Anaplastic large cell lymphoma pathophysiology: Difference between revisions

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__NOTOC__
__NOTOC__
{{Anaplastic large cell lymphoma}}
{{Anaplastic large cell lymphoma}}
{{CMG}};{{AE}}{{SM}}{{AS}}
{{CMG}}; {{AE}} {{SM}}, {{AS}}, {{kakbar}}; {{GRR}} {{Nat}}
==Overview==
==Overview==
On microscopic histopathological analysis, medium sized cells, abundant cytoplasm, kidney shaped nuclei, and paranuclear eosinophilic region are characteristic findings of anaplastic large cell lymphoma.
The ''ALK'' gene is involved in the pathogenesis of ALK positive anaplastic large cell lymphoma. The ''[[DUSP22]] ''gene is involved in the pathogenesis of ALK negative anaplastic large cell lymphoma. On microscopic histopathological analysis, medium sized cells, abundant cytoplasm, kidney shaped nuclei, and a paranuclear eosinophilic region are characteristic findings of anaplastic large cell lymphoma.
==Genetics==
ALK negative anaplastic large cell lymphoma is characterized by a translocation T(6;7)(p25.3;q32.3), which inactivates the ''DUSP22 ''gene and leads to a higher proliferation rate.<ref name="pmid21030553">{{cite journal| author=Feldman AL, Dogan A, Smith DI, Law ME, Ansell SM, Johnson SH et al.| title=Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing. | journal=Blood | year= 2011 | volume= 117 | issue= 3 | pages= 915-9 | pmid=21030553 | doi=10.1182/blood-2010-08-303305 | pmc=PMC3035081 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21030553  }} </ref> In healthy people, the product of the ''DUSP22'' gene, the DUSP22 protein (also known as the <i>JNK pathway-associated phosphatase</i> or <i>JKAP</i>), inactivates the LCK [[tyrosine kinase]] protein during T-cell receptor signaling.<ref>{{cite web|url=http://www.nature.com/ncomms/2014/140409/ncomms4618/full/ncomms4618.html|title=The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck}}</ref>
DUSP22 mutations are also associated with breast cancer (the UDSMP22 protein can also block [[estrogen receptors]]).<ref>{{cite web|url=http://www.bloodjournal.org/content/117/3/915?sso-checked=true|title=Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing}}</ref> and primary cutaneous anaplastic large cell lymphoma.<ref name="pmid25461779">{{cite journal| author=Xing X, Feldman AL| title=Anaplastic large cell lymphomas: ALK positive, ALK negative, and primary cutaneous. | journal=Adv Anat Pathol | year= 2015 | volume= 22 | issue= 1 | pages= 29-49 | pmid=25461779 | doi=10.1097/PAP.0000000000000047 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25461779}} </ref>


