Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)

INTRODUCTION — The peripheral T cell lymphomas (PTCLs) are a heterogeneous group of generally aggressive neoplasms that constitute less than 15 percent of all non-Hodgkin lymphomas in adults. Anaplastic large cell lymphoma (ALCL), T/null cell type accounts for approximately 2 percent of adult non-Hodgkin lymphoma and is the second or third most common PTCL histology in adults depending on the series analyzed.

Primary systemic ALCL (sALCL) presents as systemic, extracutaneous disease. A high fraction of sALCL cases, particularly in children and younger adults, are associated with translocations involving ALK, the Anaplastic Lymphoma Kinase gene, located on chromosome 2p23. Contemporary disease classification schemes distinguish between ALK-positive ALCL and ALK-negative ALCL [1,2].

Four distinct forms of ALCL are recognized based on clinical features and molecular characterization:

●sALCL, ALK positive

●sALCL, ALK negative

●Breast implant-associated ALCL (BI-ALCL)

●Primary cutaneous ALCL (PC-ALCL)

BI-ALCL is caused by and arises around textured-surface breast implants placed for either reconstructive or cosmetic indications. PC-ALCL is confined to the skin of patients without a pre-existing lymphoproliferative disorder, lacks ALK translocations, and is frequently associated with translocations involving the MUM1/IRF4 gene.

The epidemiology, pathogenesis, clinical presentation, diagnosis, and differential diagnosis of systemic ALCL is discussed in this topic.

Related topics include:

●(See "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)".)

●(See "Breast implant-associated anaplastic large cell lymphoma".)

●(See "Primary cutaneous anaplastic large cell lymphoma".)

EPIDEMIOLOGY — sALCL is one of the most common types of the peripheral T cell lymphomas (PTCLs). The exact worldwide incidence of ALCL is not known, as the collection of these types of epidemiologic data is limited in some countries by a lack of resources that are needed for case ascertainment and accurate diagnosis. Epidemiologic data largely come from retrospective analyses of patients treated at major centers in the United States, Europe, and Asia.

ALCL accounts for approximately 2 percent of adult non-Hodgkin lymphoma and is the second or third most common T cell lymphoma histology in adults depending on the series analyzed [3,4]. In the United States as a whole, ALCL has an estimated incidence of 0.25 cases per 100,000 people [3]. ALCL is less common in Asian Americans than among White Americans, Black Americans, American Indians, or Asian Pacific Islanders [5,6]. ALCL has a bimodal age of incidence with a peak in the pre-teen and adolescent years and a second peak around the age of 60 years [7,8]. ALCL in older adults is usually ALK negative. There is generally a male predominance, especially in young patients with ALK-positive ALCL, in whom the male:female ratio may be as high as 3:1 [9].

The largest retrospective study was the International T cell Lymphoma Project, which assessed 1314 cases of peripheral lymphoma of T cell or NK cell origin from 22 centers worldwide diagnosed between 1990 and 2002 [8]. Approximately 6.6 and 5.5 percent were classified as ALK-positive and ALK-negative ALCL, respectively. The percentage of persons with ALCL varied with geographic region. ALCL was the most common distinct subtype of PTCL in the United States, accounting for 24 percent of cases. In contrast, ALCL accounted for approximately 16 and 6 percent of PTCLs in Europe and Asia, respectively.

Initial reports suggested that Epstein-Barr virus may be important in the development of the disease, but this has been subsequently refuted [10]. Human immunodeficiency virus (HIV), however, does remain a risk factor particularly for ALK-negative ALCL [11]. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology".)

PATHOGENESIS — The molecular pathogenesis of ALCL is a complex, multistep process leading to the outgrowth of a malignant clone. ALK-positive and ALK-negative ALCL have similar gene expression signatures that differ from other subtypes of PTCL, suggesting that the molecular lesions that drive these two subtypes converge to dysregulate a common core set of genes [12].

ALK expression and activation in ALK-positive ALCL — By definition, ALK-positive ALCLs have a rearrangement involving the Anaplastic Lymphoma Kinase gene (ALK) that results in the formation of pathogenic ALK fusion genes. Multiple chromosomal rearrangements can create ALK fusion genes, all of which encode chimeric, constitutively active ALK kinases.

The most frequent translocation, t(2;5), fuses a portion of the nucleophosmin (NPM1) gene on chromosome 5q35 with a portion of the ALK gene on chromosome 2p23 that encodes the ALK cytoplasmic domain [13,14]. The resulting fusion gene encodes NPM-ALK, a chimeric protein consisting of the amino terminus of the nucleolar phosphoprotein NPM1 with the catalytic domain of ALK [13,14]. NPM-ALK is a constitutively active, oncogenic tyrosine kinase, which stimulates signaling pathways that promote growth and inhibit apoptosis [13,15-17]. One important signaling axis involves the JAK/STAT pathway; in particular, hyperactivation of STAT3 has been implicated in a deregulated program of gene expression that is required for the maintenance of the neoplastic phenotype in ALK-positive ALCL [18].

