Anaplastic large cell lymphoma pathophysiology: Difference between revisions

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__NOTOC__
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{{Anaplastic large cell lymphoma}}
{{Anaplastic large cell lymphoma}}
{{CMG}};{{AE}}{{SM}}{{AS}}
{{CMG}}; {{AE}} {{SM}}, {{AS}}, {{kakbar}}; {{GRR}} {{Nat}}
==Overview==
==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==
==Genetics==
===Genetic===
=== Molecular Biology ===
*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>
The majority of 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. Oncogenetic potential is conferred by upregulation 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 tumour 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 ALK protein. Probes are available to identify the translocation by fluorescent in situ hybridization. The nucleophosmin component associated with the commonest translocation results in nuclear positivity as well as cytoplasmic positivity.  Positivity with the other translocations may be confined to the cytoplasm.
*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===
*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 [[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) 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>
*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(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) show immunopositivity for CD30 (also known as Ki-1). True positivity requires localisation of signal to the cell membrane and/or paranuclear region (cyptolasmic positivity is considered non-specific and non-informative). Another useful marker which helps to differentiate this lesion from Hodgkin lymphoma is Clusterin. The neoplastic cells have a golgi staining pattern (hence paranuclear staining), which is characteristic 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 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. In contrast to many B-cell anaplastic CD30 positive lymphomas, they are negative for markers of [[Epstein-Barr Virus]] (EBV).==Pathophysiology==
*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)
===Genetics===
*True positivity requires pinpointing of the signal to the cell membrane and/or paranuclear region.
Clonal [[T-cell receptor]] gene rearrangements are detected in 75% of cases<ref name="fell1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=2849301&query_hl=34&itool=pubmed_ExternalLink]
*Another useful marker, which helps to decipher this lesion from [[Hodgkin lymphoma]], is [[Clusterin]].
Feller AC, Griesser H, Schilling CV, Wacker HH, Dallenbach F, Bartels H, Kuse R, Mak TW, Lennert K. "Clonal gene rearrangement patterns correlate with immunophenotype and clinical parameters in patients with angioimmunoblastic lymphadenopathy." '''Am J Pathol'''. 1988 Dec;133(3):549-56. PMID: 2849301</ref>, and [[immunoglobin]] gene rearrangements are seen in 10% of cases, and these cases are believed to be due to expanded EBV-driven [[B-cell]] populations.<ref name="lip1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3805286&query_hl=36&itool=pubmed_ExternalLink]
*The neoplastic cells have a [[golgi]] staining pattern (hence paranuclear staining), which is tell tale indicator of this lymphoma.
Lipford EH, Smith HR, Pittaluga S, Jaffe ES, Steinberg AD, Cossman J. "Clonality of angioimmunoblastic lymphadenopathy and implications for its evolution to malignant lymphoma." '''J Clin Invest'''. 1987 Feb;79(2):637-42. PMID: 3805286</ref>  Similarly, [[EBV]]-related sequences can be detected most cases, usually in [[B-cells]] but occasionally in [[T-cells]].<ref name="wei1"/><ref name="ana1"/>.  [[Trisomy]] 3, trisomy 5, and +X are the most frequent chromosomal abnormalities found in cases.<ref name="kane1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=3261178&query_hl=40&itool=pubmed_ExternalLink]
*The cells are also typically positive for a subset of markers of T-cell lineage.
Kaneko Y, Maseki N, Sakurai M, Takayama S, Nanba K, Kikuchi M, Frizzera G. "Characteristic karyotypic pattern in T-cell lymphoproliferative disorders with reactive "angioimmunoblastic lymphadenopathy with dysproteinemia-type" features." '''Blood'''. 1988 Aug;72(2):413-21. PMID: 3261178</ref><ref name="sch1">
*However, as with other [[T-cell lymphoma]]s, they are usually negative for the pan T-cell marker [[CD3]].
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=7919378&query_hl=42&itool=pubmed_ExternalLink]
*Occasional examples are of neither T nor B cell type. These lymphomas show immunopositivity for ALK protein in 70% of cases.
Schlegelberger B, Zhang Y, Weber-Matthiesen K, Grote W. "Detection of aberrant clones in nearly all cases of angioimmunoblastic lymphadenopathy with dysproteinemia-type T-cell lymphoma by combined interphase and metaphase cytogenetics." '''Blood'''. 1994 Oct 15;84(8):2640-8. PMID: 7919378</ref>
*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).