==Pathophysiology==
===Genetic===
*ALK-positive lymphoma is associated with a translocation in the ''ALK'' gene [T(2;5)(p23;q35)], which expresses the ALK protein.<ref name="Swerdlow">{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>
*ALK negative anaplastic large cell lymphoma is characterized by a [[translocation]] T(6;7)(p25.3;q32.3), which inactivates the ''DUSP22 ''gene and leads to a higher proliferation rate.<ref name="pmid21030553">{{cite journal| author=Feldman AL, Dogan A, Smith DI, Law ME, Ansell SM, Johnson SH et al.| title=Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing. | journal=Blood | year= 2011 | volume= 117 | issue= 3 | pages= 915-9 | pmid=21030553 | doi=10.1182/blood-2010-08-303305|pmc=PMC3035081|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21030553}}</ref>
*In healthy people, the product of the ''DUSP22'' gene, the DUSP22 protein (also known as the <i>JNK pathway-associated phosphatase</i> or <i>JKAP</i>), inactivates the  lymphocyte-specific [[tyrosine kinase]] protein during T-cell receptor signaling.<ref>{{cite web|url=http://www.nature.com/ncomms/2014/140409/ncomms4618/full/ncomms4618.html|title=The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck}}</ref>
*DUSP22 mutations are also associated with breast cancer (the UDSMP22 protein can also block [[estrogen receptors]])<ref>{{cite web|url=http://www.bloodjournal.org/content/117/3/915?sso-checked=true|title=Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing}}</ref> and primary cutaneous anaplastic large cell lymphoma.<ref name="pmid25461779">{{cite journal| author=Xing X, Feldman AL| title=Anaplastic large cell lymphomas: ALK positive, ALK negative, and primary cutaneous. | journal=Adv Anat Pathol | year= 2015 | volume= 22 | issue= 1 | pages= 29-49 | pmid=25461779 | doi=10.1097/PAP.0000000000000047 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25461779}} </ref>
===Molecular biology===
===Molecular biology===
The majority of anaplastic large cell lymphoma cases, greater than 90%, contain a clonal rearrangement of the [[T-cell receptor]]. This may be identified using [[PCR]] techniques, such as T-gamma multiplex PCR. Oncogeneic potential is conferred by up regulation of a [[tyrosine kinase]] gene on [[chromosome]] 2. Several different translocations involving this gene have been identified in different cases of this lymphoma.  The most common is a [[chromosomal translocation]] involving the nucleophosmin gene on chromosome 5. The translocation may be identified by analysis of giemsa-banded metaphase spreads of tumor cells and is characterised by t(2;5)(p23;q35). The product of this [[Gene fusion|fusion]] [[gene]] may be identified by [[immunohistochemistry]] using antiserum to [[Anaplastic_lymphoma_kinase|ALK protein]]. Probes are available to identify the translocation by fluorescent in situ hybridization ([[FISH]]). The nucleophosmin component associated with the common translocation results in nuclear positivity as well as cytoplasmic positivity.  Positivity with the other translocations may be confined to the cytoplasm. Mutagenesis and functional studies have identified a plethora of [[NPM1]]–[[Anaplastic_lymphoma_kinase|ALK]] interacting molecules which ultimately lead to the activation of key pathways including [[Extracellular signal-regulated kinases|Erk]], PLC-γ, [[PI3K]], and [[Janus kinase|Jak]]/signal transducers and activators of [[transcription]] (STAT) path- ways, which in turn control cell proliferation and survival and cytoskeletal rearrangements.