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| __NOTOC__
| | #REDIRECT[[Anaplastic large cell lymphoma]] |
| {{SI}}
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| {{DiseaseDisorder infobox |
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| Name = auses
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| Anaplastic large cell lymphoma, ALK positive
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| ls|
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| ICD10 = {{ICD10|C|84|4|c|81}} |
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| OMIM = |
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| MedlinePlus = |
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| eMedicineSubj = |
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| eMedicineTopic = |
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| {{CMG}}; {{AE}} {{AP}}
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| {{SK}} ALCL-ALK(+); ALK-positive ALCL; ALK positive ALCL; ALK positive anaplastic large cell lymphoma
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| ==Overview==
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| The anaplastic large cell lymphoma (ALCL) ALK-positive ('''A'''naplastic '''L'''lymphoma '''K'''inase) is a [[peripheral T-cell lymphoma]] ([[non-Hodgkin lymphoma]]) characterized by the proliferation of [[CD30]]-positive T-cells which have an abundant cytoplasm, a pleomorphic nucleus (horseshoe-shaped nucleus), and an eosinophilic paranuclear region.<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> This type of 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>
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| ==Classification==
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| ===Morphologic Classification<ref>{{cite web|url=http://go.galegroup.com/ps/retrieve.do?sgHitCountType=None&sort=RELEVANCE&inPS=true&prodId=HRCA&userGroupName=mlin_b_bethidmc&tabID=T002&searchId=R1&resultListType=RESULT_LIST&contentSegment=&searchType=AdvancedSearchForm¤tPosition=1&contentSet=GALE%7CA188154738&&docId=GALE|A188154738&docType=GALE&role=|title=The anaplastic lymphoma kinase in the pathogenesis of cancer}}</ref>===
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| ====Classical Variants====
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| *'''Common pattern''' ALK positive anaplastic large cell lymphoma
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| ====Atypical Variants====
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| *'''Small cell''' ALK positive anaplastic large cell lymphoma
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| *'''Lymphohistiocytic''' ALK positive anaplastic large cell lymphoma
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| *'''Giant cell''' ALK positive anaplastic large cell lymphoma
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| *'''Hodgkin's like''' ALK positive anaplastic large cell lymphoma
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| ====Rare Variants====
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| *'''Sarcomatoid''' ALK positive anaplastic large cell lymphoma
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| ==Pathophysiology ==
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| 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>
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| *'''"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.
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| *'''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=
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| 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>
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| *'''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>
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| **Positive: [[CD30]], [[ALK]], [[epithelial membrane antigen]] ([[EMA]]), [[CD43]] (only 66% of the times) and [[perforin]]
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| **Negative: [[CD15]], [[CD20]], Pax5/BSAP and [[EBV]]
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| *'''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>
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| *'''Giant cell pattern (3.3%)'''
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| <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>.
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| ==Causes==
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| ALK positive anaplastic large cell lymphoma is associated with a rearrangement in the anaplastic lymphoma kinase (ALK) gene. The most frequent gene translocation is T(2;5)(p23;q35).<ref name="pmid8122112">{{cite journal| author=Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL et al.| title=Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. | journal=Science | year= 1994 | volume= 263 | issue= 5151 | pages= 1281-4 | pmid=8122112 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8122112 }} </ref> This translocation leads to a chimeric protein between the nucleolar phosphoprotein (NPM) gene (5q35) and ALK gene (2p23), which has structural similarity to the insulin growth factor receptor.<ref>{{cite web|url=http://go.galegroup.com/ps/retrieve.do?sgHitCountType=None&sort=RELEVANCE&inPS=true&prodId=HRCA&userGroupName=mlin_b_bethidmc&tabID=T002&searchId=R2&resultListType=RESULT_LIST&contentSegment=&searchType=AdvancedSearchForm¤tPosition=1&contentSet=GALE%7CA15341631&&docId=GALE|A15341631&docType=GALE&role=|title=Fusion of kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma}}</ref> Normal [[T-cell]]s require [[IL-2]] as a growth factor; [[T-cell]]s of patients with ALK positive anaplastic large cell lymphoma have a constitutive activation of [[IL-2 receptor]] caused by the new NMP-ALK chimeric protein.<ref>{{cite web|url=http://go.galegroup.com/ps/retrieve.do?sgHitCountType=None&sort=RELEVANCE&inPS=true&prodId=HRCA&userGroupName=mlin_b_bethidmc&tabID=T002&searchId=R3&resultListType=RESULT_LIST&contentSegment=&searchType=AdvancedSearchForm¤tPosition=1&contentSet=GALE%7CA15341631&&docId=GALE|A15341631&docType=GALE&role=|title=Fusion of kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma}}</ref>