In vitro and mouse model studies have demonstrated that expression of human NPM-ALK induces lymphoproliferative disorders of both B and T cell lineage [13,19]. The occurrence of rare human plasmablastic B cell lymphomas with ALK gene rearrangements (a distinct entity in the 2017 World Health Organization classification of lymphoid neoplasms) is consistent with the ability of NPM-ALK to cause both B and T cell tumors in mice [20,21].

In addition to fusion with NPM, ALK participates in less common rearrangements, which also appear to give rise to ALK fusion proteins that have constitutive tyrosine kinase activity [16]. In each instance, the ALK tyrosine kinase domain is fused to a protein domain that dimerizes, which appears to lead to constitutive activation of the ALK tyrosine kinase domain. It remains to be seen whether ALK-positive lymphomas with variant ALK rearrangements (eg, inv20, t(1;2), and t(2;3)) have an identical biology and clinical behavior to the more common tumors associated with the t(2;5) [22-24]. (See 'ALK gene rearrangements' below.)

DUSP22 in ALK-negative ALCL — Up to 30 percent of ALK-negative systemic and primary cutaneous ALCL have t(6;7)(p25.3;q32.3), a translocation involving the DUSP22 gene and the FRA7H fragile site [25]. DUSP22 rearrangements result in markedly decreased expression of DUSP22, which encodes a dual specificity phosphatase that regulates mitogen-activated protein kinase signaling. The DUSP22-IRF4 rearrangement is not associated with altered expression of IRF4 and is distinct from rare IRF4/TRA rearrangements in CD30-negative PTCL, not otherwise specified [26]. However, IRF4 is commonly expressed in ALK-positive and ALK-negative ALCL, and knockdown of IRF4 by RNA interference is toxic to ALCL cell lines in vitro and in ALCL xenograft mouse models in vivo. IRF4 may act through MYC, as gene expression profiling after IRF4 knockdown has shown significant downregulation of known MYC target genes, and knockdown of MYC and pharmacologic inhibition of MYC signaling are both toxic to ALCL cell lines [27].

ALCLs harboring t(6;7)(p25.3;q32.3) may have morphologic differences from other ALK-negative ALCLs and typically consist of sheets of hallmark cells admixed with "doughnut" cells and few large pleomorphic cells [28]. The same group that identified these genetic and morphologic features used quantitative real-time polymerase chain reaction (qPCR) in frozen tissue and RNA in situ hybridization in paraffin tissue to demonstrate higher CCR8 expression in ALCLs with DUSP22 rearrangements than in non-rearranged cases [29]. The cytotoxic markers TIA-1 and granzyme B were generally absent in DUSP22-rearranged ALCL (being present in only 10 and 5 percent of cases, respectively), and they were much more commonly expressed in other types of ALCL. Although the absence of TIA-1 and granzyme B imparted a favorable prognosis, a DUSP22 rearrangement imparted a favorable prognosis independent of the expression of these two molecules [26]. This may be because DUSP22-rearranged ALCLs are more immunogenic than other ALCL subtypes due to their low level expression of the immune checkpoint molecule PD-L1 and abundant expression of the costimulatory factor CD58 and HLA class II antigens [30].

Other genetic aberrations — ALK-positive and ALK-negative ALCL have similar gene expression signatures, and they are different from other subtypes of PTCL [12]. Hyperactivation of STAT3 is a common feature of both ALK-positive and ALK-negative ALCL (ie, as a consequence of rearrangements of ALK or other tyrosine kinase genes, or activating mutations in the JAK/STAT pathway) [31-33]; a notable exception is DUSP22-rearranged ALCL, which lacks activated STAT3 [30].

Initial studies suggest that the following genes are differentially expressed in ALK-negative compared with ALK-positive ALCL: BCL6, PTPN12, CEBPB, SERPINA1, and GAS1 [12,31]. In addition, whole-exome capture and next-generation sequencing of ALK-negative ALCL have identified recurrent mutations in PRDM1, TP53, STAT3, JAK1, TET2, FAS, and STIM2 [34]. Rearrangements in TP63 have been reported in 8 percent of ALK-negative ALCL and are mutually exclusive with rearrangements involving DUSP22 [26,35]. TP63 mutations are known to impart a poor prognosis in PTCL, and this association extends to ALCL [35].

CLINICAL FEATURES — Patients with systemic ALCL generally present in a fashion similar to other aggressive lymphomas with rapidly progressive adenopathy (peripheral and/or retroperitoneal) and systemic symptoms such as fevers, night sweats, and weight loss. Approximately two-thirds of patients present with stage III or IV disease, and extranodal involvement of the skin, liver, lung, and bone is common [36-38]. ALCL is among the more common types of peripheral T cell lymphoma to affect the nervous system although the overall incidence of nervous system involvement is low [39]. Occasional cases may present with extreme neutrophilia that may be caused by secretion of interleukin (IL)-17 and could be associated with a more aggressive disease course [40].

ALCL is most commonly a de novo entity, but the primary cutaneous variant in particular can arise from antecedent lymphomatoid papulosis or mycosis fungoides [41]. The clinical features of primary cutaneous ALCL and breast implant-associated ALCL are discussed separately. (See "Breast implant-associated anaplastic large cell lymphoma" and "Primary cutaneous anaplastic large cell lymphoma".)