<ref name="pmid22649787">{{cite journal |author=Tabbó F, Barreca A, Piva R, Inghirami G; European T-Cell Lymphoma Study Group |title=ALK Signaling and Target Therapy in Anaplastic Large Cell Lymphoma |journal=Front Oncol |volume=2 |pages=41 |year=2012 |pmid=22649787 |doi= 10.3389/fonc.2012.00041|url=http://www.frontiersin.org/Cancer_Molecular_Targets_and_Therapeutics/10.3389/fonc.2012.00041/abstract |pmc=3355932}}</ref>
*The majority of anaplastic large cell lymphomas, greater than 90%, contain a clonal rearrangement of the [[T-cell receptor]]. This may be identified using [[PCR]] techniques, such as T-gamma multiplex PCR.
Other gene mutations include:<ref>{{cite web|url=http://www.nature.com/nrc/journal/v8/n1/abs/nrc2291.html|title=The anaplastic lymphoma kinase in the pathogenesis of cancer}}</ref>
*Oncogenic potential is conferred by up regulation of a [[tyrosine kinase]] gene on [[chromosome]] 2. Several different [[translocations]] involving this gene have been identified in different cases of this lymphoma
* T(1;2), encoding a tropomyosin3 (TPM3)/ALK fusion protein (10 to 20%)
*The most common is a [[chromosomal translocation]] involving the nucleophosmin gene on chromosome 5.  
* T(2;3), encoding a TRK fusion gene (TFP)/ALK fusion protein (2 to 5%)
*The [[translocation]] may be identified by analysis of giemsa-banded metaphase spreads of tumor cells and is characterized by t(2;5)(p23;q35).
* Inv(2), encoding a ATIC (Pur H gene)/ALK fusion protein (2 to 5%)
*The product of this [[Gene fusion|fusion]] [[gene]] may be identified by [[immunohistochemistry]] using antiserum to [[Anaplastic_lymphoma_kinase|ALK protein]]. Probes are available to identify the translocation by fluorescent in-situ hybridization ([[FISH]]).
* T(2;17), encoding a clathrin heavy (CLTC)/ALK fusion protein (2 to 5%)
*The nucleophosmin component associated with the common translocation results in nuclear positivity as well as cytoplasmic positivity.  Positivity with the other translocations may be confined to the cytoplasm.
* T(2;17), encoding a ALO17/ALK fusion protein (2 to 5 percent of cases)
*Mutagenesis and functional studies have identified a plethora of [[NPM1]]–[[Anaplastic_lymphoma_kinase|ALK]] interacting molecules, which ultimately lead to the activation of key pathways including: [[Extracellular signal-regulated kinases|Erk]], PLC-γ, [[PI3K]], and [[Janus kinase|Jak]]/signal transducers and activators of [[transcription]] (STAT) pathways. These molecules then control cell proliferation and survival and cytoskeletal rearrangements.<ref name="pmid22649787">{{cite journal |author=Tabbó F, Barreca A, Piva R, Inghirami G; European T-Cell Lymphoma Study Group |title=ALK Signaling and Target Therapy in Anaplastic Large Cell Lymphoma |journal=Front Oncol |volume=2 |pages=41 |year=2012 |pmid=22649787 |doi= 10.3389/fonc.2012.00041|url=http://www.frontiersin.org/Cancer_Molecular_Targets_and_Therapeutics/10.3389/fonc.2012.00041/abstract |pmc=3355932}}</ref>
* T(2;19), encoding a tropomyosin 4 (TPM4)/ALK fusion protein (<1%)
