ALK-positive anaplastic large cell lymphoma C84.6

Last updated on: 09.10.2022

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Stone H, 1985

The cloning of ALK in 1994 was groundbreaking for further lymphoma studies. For the first time, it was possible to elucidate mechanisms contributed by the ALK oncogene in lymphoma development. Based on ALK expression, two subclasses of ALCL are defined, which exhibit significantly different clinicopathological characteristics.

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Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, CD30-positive non-Hodgkin lymphoma that is clustered in childhood and early adulthood (Hapgood G et al. 2015).

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In the WHO classification of peripheral T-cell lymphomas of 2017, ALK - rearranged lymphomas are listed in a separate group as "ALK+ ALCL" (ALK=Anaplastic Lymphoma Kinase) due to their clinicopathological characteristics and are distinguished from "ALK- ALCL". Primary cutaneous ALCL: Furthermore, a group with primary cutaneous ALCL (cALCL) is delineated (Stein H et al. 2000; Onaindia A et al. 2015).

Primary cutaneous ALCLs are ALK-negative in almost all cases and present as localized or solitary, often ulcerated skin tumors with mostly favorable prognosis (see also Primary cutaneous CD30 positive anaplastic large T-cell lymphoma).

Sporadically, ALK-ALCL may also occur primarily in the CNS or intestinally (Magaki S et al. 2021).

Another entity that is still provisional is the rare "breast implant"-associated ALCL (biALCL) (Parrilla Castellar ER et al. 2014).

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ALCL typically show planar clusters of large tumor cells, with a sinusoidal spread with perivascular accentuation being characteristic. Cytologically, ALK+ ALCL show a heterogeneous cellular composition: about 60 % of the cases show a pure "common" subtype with cohesive tumor cells possessing eccentric, partly renal nuclei; in addition, they show a typical paranuclear eosinophilic brightening. These cells are so-called "Hallmark Cells" and should be identifiable in all morphological variants (Irshaid L et al. 2020).

The most common morphological variants found are the lymphohistiocytic and Hodgkin-like types. A small cell type is found in 5-10% of cases (5-10%), and a combination type in 20% of cases.

The small cell variant is mostly characterized by small, monomorphic cells. This variant is the most commonly misdiagnosed as peripheral T-cell lymphoma (PTCL). A combination of several different patterns is seen in 1/5 of cases.
ALK-negative ALCL are morphologically indistinguishable from ALK+ ALCL. However, a small cell variant does not occur.

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In childhood and early adulthood, anaplastic large cell lymphomas account for 10-15% of all NHL; in adulthood, they affect about 1-2% of non-Hodgkin lymphomas.

Clinical features
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Systemic ALCLs are often diagnosed clinically only at a higher clinical stage (III and IV). They are clinically characterized by a frequently occurring B-symptomatology. Extranodal infiltrates (skin, liver, lung, soft tissues, bone) are present from the beginning in many cases. Bone marrow infiltration is rare (about 15%). It is often only very discretely expressed and is sometimes only detected immunohistologically.

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Standard first-line therapy for systemic ALCL: Anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine , and prednisone (CHOP) are standard first-line therapy for systemic ALCL. In versch. Studies for younger (<60 years) patients an overall survival rate after 5 years of 90% can be achieved.

ALK- ALCL: In this variant, In many patients with ALK- ALCL, anthracycline-based chemotherapy is ineffective (Hapgood G et al. 2015). so that it often needs to be supplemented by consolidative autologous stem cell transplantation (Parrilla Castellar ER et al. 2014). However, selecting appropriate patients for intensified therapy remains a challenge, especially given genetic and clinical heterogeneity and the emergence of new, effective therapies. The antibody-drug conjugate brentuximab vedotin is characterized by a high response rate (86%) (Hapgood G et al 2015).

Radiotherapy: The indication for radiotherapy must be adapted to the individual case.

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ALK+ ALCL typically occurs in younger patients and has a more favorable prognosis with 5-year survival rates of 70% to 90% compared with 40% to 60% for ALK-negative (ALK-) ALCL (Hapgood G et al. 2015; Parrilla Castellar ER et al. 2014).

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The prognostically important rearrangements of ALK, DUSP22 and TP63 can be detected by IHC and FISH. The elucidation of genetic alterations with detection of non-ALK kinase genes in ALK-negative ALCL, which lead to an activation of STAT3, will allow innovative therapeutic approaches in the future in ALK-negative ALCL, which has so far been clinically unfavorable in some cases.

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Last updated on: 09.10.2022