Anaplastic large cell lymphoma pathophysiology
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Anaplastic large cell lymphoma Microchapters |
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Differentiating Anaplastic large cell lymphoma from other Diseases |
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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]
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 paranuclear eosinophilic region are characteristic findings of anaplastic large cell lymphoma.
Genetics
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. 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 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) path- ways, which in turn 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 (and variants) show immunopositivity for CD30[8][9] (also known as Ki-1). True positivity requires localisation of signal to the cell membrane and/or paranuclear region (cytoplasmic 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).
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 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.
| Name | Description | ||||
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| Classical Variants | |||||
| Common pattern |
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| Atypical Variants | |||||
| Small cell | |||||
| Lymphohistiocytic |
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| Giant cell |
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| Hodgkin's like |
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| Rare Variants | |||||
| Sarcomatoid |
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References
- ↑ 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.
- ↑ 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.
- ↑ "The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck".
- ↑ "Discovery of recurrent t(6;7)(p25.3;q32.3) translocations in ALK-negative anaplastic large cell lymphomas by massively parallel genomic sequencing".
- ↑ 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.
- ↑ 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.
- ↑ "The anaplastic lymphoma kinase in the pathogenesis of cancer".
- ↑ 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.
- ↑ Park SJ, Kim S, Lee DH; et al. (August 2008). "Primary systemic anaplastic large cell lymphoma in Korean adults: 11 years' experience at Asan Medical Center". Yonsei Med. J. 49 (4): 601–9. doi:10.3349/ymj.2008.49.4.601. PMC 2615286. PMID 18729302.[dead link]
- ↑ 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¤tPosition=1&contentSet=GALE%7CA188154738&&docId=GALE Accessed on October 8, 2015
- ↑ 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.
- ↑ 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.
- ↑ "Frequent Expression ofthe NPM-ALK Chimeric Fusion Protein inAnaplastic Large-Cell Lymphoma, Lympho-Histiocytic Type" (PDF).
- ↑ 14.0 14.1 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.