*Other gene mutations include:<ref>{{cite web|http://www.nature.com/nrc/journal/v8/n1/abs/nrc2291.html|title=The anaplastic lymphoma kinase in the pathogenesis of cancer}}</ref>
* T(2;22), encoding a non-muscle myosin (MYH9)/ALK fusion protein (<1%)
**T(1;2), encoding a [[tropomyosin]] 3 (TPM3)/[[Anaplastic_lymphoma_kinase|ALK]] fusion protein (10 to 20%)
**T(2;3), encoding a TRK fusion gene (TFP)/[[Anaplastic_lymphoma_kinase|ALK]] fusion protein (2 to 5%)
**Inv(2), encoding a ATIC (Pur H gene)/[[Anaplastic_lymphoma_kinase|ALK]] fusion protein (2 to 5%)
**T(2;17), encoding a [[clathrin]] heavy (CLTC)/[[Anaplastic_lymphoma_kinase|ALK]] fusion protein (2 to 5%)
**T(2;17), encoding a ALO17/[[Anaplastic_lymphoma_kinase|ALK]] fusion protein (2 to 5 percent of cases)
**T(2;19), encoding a [[tropomyosin]] 4 (TPM4)/[[Anaplastic_lymphoma_kinase|ALK]] fusion protein (<1%)
**T(2;22), encoding a non-muscle myosin (MYH9)/[[Anaplastic_lymphoma_kinase|ALK]] fusion protein (<1%)
===Immunophenotype===
===Immunophenotype===
* The hallmark cells (and variants) of anaplastic large cell lymphoma show immunopositivity for [[CD30]] (also known as Ki-1)
*The hallmark cells portray immunopositivity for [[CD30]]<ref name="pmid17965727">{{cite journal |author=Watanabe M, Ogawa Y, Itoh K |title=Hypomethylation of CD30 CpG islands with aberrant JunB expression drives CD30 induction in Hodgkin lymphoma and anaplastic large cell lymphoma |journal=Lab. Invest. |volume=88 |issue=1 |pages=48–57 |date=January 2008 |pmid=17965727 |doi=10.1038/labinvest.3700696|display-authors=etal}}</ref> (also known as Ki-1)
* Nuclear negativity for the [[PAX5]] transcription factor (usually expressed in [[Hodgkin’s lymphoma]] classic variant)
*True positivity requires pinpointing of the signal to the cell membrane and/or paranuclear region.
* Negativity for the [[EBV]] markers EBER and LMP1 (which may be expressed in [[Hodgkin’s lymphoma]] classic variant)
*Another useful marker, which helps to decipher this lesion from [[Hodgkin lymphoma]], is [[Clusterin]].
* Presence of clonal [[T-cell receptor]] rearrangements (usually absent in [[Hodgkin’s lymphoma]] classic variant)
*The neoplastic cells have a [[golgi]] staining pattern (hence paranuclear staining), which is tell tale indicator of this lymphoma.
* Another useful marker which helps to differentiate this lesion from [[Hodgkin lymphoma]] is [[Clusterin]]
*The cells are also typically positive for a subset of markers of T-cell lineage.
* The neoplastic cells have a [[golgi]] staining pattern (hence paranuclear staining), which is characteristic of this lymphoma
*However, as with other [[T-cell lymphoma]]s, they are usually negative for the pan T-cell marker [[CD3]].
* The cells are also typically positive for a subset of markers of T-cell lineage  
*Occasional examples are of neither T nor B cell type. These lymphomas show immunopositivity for ALK protein in 70% of cases.
:* However, as with other T-cell lymphomas, they are usually negative for the pan T-cell marker [[CD3]]  
*They are also typically positive for epithelial membrane antigen (EMA). In contrast to many B-cell anaplastic CD30 positive lymphomas, the neoplastic cells are negative for markers of [[Epstein-Barr Virus]] (EBV).
* Occasional examples are of null (neither T nor B) cell type
 