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| 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>
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| *T(1;2), encoding a tropomyosin3 (TPM3)/ALK fusion protein (10 to 20%)
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| *T(2;3), encoding a TRK fusion gene (TFP)/ALK fusion protein (2 to 5%)
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| *Inv(2), encoding a ATIC (Pur H gene)/ALK fusion protein (2 to 5%)
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| *T(2;17), encoding a clathrin heavy (CLTC)/ALK fusion protein (2 to 5%)
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| *T(2;17), encoding a ALO17/ALK fusion protein (2 to 5 percent of cases)
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| *T(2;19), encoding a tropomyosin 4 (TPM4)/ALK fusion protein (<1%)
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| *T(2;22), encoding a non-muscle myosin (MYH9)/ALK fusion protein (<1%)
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| == Differential Diagnosis ==
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| *[[ALCL ALK negative]]
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| *Primary cutaneous ALCL
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| *Diffuse large B-cell lymphoma, anaplastic type
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| *Diffuse large B-cell lymphoma, plasmablastic type
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| *[[Hodgkin lymphoma]]
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| == Epidemiology and Demographics==
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| ALK positive anaplastic large cell lymphoma affects primarily young (between 10 and 29 years), male patients<ref name="pmid11090048">{{cite journal| author=Stein H, Foss HD, Dürkop H, Marafioti T, Delsol G, Pulford K et al.| title=CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. | journal=Blood | year= 2000 | volume= 96 | issue= 12 | pages= 3681-95 | pmid=11090048 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11090048 }} </ref> and accounts for 3% of all [[NHL]], 40% of all large cell lymphomas<ref>{{cite web|url=http://www.bloodjournal.org/content/93/8/2697?sso-checked=true|title=ALK+ Lymphoma: Clinico-Pathological Findings and Outcome}}</ref> and 10%-20% of childhood lymphomas.<ref>{{cite web|url=http://www.bloodjournal.org/content/93/8/2697?sso-checked=true|title=ALK+ Lymphoma: Clinico-Pathological Findings and Outcome}}</ref>
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| According to a study on 1,320 cases of [[peripheral T-cell lymphomas]] and NK cell lymphomas between 1990 and 2002 in 22 different centers, ALK-Positive ALCL is the fifth most common type of peripheral T cell lymphoma (6.6% of total patients).<ref>{{cite web|url=http://jco.ascopubs.org/content/26/25/4124.full.pdf|title=International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes}}</ref> In the United states, ALK-Positive ALCL is the most frequent type of [[peripheral T-cell lymphoma]].
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| ==Natural History, Complications and Prognosis==
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| ===Prognosis===
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| The '''I'''nternational '''P'''rognostic '''I'''index (IPI) is used to estimate the prognosis of patients.<ref>{{cite web|url=http://www.uptodate.com/contents/image?imageKey=HEME%2F70850&topicKey=HEME%2F4705&rank=1%7E150&source=see_link&search=Anaplastic+large+cell+lymphoma%2C+ALK+positive&utdPopup=true|title=International Prognostic Index for non-Hodgkin lymphoma}}</ref> The IPI takes into account 5 variables:
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| *Patient's age (>60 years)
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| *Elevated serum [[lactate dehydrogenase]] ([[LDH]])
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| *Eastern Cooperative Oncology Group (ECOG) performance status
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| *Ann Arbor clinical stage III or IV
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| *Number of involved extra nodal sites > 1
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| If any of this criteria is met, one point is awarded for the IPI. The interpretation of the total score is as follows:
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| *0 to 1: Low risk
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| *2: Low-intermediate risk
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| *3: High-intermediate risk
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| *4 to 5: High risk
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| According to the International Peripheral T cell Lymphoma Project, the estimated 5-years survival for each of the IPI stages are as follows:<ref>{{cite web|url=http://www.bloodjournal.org/content/111/12/5496.abstract?sso-checked=true|title=ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project}}</ref>