===Gross Pathology===
The normal architecture of a lymph node is partially effaced by a polymorphous infiltrate and residual follicles are commonly seen.  The polymorphous infiltrate consists of lymphocytes of moderate size with pale/clear cytoplasm and smaller reactive [[lymphocytes]], [[eosinophils]], [[histiocytes]], [[plasma cells]], and [[follicular dendritic cells]].  In addition, blast-like [[B-cells]] are occasionally seen.  A classic morphological finding is the aborization and proliferation of [[high endothelial venules]].<ref name="who1"/> Hyperplastic [[germinal centers]] and [[Reed-Sternberg cells]] can also be seen.<ref name="quin1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10524524&query_hl=30&itool=pubmed_ExternalLink]
Quintanilla-Martinez L, Fend F, Moguel LR, Spilove L, Beaty MW, Kingma DW, Raffeld M, Jaffe ES. "Peripheral T-cell lymphoma with Reed-Sternberg-like cells of B-cell phenotype and genotype associated with Epstein-Barr virus infection." '''Am J Surg Pathol'''. 1999 Oct;23(10):1233-40. PMID: 10524524</ref><ref name="ree1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9630171&query_hl=32&itool=pubmed_ExternalLink]
Ree HJ, Kadin ME, Kikuchi M, Ko YH, Go JH, Suzumiya J, Kim DS. "Angioimmunoblastic lymphoma (AILD-type T-cell lymphoma) with hyperplastic germinal centers." '''Am J Surg Pathol'''. 1998 Jun;22(6):643-55. PMID: 9630171</ref>
===Microscopic Pathology===
AILT typically has the phenotype of a mixture of [[CD4]]+ and [[CD8]]+ [[T-cells]], with a CD4:CD8 ratio greater than unity.  Polyclonal [[plasma cells]] and [[CD21]]+ [[follicular dendritic cells]] are also seen.<ref name="who1"/>  Due to the systemic nature of this disease, neoplastic cells can be found in [[lymph nodes]], [[liver]], [[spleen]], [[skin]], and [[bone marrow]].
==Causes==
AILT was originally thought to be a premalignant condition, termed angioimmunoblastic lymphadenopathy, and this atypical reactive lymphadenopathy carried a risk for transformation into a lymphoma.  Currently, it is postulated that the originating cell for this disease is a mature (post-thymic) CD4+ [[T-cell]] that arises ''de novo'', although some researchers argue that there is a premalignant subtype of this disease.<ref name="fri1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=2642571&query_hl=22&itool=pubmed_ExternalLink]
Frizzera G, Kaneko Y, Sakurai M. "Angioimmunoblastic lymphadenopathy and related disorders: a retrospective look in search of definitions." '''Leukemia'''. 1989 Jan;3(1):1-5. PMID: 2642571</ref><ref name="smi1">
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10666395&query_hl=26&itool=pubmed_ExternalLink]
Smith JL, Hodges E, Quin CT, McCarthy KP, Wright DH. "Frequent T and B cell oligoclones in histologically and immunophenotypically characterized angioimmunoblastic lymphadenopathy." '''Am J Pathol'''. 2000 Feb;156(2):661-9. PMID: 10666395</ref>  The [[Epstein Barr virus]] ([[EBV]]) is observed in the majority of cases, and the virus has been found in the reactive B-cells that comprise part of the polymorphous infiltrate of this disease<ref name="wei1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=1373088&query_hl=15&itool=pubmed_ExternalLink]
Weiss LM, Jaffe ES, Liu XF, Chen YY, Shibata D, Medeiros LJ. "Detection and localization of Epstein-Barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma." '''Blood'''. 1992 Apr 1;79(7):1789-95. PMID: 1373088</ref> and in the neoplastic T-cells.<ref name="ana1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=1327284&query_hl=19&itool=pubmed_ExternalLink]
Anagnostopoulos I, Hummel M, Finn T, Tiemann M, Korbjuhn P, Dimmler C, Gatter K, Dallenbach F, Parwaresch MR, Stein H. "Heterogeneous Epstein-Barr virus infection patterns in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type."'''Blood'''. 1992 Oct 1;80(7):1804-12. PMID: 1327284</ref>  [[Immunodeficiency]] is also seen with this disease, but it is thought to be a sequela to the condition and not a predisposing factor.
==Microscopic Pathology==
==Microscopic Pathology==
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.
The morphologic features of ALCL are variable.  There are five morphological patterns:<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="border: 0px; font-size: 90%; margin: 3px;" align="center"
 
