View source for HAEM4:Primary Cutaneous Anaplastic Large Cell Lymphoma

{{DISPLAYTITLE:Primary Cutaneous Anaplastic Large Cell Lymphoma}}


<blockquote class='blockedit'>{{Box-round|title=PREVIOUS EDITION|This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition [[HAEM5:Table_of_Contents|Table of Contents]].
}}</blockquote>
{{Under Construction}}
==Primary Author(s)*==

Theresa Spivey, MD, Shashirekha Shetty, PhD

__TOC__

==Cancer Category/Type==

*Mature T- and NK-cell Neoplasms

==Cancer Sub-Classification / Subtype==

*[[Primary Cutaneous CD30-positive T-cell lymphoproliferative disorders|Primary Cutaneous CD30-positive T-cell lymphoproliferative disorders (CD30+ LPDs)]]

==Definition / Description of Disease<ref name=":1">Arber DA, et al., (2017). Primary Cutaneous CD30-positive T-cell Lymphoproliferative Disorders, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p392-396.</ref><ref name=":2" /><ref name=":3">{{Cite journal|last=Willemze|first=Rein|last2=Cerroni|first2=Lorenzo|last3=Kempf|first3=Werner|last4=Berti|first4=Emilio|last5=Facchetti|first5=Fabio|last6=Swerdlow|first6=Steven H.|last7=Jaffe|first7=Elaine S.|date=2019-04-18|title=The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas|url=https://doi.org/10.1182/blood-2018-11-881268|journal=Blood|volume=133|issue=16|pages=1703–1714|doi=10.1182/blood-2018-11-881268|issn=0006-4971}}</ref>==

*Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is a form of cutaneous T-cell lymphoma with majority (>75%) of tumor cells expressing CD30.
*CD30+ LPDs are a part of a spectrum of diseases with overlapping features and are associated with an excellent prognosis. The group includes lymphomatoid papulosis (LyP) and C-ALCL, which are distinguished by clinical features and disease course.
*C-ALCL is a distinct entity from systemic anaplastic large cell lymphoma (ALCL), which can have cutaneous involvement.
*Diagnosis must exclude large cell transformation of mycosis fungoides, which can express CD30.
*

==Synonyms / Terminology==

*Primary Cutaneous CD30-positive T-cell lymphoproliferative disorder

==Epidemiology / Prevalence<ref name=":1" /><ref name=":3" />==

*Second most common type of cutaneous T-cell lymphoma
*Median age: 60 years. Cases have been reported in children.
*Male:Female 2-3:1
*Disease-specific 5-year survival rate 95%

==Clinical Features<ref name=":1" /><ref name=":2" /><ref name=":3" />==

*Solitary or localized nodules or tumors, with frequent ulceration. Multifocal lesions are seen in 20% of patients.
*Lesions may regress, either partially or completely, but cutaneous relapse is common.
*Extracutaneous dissemination is seen in 10-15% of cases, most cases involving regional lymph nodes.
*Associated with excellent prognosis, even in those with regional lymph node involvement or multifocal skin lesions.
*Anaplastic morphology does not impact disease course or prognosis.
*Distinguishing from LyP is important for therapy, as surgical excision and radiotherapy are first-line treatments in patients with C-ALCL.

==Sites of Involvement<ref name=":1" />==

*Limited to cutaneous sites, most frequently affecting the trunk, face, and extremities.

==Morphologic Features<ref name=":1" /><ref name=":2" /><ref name=":3" />==

*Sheets or nodular dermal infiltrate of large pleomorphic, anaplastic, or immunoblastic cells
*Irregularly shaped nuclei
*Abundant, pale to eosinophilic, cytoplasm
*Reactive lymphocytes in the periphery
*Ulcerated lesions may resemble lymphomatoid papulosis with increased inflammatory infiltrate composed of T-cells, histiocytes, eosinophils, and neutrophils, with fewer CD30+ cells.

*In cases harboring ''DUSP22-IRF4'' translocations, CD30+ cells commonly display biphasic morphology - small, cerebriform lymphocytes within the epidermis and large transformed cells in dermis.

