosis takes place. Moreover, uninhibited proliferation of Reed-Sterburg cells.
    • Activation of (NF-kB) occurs due to the following causes:[6][7]
      • Loss of function Mutation of the IkB protein which is responsible for inhibiting NF-kB
      • Alteration in the NF-kB itself protecting it from inhibition by IkB
      • Gain of function mutation of the MAP3K14 gene which is an activator of NF-kB
    • NF-kB leads to activation of many genes which appear to be related to HL. Some examples of the genes expressed in HL include the following:[8]
      • (ICAM-1) gene
      • GM-CSF gene
      • IL-6 gene
      • IKBA gene
  • Besides NF-kB signaling pathway, Hodgkin's lymphoma can be caused by mutations in JAK-STAT pathway. Alterations in JAK tyrosine kinases signaling lead to high levels of activated STAT pathway which is considered an observed feature in some cases of HL.[9]

Associated Conditions

Reports from countries like Honduras,[10] China,[11] Mexico,[12] Peru,[13] and Malaysia[14] suggest an association between EBV infection and Hodgkin's lymphoma, an association that is more evident in the pediatric population[15] and in the subtype of mixed cellularity.[16]

Gross Pathology

On gross pathology, affected lymph nodes (most often, latero cervical lymph nodes) are enlarged, but their shape is preserved because the capsule is not invaded. Usually, the cut surface is white-grey and uniform. In some histological subtypes (e.g. nodular sclerosis), the cut surface may have a nodular aspect.

  • Hodgkin lymphoma - Massive involvement of para tracheal, hilar and sub carinal lymph nodes as well as two vertebral bodies.[17]

    Hodgkin lymphoma - Massive involvement of para tracheal, hilar and sub carinal lymph nodes as well as two vertebral bodies.[17]

Microscopic Pathology

Microscopic examination of the lymph node biopsy reveals complete or partial effacement of the lymph node architecture by scattered large malignant cells known as Reed-Sternberg cells (typical and variants) admixed within a reactive cell infiltrate composed of variable proportions of lymphocytes, histiocytes, eosinophils, and plasma cells. The Reed-Sternberg cells are identified as large often bi-nucleated cells with prominent nucleoli and an unusual CD45-, CD30+, and CD15+/- immuno phenotype. In approximately 50% of cases, the Reed-Sternberg cells are infected by the Epstein-Barr virus.

  • Reed-Sternberg Hodgkin's Lymphoma

    Reed-Sternberg Hodgkin's Lymphoma

  • Micrograph of Hodgkin lymphoma, abbreviated HL. Lymph node FNA specimen. Field stain. The micrograph shows a mixture of cells common in Hodgkin's lymphoma: eosinophils, Reed-Sternberg cells, plasma cells, and histocytes.

    Micrograph of Hodgkin lymphoma, abbreviated HL. Lymph node FNA specimen. Field stain. The micrograph shows a mixture of cells common in Hodgkin's lymphoma: eosinophils, Reed-Sternberg cells, plasma cells, and histocytes.

  • Micrograph showing a "popcorn cell", the Reed–Sternberg cell variant seen in nodular lymphocyte predominant Hodgkin lymphoma. H&E stain

    Micrograph showing a "popcorn cell", the Reed–Sternberg cell variant seen in nodular lymphocyte predominant Hodgkin lymphoma. H&E stain


Reed-Sternberg cells (RSC) (Classical and variants)
Type of cell Characteristics
Classic
Reed-Sternberg cells (RSC) Include large size (20–50 micro metres), abundant, amphophilic, finely granular/homogeneous cytoplasm; two mirror-image nuclei (owl eyes) each with an eosinophilic nucleolus and a thick nuclear membrane (chromatin is distributed close to the nuclear membrane).
Variants
Hodgkin cells (Atypical mononuclear Reed-Sternberg cell) Have the same characteristics as Reed-Sternberg cells (RSC), but is mono nucleated.
Lacunar Reed-Sternberg cells Have a single hyper lobulated nucleus, multiple, small nucleoli and eosinophilic cytoplasm which is retracted around the nucleus, creating an empty space ("lacunae").
Pleomorphic Reed-Sternberg cells Have multiple irregular nuclei.
"Popcorn" Reed-Sternberg cells (Lympho-histiocytic variant) Have a very lobulated nucleus and small nucleoli.
"Mummy" Reed-Sternberg cells Have a compact nucleus with no nucleolus and basophilic cytoplasm.