|+ '''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>
*'''"Common" pattern''': This is the 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> The cytoplasm may be either basophilic or eosinophilic and the cell might have many nuclei with dispersed or clumped chromatin. In large cells, nucleoli tend to be more prominent. Given that the lymphomatous cells grow in the lymph node's sinuses, this variant may resemble a metastatic tumor.
! style="background: #4479BA;; color:#FFF;" | Name
 
! style="background: #4479BA;; color:#FFF;" | Description
*'''Lymphohistiocytic pattern (10%)''': 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>  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>
| colspan="2" style="padding: 5px 5px; background: #DCDCDC;" | '''Classical Variants'''
 
|-
*'''Hodgkin's like pattern (3.3%)''': 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. 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>
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Common pattern
**Positive: [[CD30]], [[ALK]], [[epithelial membrane antigen]] ([[EMA]]), [[CD43]] (only 66% of the times) and [[perforin]]
| style="padding: 5px 5px; background: #F5F5F5;" |
**Negative: [[CD15]], [[CD20]], Pax5/BSAP and [[EBV]]
* 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>
*'''Small cell pattern (8.3%)''': 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>
* In large cells, nucleoli tend to be more prominent.
*'''Giant cell pattern (3.3%)'''
* 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.
<i>One single patient may present more than one morphologic pattern in the same or progressive biopsies</i><ref name="pmid9490693">{{cite journal| author=Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ et al.| title=ALK-positive lymphoma: a single disease with a broad spectrum of morphology. | journal=Blood | year= 1998 | volume= 91 | issue= 6 | pages= 2076-84 | pmid=9490693 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9490693  }} </ref>.
|-
 
| colspan="6" style="padding: 5px 5px; background: #DCDCDC;" | '''Atypical Variants'''
[[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===
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" | Small cell
| style="padding: 5px 5px; background: #F5F5F5;" |
* 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>  
* 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="padding: 5px 5px; background: #F5F5F5;" |  
* 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=
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>
|-
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" | Giant cell
| style="padding: 5px 5px; background: #F5F5F5;" |
* ALK positive anaplastic large cell lymphoma
|-
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" | Hodgkin's like
| 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>
* 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>
**Positive: [[CD30]], ALK, epithelial membrane antigen (EMA), [[CD43]] (only 66% of the times), and [[perforin]]
**Negative: [[CD15]], [[CD20]], Pax5/BSAP, and [[EBV]]
|-
| colspan="6" style="padding: 5px 5px; background: #DCDCDC;" | '''Rare Variants'''
|-
| style="text-align: center; padding: 5px 5px; background: #F5F5F5;" |  Sarcomatoid
| style="padding: 5px 5px; background: #F5F5F5;" |
* ALK positive anaplastic large cell lymphoma
|}
==Video==
{{#ev:youtube|3-ajNCAGP4Y}}
{{#ev:youtube|3-ajNCAGP4Y}}


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[[Category:Hematology]]
[[Category:Hematology]]
[[Category:Types of cancer]]
[[Category:Types of cancer]]
[[Category:Up-To-Date]]
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[[Category:Medicine]]
[[Category:Hematology]]
[[Category:Immunology]]

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

Video

{{#ev:youtube|3-ajNCAGP4Y}}

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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