==Immunophenotype<ref name=":1" /><ref name=":2">{{Cite journal|last=Kempf|first=Werner|last2=Pfaltz|first2=Katrin|last3=Vermeer|first3=Maarten H.|last4=Cozzio|first4=Antonio|last5=Ortiz-Romero|first5=Pablo L.|last6=Bagot|first6=Martine|last7=Olsen|first7=Elise|last8=Kim|first8=Youn H.|last9=Dummer|first9=Reinhard|date=2011-10-13|title=EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma*|url=https://ashpublications.org/blood/article/118/15/4024/29010/EORTC-ISCL-and-USCLC-consensus-recommendations-for|journal=Blood|language=en|volume=118|issue=15|pages=4024–4035|doi=10.1182/blood-2011-05-351346|issn=0006-4971|pmc=PMC3204726|pmid=21841159}}</ref>==

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (activated T-cell markers)*||CD4, CD30 (diagnosis requires >75% expression of tumor cells)
|-
|Variable (pan T-cell markers)||CD2, CD3, CD5
|-
|Positive||Cytotoxic proteins<sup>†</sup>: Granzyme B, TIA1, perforin

CD15 (40%), IRF4/MUM1, CLA (cutaneous lymphocyte antigen)
|-
|Negative
|EMA<sup>‡</sup>, ALK<sup>‡</sup>, PAX5, EBV, CD56 (rare cases with coexpression)
|}
<nowiki>*</nowiki>Some cases may have a T-cell phenotype of CD4-/CD8+ or CD4+/CD8+ or null-cell phenotype.

<sup>†</sup>Cases with DUSP22-IRF4 rearrangement tend to express 

<sup>‡</sup>EMA and ALK are typically positive in systemic ALCL, however there are rare cases of ALK+ primary C-ALCL.

==Chromosomal Rearrangements (Gene Fusions)==

*Rearrangements of ''DUSP22-IRF4'' locus on chromosome 6p25.3 are found in 25% of primary C-ALCL and in rare cases of LyP and transformed mycosis fungoides. The rearrangements have not found in systemic ALCL or other T-cell LPDs.<ref>{{Cite journal|last=Wada|first=David A.|last2=Law|first2=Mark E.|last3=Hsi|first3=Eric D.|last4=Dicaudo|first4=David J.|last5=Ma|first5=Linglei|last6=Lim|first6=Megan S.|last7=Souza|first7=Aieska de|last8=Comfere|first8=Nneka I.|last9=Weenig|first9=Roger H.|date=2011-04|title=Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies|url=https://pubmed.ncbi.nlm.nih.gov/21169992|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=24|issue=4|pages=596–605|doi=10.1038/modpathol.2010.225|issn=1530-0285|pmc=3122134|pmid=21169992}}</ref>
*''TYK2''  (19p13) rearrangements in 15% of CD30+ lymphoproliferative disorders, with recurrent ''NPM1-TYK2'' fusions reported in primary C-ALCL and LyP.<ref name=":4">{{Cite journal|last=Velusamy|first=Thirunavukkarasu|last2=Kiel|first2=Mark J.|last3=Sahasrabuddhe|first3=Anagh A.|last4=Rolland|first4=Delphine|last5=Dixon|first5=Catherine A.|last6=Bailey|first6=Nathanael G.|last7=Betz|first7=Bryan L.|last8=Brown|first8=Noah A.|last9=Hristov|first9=Alexandra C.|date=2014-12-11|title=A novel recurrent NPM1-TYK2 gene fusion in cutaneous CD30-positive lymphoproliferative disorders|url=https://doi.org/10.1182/blood-2014-07-588434|journal=Blood|volume=124|issue=25|pages=3768–3771|doi=10.1182/blood-2014-07-588434|issn=0006-4971}}</ref>
*''TP63'' rearrangements on 3q28 are rare in C-ALCL.<ref name=":0">{{Cite journal|last=Pedersen|first=Martin Bjerregård|last2=Hamilton-Dutoit|first2=Stephen Jacques|last3=Bendix|first3=Knud|last4=Ketterling|first4=Rhett P.|last5=Bedroske|first5=Patrick P.|last6=Luoma|first6=Ivy M.|last7=Sattler|first7=Christopher A.|last8=Boddicker|first8=Rebecca L.|last9=Bennani|first9=N. Nora|date=2017-07-27|title=DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort study|url=https://doi.org/10.1182/blood-2016-12-755496|journal=Blood|volume=130|issue=4|pages=554–557|doi=10.1182/blood-2016-12-755496|issn=0006-4971|pmc=PMC5533203|pmid=28522440}}</ref>
*Rare cases of primary C-ALCL contain ''ALK'' rearrangements and associated expression of ALK.<ref>{{Cite journal|last=Melchers|first=Rutger C.|last2=Willemze|first2=Rein|last3=van de Loo|first3=Merel|last4=van Doorn|first4=Remco|last5=Jansen|first5=Patty M.|last6=Cleven|first6=Arjen H. G.|last7=Solleveld|first7=Nienke|last8=Bekkenk|first8=Marcel W.|last9=van Kester|first9=Marloes S.|date=2020-06|title=Clinical, Histologic, and Molecular Characteristics of Anaplastic Lymphoma Kinase-positive Primary Cutaneous Anaplastic Large Cell Lymphoma|url=https://journals.lww.com/ajsp/Abstract/2020/06000/Clinical,_Histologic,_and_Molecular.8.aspx|journal=The American Journal of Surgical Pathology|language=en-US|volume=44|issue=6|pages=776–781|doi=10.1097/PAS.0000000000001449|issn=0147-5185}}</ref>
*