:* These lymphomas show immunopositivity for ALK protein in 70% of cases
:* They are also typically positive for EMA
==Microscopic Pathology==
==Microscopic Pathology==
The histologic features of anaplastic large cell lymphoma are variable. The hallmark cells are of medium size and feature abundant [[cytoplasm]] (which may be clear, amphophilic or [[eosinophilic]]), kidney shaped [[cell nucleus|nuclei]], and a paranuclear [[eosinophilic]] region. Occasional cells may be identified in which the plane of section passes through the nucleus in such a way that it appears to enclose a region of cytoplasm within a ring; such cells are called "doughnut" cells.
The histological features of anaplastic large cell lymphoma are variable. The hallmark cells are of medium size and feature abundant [[cytoplasm]] (which may be clear, amphophilic or [[eosinophilic]]), kidney shaped [[cell nucleus|nuclei]], and a paranuclear [[eosinophilic]] region. Occasional cells may be identified in which the plane of section passes through the nucleus in such a way that it appears to enclose a region of cytoplasm within a ring; such cells are called "doughnut" cells.
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
{| style="border: 0px; font-size: 90%; margin: 3px;" align="center"
|+ '''Histologic Classification''' <ref>The anaplastic lymphoma kinase in the pathogenesis of cancer. http://go.galegroup.com/ps/retrieve.dosgHitCountType=None&sort=RELEVANCE&inPS=true&prodId=HRCA&userGroupName=mlin_b_bethidmc&tabID=T002&searchId=R1&resultListType=RESULT_LIST&contentSegment=&searchType=AdvancedSearchForm&currentPosition=1&contentSet=GALE%7CA188154738&&docId=GALE Accessed on October 8, 2015</ref> <ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>  
|+ '''Histological Classification''' <ref>The anaplastic lymphoma kinase in the pathogenesis of cancer. http://go.galegroup.com/ps/retrieve.dosgHitCountType=None&sort=RELEVANCE&inPS=true&prodId=HRCA&userGroupName=mlin_b_bethidmc&tabID=T002&searchId=R1&resultListType=RESULT_LIST&contentSegment=&searchType=AdvancedSearchForm&currentPosition=1&contentSet=GALE%7CA188154738&&docId=GALE Accessed on October 8, 2015</ref> <ref name="Swerdlow">{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>  
! style="background: #4479BA;; color:#FFF;" | Name
! style="background: #4479BA;; color:#FFF;" | Name
! style="background: #4479BA;; color:#FFF;" | Description
! style="background: #4479BA;; color:#FFF;" | Description
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;" colspan=2 | '''Classical Variants'''
| colspan="2" style="padding: 5px 5px; background: #DCDCDC;" | '''Classical Variants'''
|-
|-
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Common pattern
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Common pattern
Line 43: Line 50:
* ALK positive anaplastic large cell lymphoma
* ALK positive anaplastic large cell lymphoma
* Most common morphological variant (75%)<ref name="pmid9736036">{{cite journal| author=Falini B, Bigerna B, Fizzotti M, Pulford K, Pileri SA, Delsol G et al.| title=ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum. | journal=Am J Pathol | year= 1998 | volume= 153 | issue= 3 | pages= 875-86 | pmid=9736036 | doi=10.1016/S0002-9440(10)65629-5 | pmc=PMC1853018 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9736036  }}</ref>
* Most common morphological variant (75%)<ref name="pmid9736036">{{cite journal| author=Falini B, Bigerna B, Fizzotti M, Pulford K, Pileri SA, Delsol G et al.| title=ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum. | journal=Am J Pathol | year= 1998 | volume= 153 | issue= 3 | pages= 875-86 | pmid=9736036 | doi=10.1016/S0002-9440(10)65629-5 | pmc=PMC1853018 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9736036  }}</ref>
* In large cells, nucleoli tend to be more prominent  
* In large cells, nucleoli tend to be more prominent.
* The cytoplasm may be either [[basophilic]] or [[eosinophilic]] and the cell might have many nuclei with dispersed or clumped [[chromatin]]  
* The cytoplasm may be either [[basophilic]] or [[eosinophilic]], and the cell might have many nuclei with dispersed or clumped [[chromatin]].
* Given that the lymphomatous cells grow in the lymph node's sinuses, this variant may resemble a metastatic tumor
* Given that the lymphomatous cells grow in the lymph node's sinuses, this variant may resemble a [[metastatic]] tumor.
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;" colspan=6 | '''Atypical Variants'''
| colspan="6" style="padding: 5px 5px; background: #DCDCDC;" | '''Atypical Variants'''
|-
|-
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Small cell
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Small cell
| style="padding: 5px 5px; background: #F5F5F5;" |  
| style="padding: 5px 5px; background: #F5F5F5;" |  
* ALK positive anaplastic large cell lymphoma
* ALK positive anaplastic large cell lymphoma
* Cells have nuclear irregularity and perivascular/intravascular distribution<ref name="pmid8394652">{{cite journal| author=Kinney MC, Collins RD, Greer JP, Whitlock JA, Sioutos N, Kadin ME| title=A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma. | journal=Am J Surg Pathol | year= 1993 | volume= 17 | issue= 9 | pages= 859-68 | pmid=8394652 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8394652  }}</ref>  