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| *Low risk (IPI 0-1): 90%
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| *Low-intermediate risk (IPI 2): 68%
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| *High-intermediate risk (IPI 3): 23%
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| *High risk (IPI 4-5): 33%
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| == Diagnosis ==
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| ===History and Symptoms===
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| Most adult patients present with painless [[lymphadenopathy]]. Although retroperitoneal and peripheral [[lymphadenopathy]] is very common,<ref name="pmid25674293">{{cite journal| author=Yu G, Gao Z, Huang X| title=ALK-positive anaplastic large cell lymphoma with an unusual alveolar growth pattern. | journal=Int J Clin Exp Pathol | year= 2014 | volume= 7 | issue= 12 | pages= 9086-9 | pmid=25674293 | doi= | pmc=PMC4314028 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25674293 }} </ref> other possible locations for enlarged lymph nodes include the gastrointestinal tract, the breast,<ref name="pmid25490539">{{cite journal| author=Gidengil CA, Predmore Z, Mattke S, van Busum K, Kim B| title=Breast implant-associated anaplastic large cell lymphoma: a systematic review. | journal=Plast Reconstr Surg | year= 2014 | volume= | issue= | pages= | pmid=25490539 | doi=10.1097/PRS.0000000000001037 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25490539 }} </ref> the spleen,<ref name="pmid11097375">{{cite journal| author=Hebeda KM, MacKenzie MA, van Krieken JH| title=A case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting with spontaneous splenic rupture: an extremely unusual presentation. | journal=Virchows Arch | year= 2000 | volume= 437 | issue= 4 | pages= 459-64 | pmid=11097375 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11097375 }} </ref> the liver,<ref name="pmid17396261">{{cite journal| author=Grewal JS, Smith LB, Winegarden JD, Krauss JC, Tworek JA, Schnitzer B| title=Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature. | journal=Ann Hematol | year= 2007 | volume= 86 | issue= 7 | pages= 499-508 | pmid=17396261 | doi=10.1007/s00277-007-0289-3 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17396261 }} </ref> the bone,<ref name="pmid17396261">{{cite journal| author=Grewal JS, Smith LB, Winegarden JD, Krauss JC, Tworek JA, Schnitzer B| title=Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature. | journal=Ann Hematol | year= 2007 | volume= 86 | issue= 7 | pages= 499-508 | pmid=17396261 | doi=10.1007/s00277-007-0289-3 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17396261 }} </ref> the heart,<ref name="pmid16313264">{{cite journal| author=Lim ZY, Grace R, Salisbury JR, Creamer D, Jayaprakasam A, Ho AY et al.| title=Cardiac presentation of ALK positive anaplastic large cell lymphoma. | journal=Eur J Haematol | year= 2005 | volume= 75 | issue= 6 | pages= 511-4 | pmid=16313264 | doi=10.1111/j.1600-0609.2005.00542.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16313264 }} </ref> and the respiratory tract.<ref name="pmid18670314">{{cite journal| author=Tan DS, Eng PC, Lim ST, Thye LS, Tao M| title=Primary tracheal lymphoma causing respiratory failure. | journal=J Thorac Oncol | year= 2008 | volume= 3 | issue= 8 | pages= 929-30 | pmid=18670314 | doi=10.1097/JTO.0b013e318180271d | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18670314 }} </ref>
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| Common symptoms include typical [[B symptoms]]: [[fever]], [[weight loss]], and [[night sweats]].<ref>{{cite web|url=http://www.lymphomas.org.uk/sites/default/files/pdfs/T-cell-lymphomas.pdf|title=T-cell lymphomas (Lymphoma Association)}}</ref>
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| ===Laboratory Findings===
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| *[[Anemia]]
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| *[[Thrombocytopenia]]
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| *Elevated [[lactate dehydrogenase]] ([[LDH]])<ref>{{cite web|url=http://www.bloodjournal.org/content/111/12/5496|title=ALK− anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project}}</ref>
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| == Treatment ==
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| ====CHOP-E Regimen====
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| The CHOP-E regimen includes:
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| *[[Cyclophosphamide]]
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| *[[Doxorubicin]]
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| *[[Vincristine]]
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| *[[Prednisone]]
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| *[[Etoposide]]
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| [[Crizotinib]] has successfully treated patients with ALK positive ALCL refractory to CHOP therapy.<ref>{{cite web|url=http://www.ascopost.com/ViewNews.aspx?nid=12946|title=Crizotinib Produces Durable Responses in Small Study of Patients With Advanced, Chemoresistant ALK-Positive Lymphoma}}</ref> [[Crizotinib]] was administered twice daily, each dose of 250mg.
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| ==References==
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| {{Reflist|2}}
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