==Characteristic Chromosomal Aberrations / Patterns==

*Clonal T-cell receptor gene rearrangement is detected in majority of cases. <ref>{{Cite journal|last=Greisser|first=Johannes|last2=Palmedo|first2=Gabriele|last3=Sander|first3=Christian|last4=Kutzner|first4=Heinz|last5=Kazakov|first5=Dmitry V.|last6=Roos|first6=Malgorzata|last7=Burg|first7=Günter|last8=Kempf|first8=Werner|date=2006-11|title=Detection of clonal rearrangement of T-cell receptor genes in the diagnosis of primary cutaneous CD30 lymphoproliferative disorders|url=https://pubmed.ncbi.nlm.nih.gov/17083688|journal=Journal of Cutaneous Pathology|volume=33|issue=11|pages=711–715|doi=10.1111/j.1600-0560.2006.00560.x|issn=0303-6987|pmid=17083688}}</ref>

==Genomic Gain/Loss/LOH<ref>{{Cite journal|last=van Kester|first=Marloes S.|last2=Tensen|first2=Cornelis P.|last3=Vermeer|first3=Maarten H.|last4=Dijkman|first4=Remco|last5=Mulder|first5=Aat A.|last6=Szuhai|first6=Karoly|last7=Willemze|first7=Rein|last8=van Doorn|first8=Remco|date=2010-02|title=Cutaneous Anaplastic Large Cell Lymphoma and Peripheral T-Cell Lymphoma NOS Show Distinct Chromosomal Alterations and Differential Expression of Chemokine Receptors and Apoptosis Regulators|url=http://dx.doi.org/10.1038/jid.2009.270|journal=Journal of Investigative Dermatology|volume=130|issue=2|pages=563–575|doi=10.1038/jid.2009.270|issn=0022-202X}}</ref>==

{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH
!Associated Genes
|-
|7q31||Gain
|''MET''
|-
|6q16-6q21||Loss
|''PRDM1''
|-
|13q34
|Loss
|''CDC16/CUL4A''
|}

*The genomic gains and losses listed above are the most common and seen in 45% of cases.
*

==Gene Mutations (SNV/INDEL)==
N/A

==Epigenomics (Methylation)==

N/A

==Genes and Main Pathways Involved==

*''DUSP22'' rearrangements associated with decreased production in the enzyme, dual-specificity phosphatase-22, which regulates MAPK signaling pathway.<ref name=":0" />
*''NPM1-TYK2'' fusion is associated with constitutive STAT signaling.<ref name=":4" />

==Diagnostic Testing Methods<ref name=":1" />==

*Requires clinical and histopathologic correlation to diagnose and separate from lymphomatoid papulosis and large cell transformation of mycosis fungoides.
*Must exclude systemic involvement by ALCL with cutaneous involvement or history of mycosis fungoides.

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

*''DUSP22-IRF4'' rearrangement have not been shown to impact disease behavior prognosis.<ref>{{Cite journal|last=Willemze|first=Rein|last2=Cerroni|first2=Lorenzo|last3=Kempf|first3=Werner|last4=Berti|first4=Emilio|last5=Facchetti|first5=Fabio|last6=Swerdlow|first6=Steven H.|last7=Jaffe|first7=Elaine S.|date=2019-04-18|title=The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas|url=https://ashpublications.org/blood/article/133/16/1703/260505/The-2018-update-of-the-WHOEORTC-classification-for|journal=Blood|language=en|volume=133|issue=16|pages=1703–1714|doi=10.1182/blood-2018-11-881268|issn=0006-4971|pmc=PMC6473500|pmid=30635287}}</ref>
*''TP63'' rearrangements are associated with refractoriness to chemotherapy and poor prognosis<ref name=":0" />
*

==Familial Forms==

N/A

==Other Information==

N/A

==Links==

*[[HAEM4:Primary Cutaneous CD30 Positive T-cell Lymphoproliferative Disorders]]
*[[HAEM5:Primary cutaneous CD30-positive T-cell lymphoproliferative disorder: Lymphomatoid papulosis]]
*[[HAEM5:ALK-negative anaplastic large cell lymphoma]]
*[[HAEM5:ALK-positive anaplastic large cell lymphoma]]
*[[HAEM5:Mycosis fungoides]]

==References==
<references />

==Notes==
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
[[Category:HAEM4]] [[Category:DISEASE]]