* Cells have nuclear irregularity and perivascular/intravascular distribution.<ref name="pmid8394652">{{cite journal| author=Kinney MC, Collins RD, Greer JP, Whitlock JA, Sioutos N, Kadin ME| title=A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma. | journal=Am J Surg Pathol | year= 1993 | volume= 17 | issue= 9 | pages= 859-68 | pmid=8394652 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8394652  }}</ref>  
* Occasionally, lymphomatous cells have a pale cytoplasm with a central nucleus, described as "fried egg cell"<ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>
* Occasionally, lymphomatous cells have a pale cytoplasm with a central nucleus, described as "fried egg cell".<ref name="Swerdlow">{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>
|-
|-
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Lymphohistiocytic
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Lymphohistiocytic
| style="padding: 5px 5px; background: #F5F5F5;" |  
| style="padding: 5px 5px; background: #F5F5F5;" |  
* ALK positive anaplastic large cell lymphoma
* ALK positive anaplastic large cell lymphoma
* [[Histiocytes]] have an [[acidophilic]] cytoplasm and a perinuclear clear area, with an eccentric nuclei and condensed chromatin<ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1858171/pdf/amjpathol00028-0072.pdf|title=
* [[Histiocytes]] have an [[acidophilic]] cytoplasm and a perinuclear clear area, with an eccentric nuclei and condensed chromatin.<ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1858171/pdf/amjpathol00028-0072.pdf|title=
Frequent Expression ofthe NPM-ALK Chimeric Fusion Protein inAnaplastic Large-Cell Lymphoma, Lympho-Histiocytic Type}}</ref>   
Frequent Expression ofthe NPM-ALK Chimeric Fusion Protein inAnaplastic Large-Cell Lymphoma, Lympho-Histiocytic Type}}</ref>   
* Lymphomatous cells cluster around the perivascular area as demonstrated by immunostaining with [[CD30]] and ALK antibodies<ref name=Swerdlow>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>
* Lymphomatous cells cluster around the perivascular area as demonstrated by immunostaining with [[CD30]] and ALK antibodies.<ref name="Swerdlow">{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon, France | year = 2008 | isbn = 9789283224310 }}</ref>
|-
|-
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Giant cell
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Giant cell
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| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Hodgkin's like
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Hodgkin's like
| style="padding: 5px 5px; background: #F5F5F5;" |  
| style="padding: 5px 5px; background: #F5F5F5;" |  
* The morphological characteristics of this pattern are similar to the nodular sclerosis variant of [[Hodgkin's lymphoma]]<ref name="pmid16434897">{{cite journal| author=Vassallo J, Lamant L, Brugieres L, Gaillard F, Campo E, Brousset P et al.| title=ALK-positive anaplastic large cell lymphoma mimicking nodular sclerosis Hodgkin's lymphoma: report of 10 cases. | journal=Am J Surg Pathol | year= 2006 | volume= 30 | issue= 2 | pages= 223-9 | pmid=16434897 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16434897  }}</ref>  
* The morphological characteristics of this pattern are similar to the nodular sclerosis variant of [[Hodgkin's lymphoma]].<ref name="pmid16434897">{{cite journal| author=Vassallo J, Lamant L, Brugieres L, Gaillard F, Campo E, Brousset P et al.| title=ALK-positive anaplastic large cell lymphoma mimicking nodular sclerosis Hodgkin's lymphoma: report of 10 cases. | journal=Am J Surg Pathol | year= 2006 | volume= 30 | issue= 2 | pages= 223-9 | pmid=16434897 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16434897  }}</ref>  
* This pattern is predominately more common among female
* This pattern is predominately more common among females.
* There are two immunophenotype:<ref name="pmid16434897">{{cite journal| author=Vassallo J, Lamant L, Brugieres L, Gaillard F, Campo E, Brousset P et al.| title=ALK-positive anaplastic large cell lymphoma mimicking nodular sclerosis Hodgkin's lymphoma: report of 10 cases. | journal=Am J Surg Pathol | year= 2006 | volume= 30 | issue= 2 | pages= 223-9 | pmid=16434897 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16434897  }}</ref>
* There are two immunophenotype:<ref name="pmid16434897">{{cite journal| author=Vassallo J, Lamant L, Brugieres L, Gaillard F, Campo E, Brousset P et al.| title=ALK-positive anaplastic large cell lymphoma mimicking nodular sclerosis Hodgkin's lymphoma: report of 10 cases. | journal=Am J Surg Pathol | year= 2006 | volume= 30 | issue= 2 | pages= 223-9 | pmid=16434897 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16434897  }}</ref>
**Positive: [[CD30]], ALK, epithelial membrane antigen (EMA), [[CD43]] (only 66% of the times), and [[perforin]]
**Positive: [[CD30]], ALK, epithelial membrane antigen (EMA), [[CD43]] (only 66% of the times), and [[perforin]]
**Negative: [[CD15]], [[CD20]], Pax5/BSAP, and [[EBV]]
**Negative: [[CD15]], [[CD20]], Pax5/BSAP, and [[EBV]]
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;" colspan=6 | '''Rare Variants'''
| colspan="6" style="padding: 5px 5px; background: #DCDCDC;" | '''Rare Variants'''
|-
|-
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Sarcomatoid
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Sarcomatoid
Line 80: Line 87:
* ALK positive anaplastic large cell lymphoma
* ALK positive anaplastic large cell lymphoma
|}
|}
 