References

  1. ↑ Scientific Style and Format: The CBE Manual for Authors, Editors, and Publishers. Cambridge University Press. 1994. pp. 97–. ISBN 978-0-521-47154-1.
  2. ↑ Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. (Dec 15, 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet. 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. OCLC 23245604.
  3. ↑ 3.0 3.1 Shishodia S, Aggarwal BB (2004). "Nuclear factor-kappaB activation mediates cellular transformation, proliferation, invasion angiogenesis and metastasis of cancer". Cancer Treat Res. 119: 139–73. PMID 15164877.
  4. ↑ Bargou RC, Leng C, Krappmann D, Emmerich F, Mapara MY, Bommert K; et al. (1996). "High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells". Blood. 87 (10): 4340–7. PMID 8639794.
  5. ↑ Ghosh S, May MJ, Kopp EB (1998). "NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses". Annu Rev Immunol. 16: 225–60. doi:10.1146/annurev.immunol.16.1.225. PMID 9597130.
  6. ↑ Joos S, Menz CK, Wrobel G, Siebert R, Gesk S, Ohl S; et al. (2002). "Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2". Blood. 99 (4): 1381–7. PMID 11830490.
  7. ↑ Mathas S, Hartmann S, Küppers R (2016). "Hodgkin lymphoma: Pathology and biology". Semin Hematol. 53 (3): 139–47. doi:10.1053/j.seminhematol.2016.05.007. PMID 27496304.
  8. ↑ Buri C, Körner M, Schärli P, Cefai D, Uguccioni M, Mueller C; et al. (2001). "CC chemokines and the receptors CCR3 and CCR5 are differentially expressed in the nonneoplastic leukocytic infiltrates of Hodgkin disease". Blood. 97 (6): 1543–8. PMID 11238088.
  9. ↑ Zahn M, Marienfeld R, Melzner I, Heinrich J, Renner B, Wegener S; et al. (2017). "A novel PTPN1 splice variant upregulates JAK/STAT activity in classical Hodgkin lymphoma cells". Blood. 129 (11): 1480–1490. doi:10.1182/blood-2016-06-720516. PMID 28082443.
  10. ↑ Ambinder RF, Browning PJ, Lorenzana I, Leventhal BG, Cosenza H, Mann RB; et al. (1993). "Epstein-Barr virus and childhood Hodgkin's disease in Honduras and the United States". Blood. 81 (2): 462–7. PMID 8380725.
  11. ↑ Zhou XG, Hamilton-Dutoit SJ, Yan QH, Pallesen G (1993). "The association between Epstein-Barr virus and Chinese Hodgkin's disease". Int J Cancer. 55 (3): 359–63. PMID 8397160.
  12. ↑ Zarate-Osorno A, Roman LN, Kingma DW, Meneses-Garcia A, Jaffe ES (1995). "Hodgkin's disease in Mexico. Prevalence of Epstein-Barr virus sequences and correlations with histologic subtype". Cancer. 75 (6): 1360–6. PMID 7882287.
  13. ↑ Chang KL, Albújar PF, Chen YY, Johnson RM, Weiss LM (1993). "High prevalence of Epstein-Barr virus in the Reed-Sternberg cells of Hodgkin's disease occurring in Peru". Blood. 81 (2): 496–501. PMID 8380728.
  14. ↑ Peh SC, Looi LM, Pallesen G (1997). "Epstein-Barr virus (EBV) and Hodgkin's disease in a multi-ethnic population in Malaysia". Histopathology. 30 (3): 227–33. PMID 9088951.
  15. ↑ Armstrong AA, Alexander FE, Paes RP, Morad NA, Gallagher A, Krajewski AS; et al. (1993). "Association of Epstein-Barr virus with pediatric Hodgkin's disease". Am J Pathol. 142 (6): 1683–8. PMC 1886981. PMID 8389527.
  16. ↑ Andriko JA, Aguilera NS, Nandedkar MA, Abbondanzo SL (1997). "Childhood Hodgkin's disease in the United States: an analysis of histologic subtypes and association with Epstein-Barr virus". Mod Pathol. 10 (4): 366–71. PMID 9110300.
  17. ↑ Image courtesy of Dr Yale Rosen Radiopaedia(original file ‘’here’’). Creative Commons BY-SA-NC


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