| Disease |
Anaplastic large cell lymphoma (ALCL), ALK-negative is a CD30-positive T-cell non-Hodgkin lymphoma that by definition resembles ALCL, ALK-positive but lacks ALK expression (Mason, Harris et al. 2008). ALCL, ALK-negative was classified as a provisional entity distinct from ALCL, ALK-positive in the 2008 WHO classification, and is anticipated to be upgraded to a definite entity in the 2016 WHO update (Swerdlow, Campo et al. 2016). |
| Etiology | The etiology of ALCL, ALK negative is unknown. |
| Epidemiology | ALCL, ALK-negative makes up between 2.6% and 9.4% of T-/NK-cell non-Hodgkin lymphomas, with the lowest proportion occurring in Asia and the highest in Europe (Vose, Armitage et al. 2008). ALCL, ALK-negative generally occurs in older patients, with a median age of diagnosis of 55-60 years, compared to 25-35 years for ALK-positive ALCL (Ferreri, Govi et al. 2013). Males are affected more commonly than females (M:F, ~1.5:1). |
| Clinics | Patients with ALCL, ALK-negative typically present with lymphadenopathy, often with stage III/IV disease, and B symptoms (ten Berge, de Bruin et al. 2003). Extranodal sites also may be involved, including skin, bone, and soft tissues. Secondary cutaneous involvement by ALCL, ALK-negative must be distinguished from primary cutaneous ALCL, which is a distinct entity (Bekkenk, Geelen et al. 2000). |
| Pathology | By definition, the morphologic appearance is similar to that seen in ALCL, ALK-positive (Mason, Harris et al. 2008). Specifically, most cases resemble the so-called "common" pattern of ALK, ALK-positive and show sheet-like growth of tumor cells, sometimes sparing residual lymphoid follicles (Delsol, Falini et al. 2008). Sinusoidal involvement is common, and cohesive clusters of intrasinusoidal tumor cells may mimic metastatic carcinoma. The tumor cells typically are large and may show significant pleomorphism. So-called "hallmark" cells, with horseshoe-shaped or reniform nuclei, always can be identified (Benharroch, Meguerian-Bedoyan et al. 1998). Immunophenotyping studies are essential to the diagnosis of ALCL, ALK-negative. All cases express CD30 by definition. Aberrant loss of pan-T-cell antigen expression is common, and about two-thirds of cases express cytotoxic proteins (TIA1, granzyme B, or perforin) (Savage, Harris et al. 2008). ALK protein is absent. |
| |  |
|
| ALCL, ALK-negative. The tumor is composed of sheets of large pleomorphic cells, some with horseshoe-shaped nuclei ("hallmark" cells; H&E, top). By immunohistochemical stains the tumor cells are negative for the B-cell marker, CD20; positive for the T-cell marker, CD3; positive for CD30; and negative for ALK. |
|
| Treatment | ALCL, ALK-negative is typically treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like chemotherapy, often followed by autologous stem cell transplantation (Bennani-Baiti, Ansell et al. 2016). New targeted agents such as brentuximab vedotin and histone deacetylase inhibitors have demonstrated efficacy in relapsed and refractory disease. |
| Prognosis | The prognosis for ALCL, ALK-negative is poorer than for ALCL, ALK-positive, with a 5-year overall survival (OS) rate of 49% compared to 70% for the latter (Savage, Harris et al. 2008). However, prognosis is better than for most other types of T-cell non-Hodgkin lymphomas, including peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). Recent data have shown that ALCL, ALK-negative is a genetically heterogeneous disease, and that outcomes vary widely based on genetic subtype (Parrilla Castellar, Jaffe et al. 2014). Specifically, 5-year OS was very good (90%) in patients carrying DUSP22 rearrangements, poor (17%) in TP63/ -rearranged cases, and intermediate (42%) in patients lacking ALK/, DUSP22, and TP63 rearrangements. |
| Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: a report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment |
| Bekkenk MW, Geelen FA, van Voorst Vader PC, Heule F, Geerts ML, van Vloten WA, Meijer CJ, Willemze R |
| Blood 2000 Jun 15;95(12):3653-61 |
| PMID 10845893 |
| |
| ALK-positive lymphoma: a single disease with a broad spectrum of morphology |
| Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ, Haralambieva E, Pulford K, Pileri S, Morris SW, Mason DY, Delsol G |
| Blood 1998 Mar 15;91(6):2076-84 |
| PMID 9490693 |
| |
| Adult systemic anaplastic large-cell lymphoma: recommendations for diagnosis and management |
| Bennani-Baiti N, Ansell S, Feldman AL |
| Expert Rev Hematol 2016;9(2):137-50 |
| PMID 26581318 |
| |
| PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma |
| Boi M, Rinaldi A, Kwee I, Bonetti P, Todaro M, Tabbò F, Piva R, Rancoita PM, Matolcsy A, Timar B, Tousseyn T, Rodríguez-Pinilla SM, Piris MA, Beà S, Campo E, Bhagat G, Swerdlow SH, Rosenwald A, Ponzoni M, Young KH, Piccaluga PP, Dummer R, Pileri S, Zucca E, Inghirami G, Bertoni F |
| Blood 2013 Oct 10;122(15):2683-93 |
| PMID 24004669 |
| |
| Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma |
| Crescenzo R, Abate F, Lasorsa E, Tabbo' F, Gaudiano M, Chiesa N, Di Giacomo F, Spaccarotella E, Barbarossa L, Ercole E, Todaro M, Boi M, Acquaviva A, Ficarra E, Novero D, Rinaldi A, Tousseyn T, Rosenwald A, Kenner L, Cerroni L, Tzankov A, Ponzoni M, Paulli M, Weisenburger D, Chan WC, Iqbal J, Piris MA, Zamo' A, Ciardullo C, Rossi D, Gaidano G, Pileri S, Tiacci E, Falini B, Shultz LD, Mevellec L, Vialard JE, Piva R, Bertoni F, Rabadan R, Inghirami G; European T-Cell Lymphoma Study Group, T-Cell Project: Prospective Collection of Data in Patients with Peripheral T-Cell Lymphoma and the AIRC 5xMille Consortium Genetics-Driven Targeted Management of Lymphoid Malignancies |
| Cancer Cell 2015 Apr 13;27(4):516-32 |
| PMID 25873174 |
| |
| International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes |
| Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project |
| J Clin Oncol 2008 Sep 1;26(25):4124-30 |
| PMID 18626005 |
| |
| Anaplastic large cell lymphoma, ALK-positive. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. |
| Delsol, G., B. Falini, et al. |
| International Agency for Research on Cancer: (2008) 312-316. |
| |
| Recurrent translocations involving the IRF4 oncogene locus in peripheral T-cell lymphomas |
| Feldman AL, Law M, Remstein ED, Macon WR, Erickson LA, Grogg KL, Kurtin PJ, Dogan A |
| Leukemia 2009 Mar;23(3):574-80 |
| PMID 18987657 |
| |
| Morphologic Features of ALK-negative Anaplastic Large Cell Lymphomas With DUSP22 Rearrangements |
| King RL, Dao LN, McPhail ED, Jaffe ES, Said J, Swerdlow SH, Sattler CA, Ketterling RP, Sidhu JS, Hsi ED, Karikehalli S, Jiang L, Gibson SE, Ondrejka SL, Nicolae A, Macon WR, Dasari S, Parrilla Castellar E, Feldman AL |
| Am J Surg Pathol 2016 Jan;40(1):36-43 |
| PMID 26379151 |
| |
| International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes |
| Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project |
| J Clin Oncol 2008 Sep 1;26(25):4124-30 |
| PMID 18626005 |
| |
| Anaplastic large cell lymphoma, ALK-positive. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. |
| Delsol, G., B. Falini, et al. |
| International Agency for Research on Cancer: (2008) 312-316. |
| |
| Anaplastic large cell lymphoma, ALK-negative. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. |
| Mason, D. Y., N. L. Harris, et al. |
| S. Swerdlow, E. Campo, N. Harris et al. Lyon, International Agency for Research on Cancer: (2008) 317-319. |
| |
| ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes |
| Parrilla Castellar ER, Jaffe ES, Said JW, Swerdlow SH, Ketterling RP, Knudson RA, Sidhu JS, Hsi ED, Karikehalli S, Jiang L, Vasmatzis G, Gibson SE, Ondrejka S, Nicolae A, Grogg KL, Allmer C, Ristow KM, Wilson WH, Macon WR, Law ME, Cerhan JR, Habermann TM, Ansell SM, Dogan A, Maurer MJ, Feldman AL |
| Blood 2014 Aug 28;124(9):1473-80 |
| PMID 24894770 |
| |
| 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 |
| Savage KJ, Harris NL, Vose JM, Ullrich F, Jaffe ES, Connors JM, Rimsza L, Pileri SA, Chhanabhai M, Gascoyne RD, Armitage JO, Weisenburger DD; International Peripheral T-Cell Lymphoma Project |
| Blood 2008 Jun 15;111(12):5496-504 |
| PMID 18385450 |
| |
| The 2016 revision of the World Health Organization classification of lymphoid neoplasms |
| Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES |
| Blood 2016 May 19;127(20):2375-90 |
| PMID 26980727 |
| |
| Genome-wide analysis reveals recurrent structural abnormalities of TP63 and other p53-related genes in peripheral T-cell lymphomas |
| Vasmatzis G, Johnson SH, Knudson RA, Ketterling RP, Braggio E, Fonseca R, Viswanatha DS, Law ME, Kip NS, Ozsan N, Grebe SK, Frederick LA, Eckloff BW, Thompson EA, Kadin ME, Milosevic D, Porcher JC, Asmann YW, Smith DI, Kovtun IV, Ansell SM, Dogan A, Feldman AL |
| Blood 2012 Sep 13;120(11):2280-9 |
| PMID 22855598 |
| |
| International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes |
| Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project |
| J Clin Oncol 2008 Sep 1;26(25):4124-30 |
| PMID 18626005 |
| |
| ALK-negative anaplastic large-cell lymphoma demonstrates similar poor prognosis to peripheral T-cell lymphoma, unspecified |
| ten Berge RL, de Bruin PC, Oudejans JJ, Ossenkoppele GJ, van der Valk P, Meijer CJ |
| Histopathology 2003 Nov;43(5):462-9 |
| PMID 14636272 |
| |