==Video==
[[Image:800px-Anaplastic_large_cell_lymphoma_-_high_mag.jpg‎|200px|left|thumb|High magnification micrograph of an anaplastic large cell lymphoma. (H&E stain)]]
===Video===
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Latest revision as of 11:21, 19 April 2019

Anaplastic large cell lymphoma Microchapters

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shivali Marketkar, M.B.B.S. [2], Sowminya Arikapudi, M.B,B.S. [3], Kamal Akbar, M.D.[4]; Grammar Reviewer: Natalie Harpenau, B.S.[5]

Overview

The ALK gene is involved in the pathogenesis of ALK positive anaplastic large cell lymphoma. The DUSP22 gene is involved in the pathogenesis of ALK negative anaplastic large cell lymphoma. On microscopic histopathological analysis, medium sized cells, abundant cytoplasm, kidney shaped nuclei, and a paranuclear eosinophilic region are characteristic findings of anaplastic large cell lymphoma.

Pathophysiology

Genetic

  • ALK-positive lymphoma is associated with a translocation in the ALK gene [T(2;5)(p23;q35)], which expresses the ALK protein.[1]
  • ALK negative anaplastic large cell lymphoma is characterized by a translocation T(6;7)(p25.3;q32.3), which inactivates the DUSP22 gene and leads to a higher proliferation rate.[2]
  • In healthy people, the product of the DUSP22 gene, the DUSP22 protein (also known as the JNK pathway-associated phosphatase or JKAP), inactivates the lymphocyte-specific tyrosine kinase protein during T-cell receptor signaling.[3]
  • DUSP22 mutations are also associated with breast cancer (the UDSMP22 protein can also block estrogen receptors)[4] and primary cutaneous anaplastic large cell lymphoma.[5]

Molecular biology

  • The majority of anaplastic large cell lymphomas, greater than 90%, contain a clonal rearrangement of the T-cell receptor. This may be identified using PCR techniques, such as T-gamma multiplex PCR.
  • Oncogenic potential is conferred by up regulation of a tyrosine kinase gene on chromosome 2. Several different translocations involving this gene have been identified in different cases of this lymphoma
  • The most common is a chromosomal translocation involving the nucleophosmin gene on chromosome 5.
  • The translocation may be identified by analysis of giemsa-banded metaphase spreads of tumor cells and is characterized by t(2;5)(p23;q35).
  • The product of this fusion gene may be identified by immunohistochemistry using antiserum to ALK protein. Probes are available to identify the translocation by fluorescent in-situ hybridization (FISH).
  • The nucleophosmin component associated with the common translocation results in nuclear positivity as well as cytoplasmic positivity. Positivity with the other translocations may be confined to the cytoplasm.
  • Mutagenesis and functional studies have identified a plethora of NPM1–ALK interacting molecules, which ultimately lead to the activation of key pathways including: Erk, PLC-γ, PI3K, and Jak/signal transducers and activators of transcription (STAT) pathways. These molecules then control cell proliferation and survival and cytoskeletal rearrangements.[6]
  • Other gene mutations include:[7]
    • T(1;2), encoding a tropomyosin 3 (TPM3)/ALK fusion protein (10 to 20%)
    • T(2;3), encoding a TRK fusion gene (TFP)/ALK fusion protein (2 to 5%)
    • Inv(2), encoding a ATIC (Pur H gene)/ALK fusion protein (2 to 5%)
    • T(2;17), encoding a clathrin heavy (CLTC)/ALK fusion protein (2 to 5%)
    • T(2;17), encoding a ALO17/ALK fusion protein (2 to 5 percent of cases)
    • T(2;19), encoding a tropomyosin 4 (TPM4)/ALK fusion protein (<1%)
    • T(2;22), encoding a non-muscle myosin (MYH9)/ALK fusion protein (<1%)

Immunophenotype

  • The hallmark cells portray immunopositivity for CD30[8] (also known as Ki-1)
  • True positivity requires pinpointing of the signal to the cell membrane and/or paranuclear region.
  • Another useful marker, which helps to decipher this lesion from Hodgkin lymphoma, is Clusterin.
  • The neoplastic cells have a golgi staining pattern (hence paranuclear staining), which is tell tale indicator of this lymphoma.
  • The cells are also typically positive for a subset of markers of T-cell lineage.
  • However, as with other T-cell lymphomas, they are usually negative for the pan T-cell marker CD3.
  • Occasional examples are of neither T nor B cell type. These lymphomas show immunopositivity for ALK protein in 70% of cases.
  • They are also typically positive for epithelial membrane antigen (EMA). In contrast to many B-cell anaplastic CD30 positive lymphomas, the neoplastic cells are negative for markers of Epstein-Barr Virus (EBV).

Microscopic Pathology

The histological features of anaplastic large cell lymphoma are variable. The hallmark cells are of medium size and feature abundant cytoplasm (which may be clear, amphophilic or eosinophilic), kidney shaped nuclei, and a paranuclear eosinophilic region. Occasional cells may be identified in which the plane of section passes through the nucleus in such a way that it appears to enclose a region of cytoplasm within a ring; such cells are called "doughnut" cells.

Histological Classification [9] [1]
Name Description
Classical Variants
Common pattern
  • ALK positive anaplastic large cell lymphoma
  • Most common morphological variant (75%)[10]
  • In large cells, nucleoli tend to be more prominent.
  • The cytoplasm may be either basophilic or eosinophilic, and the cell might have many nuclei with dispersed or clumped chromatin.
  • Given that the lymphomatous cells grow in the lymph node's sinuses, this variant may resemble a metastatic tumor.
Atypical Variants
Small cell
  • ALK positive anaplastic large cell lymphoma
  • Cells have nuclear irregularity and perivascular/intravascular distribution.[11]
  • Occasionally, lymphomatous cells have a pale cytoplasm with a central nucleus, described as "fried egg cell".[1]
Lymphohistiocytic
  • ALK positive anaplastic large cell lymphoma
  • Histiocytes have an acidophilic cytoplasm and a perinuclear clear area, with an eccentric nuclei and condensed chromatin.[12]
  • Lymphomatous cells cluster around the perivascular area as demonstrated by immunostaining with CD30 and ALK antibodies.[1]
Giant cell
  • ALK positive anaplastic large cell lymphoma
Hodgkin's like
  • The morphological characteristics of this pattern are similar to the nodular sclerosis variant of Hodgkin's lymphoma.[13]
  • This pattern is predominately more common among females.
  • There are two immunophenotype:[13]
    • Positive: CD30, ALK, epithelial membrane antigen (EMA), CD43 (only 66% of the times), and perforin
    • Negative: CD15, CD20, Pax5/BSAP, and EBV
Rare Variants
Sarcomatoid
  • ALK positive anaplastic large cell lymphoma

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References

  1. ↑ 1.0 1.1 1.2 1.3 Swerdlow, Steven (2008). WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: International Agency for Research on Cancer. ISBN 9789283224310.
  2. ↑ Feldman AL, Dogan A, Smith DI, Law ME, Ansell SM, Johnson SH; et al. (2011). "Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing". Blood. 117 (3): 915–9. doi:10.1182/blood-2010-08-303305. PMC 3035081. PMID 21030553.
  3. ↑ "The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck".
  4. ↑ "Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing".
  5. ↑ Xing X, Feldman AL (2015). "Anaplastic large cell lymphomas: ALK positive, ALK negative, and primary cutaneous". Adv Anat Pathol. 22 (1): 29–49. doi:10.1097/PAP.0000000000000047. PMID 25461779.
  6. ↑ Tabbó F, Barreca A, Piva R, Inghirami G; European T-Cell Lymphoma Study Group (2012). "ALK Signaling and Target Therapy in Anaplastic Large Cell Lymphoma". Front Oncol. 2: 41. doi:10.3389/fonc.2012.00041. PMC 3355932. PMID 22649787.
  7. ↑ "The anaplastic lymphoma kinase in the pathogenesis of cancer". Text "http://www.nature.com/nrc/journal/v8/n1/abs/nrc2291.html" ignored (help); Missing or empty |url= (help)
  8. ↑ Watanabe M, Ogawa Y, Itoh K; et al. (January 2008). "Hypomethylation of CD30 CpG islands with aberrant JunB expression drives CD30 induction in Hodgkin lymphoma and anaplastic large cell lymphoma". Lab. Invest. 88 (1): 48–57. doi:10.1038/labinvest.3700696. PMID 17965727.
  9. ↑ The anaplastic lymphoma kinase in the pathogenesis of cancer. http://go.galegroup.com/ps/retrieve.dosgHitCountType=None&sort=RELEVANCE&inPS=true&prodId=HRCA&userGroupName=mlin_b_bethidmc&tabID=T002&searchId=R1&resultListType=RESULT_LIST&contentSegment=&searchType=AdvancedSearchForm&currentPosition=1&contentSet=GALE%7CA188154738&&docId=GALE Accessed on October 8, 2015
  10. ↑ Falini B, Bigerna B, Fizzotti M, Pulford K, Pileri SA, Delsol G; et al. (1998). "ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum". Am J Pathol. 153 (3): 875–86. doi:10.1016/S0002-9440(10)65629-5. PMC 1853018. PMID 9736036.
  11. ↑ Kinney MC, Collins RD, Greer JP, Whitlock JA, Sioutos N, Kadin ME (1993). "A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma". Am J Surg Pathol. 17 (9): 859–68. PMID 8394652.
  12. ↑ "Frequent Expression ofthe NPM-ALK Chimeric Fusion Protein inAnaplastic Large-Cell Lymphoma, Lympho-Histiocytic Type" (PDF).
  13. ↑ 13.0 13.1 Vassallo J, Lamant L, Brugieres L, Gaillard F, Campo E, Brousset P; et al. (2006). "ALK-positive anaplastic large cell lymphoma mimicking nodular sclerosis Hodgkin's lymphoma: report of 10 cases". Am J Surg Pathol. 30 (2): 223–9. PMID 16434897.

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