Data regarding the clinical presentation of patients with ALCL largely come from retrospective analyses of patients treated at major centers in the United States, Europe, and Asia. The largest retrospective study was the International T cell Lymphoma Project, which assessed 1314 cases of peripheral lymphoma of T cell or NK cell origin, including 150 with systemic ALCL and reported the following findings [7,8,42]:

●ALK-positive and ALK-negative ALCL had similar rates of stage III/IV disease (65 versus 58 percent), elevated lactate dehydrogenase (LDH) (37 versus 46 percent), extranodal involvement (20 versus 21 percent), and B symptoms such as fever, drenching night sweats, and unintentional weight loss (60 versus 57 percent). The majority of patients had an Eastern Oncology Cooperative Group (ECOG) performance status of two or better (65 percent) (table 1).

●Patients with ALK-positive ALCL were much younger than those with ALK-negative ALCL and other T cell lymphomas. The median age difference was 24 years (34 versus 58 years, respectively) and many more patients with ALK-positive ALCL were younger than 60 years at presentation (85 versus 58 percent, respectively).

●Upon laboratory investigation, a subset of patients had an elevated LDH level (37 percent), anemia (27 percent), or thrombocytopenia (10 percent). Circulating tumor cells are rare at the time of diagnosis, but they are not uncommon at the time of relapse (picture 1).

PATHOLOGIC FEATURES

Histologic features

Morphology

Classical variant — Approximately 70 to 80 percent of ALCL demonstrate classical morphology, in which the tumor is composed of large cells with round or pleomorphic, often horseshoe-shaped or "embryoid" nuclei with multiple (or single) prominent nucleoli (picture 2) [43]. The cells have abundant cytoplasm, which gives them an epithelial or histiocyte-like appearance. The "hallmark cell," which is classically identified with ALCL, has an eccentric nucleus and a prominent, pale Golgi region, or paranuclear hof (picture 3) [44]. Normal and atypical appearing mitoses are common.

Atypical variants — Approximately 20 percent of ALCL demonstrate atypical morphology. Several morphologic variants exist and are more commonly present in children with ALCL [45,46]. Studies of cytogenetic and molecular genetic abnormalities as well as clinical features suggest that these cases belong to the same disease entity as the more anaplastic cases [44,47]. The most common morphologic variants are:

●Small cell variant – In these cases, the majority of cells are small to medium in size and have clear cytoplasm and irregular nuclei (picture 4 and picture 1) [43].

●Lymphohistiocytic variant – These cases have large numbers of histiocytes mixed with the neoplastic cells (picture 5).

●Monomorphic variant – The tumor cells have a more monomorphous appearance, with round to oval nuclei and no Reed-Sternberg-like cells; as in the more anaplastic cases, there is abundant cytoplasm. The monomorphous variant frequently has a deceptively cohesive appearance and often grows in the sinuses of lymph nodes, a pattern that can mimic metastatic solid tumors [48].

Other less common variants include a giant-cell-rich variant and a sarcomatoid variant [16].

Growth pattern — Tumor cells of primary systemic ALCL grow in a sheet-like cohesive pattern and often preferentially involve the lymph node sinuses or paracortex (picture 6) [49]. Tumors that preferentially involve lymph node sinuses may simulate the appearance of nodal metastases of solid tumors (eg, carcinoma, melanoma) but are easily distinguished by immunophenotyping. Early lesions can have a perifollicular pattern of growth. Small cell and lymphohistiocytic variants can show preferential perivascular infiltration of the tumor cells (picture 4).

Immunophenotype — The immunophenotype of ALCL is usually confirmed by immunohistochemistry (picture 7), but may also be demonstrated using flow cytometry.

While the immunophenotype is quite heterogeneous, ALCL tumor cells are universally positive for CD30 and negative for B cell surface markers (eg, CD19, CD20, CD22) [43]. By definition, ALK-positive ALCL expresses the ALK protein. Occasionally, ALCL may express transcription factors that are more characteristic of B cells, such as PAX5 [50] and BCL6 [51]. Most tumors have phenotypes consistent with an origin from a mature activated T cell (HLA-DR+, CD25+, and variable positivity for one or more T cell markers), but some belong to the so-called null cell type, in which the tumor cells fail to express any B or T lineage markers.

Surface receptors — A key factor in the diagnosis of ALCL is the virtually universal expression of CD30 (previously Ki-1), with a majority of the neoplastic cells having strong expression of CD30 in a membrane and Golgi pattern [43]. Epithelial membrane antigen (EMA) is often positive in systemic ALCL but negative in primary cutaneous ALCL [7,52]. (See "Primary cutaneous anaplastic large cell lymphoma".)

Approximately 60 percent of ALCL tumors express one or more T cell-associated antigens (CD3, CD43, CD45RO, or CD4). In addition, CD45, which is positive on most lymphoid tumors, can be negative in a substantial minority of cases. CD15, a marker of Hodgkin lymphoma, is rarely positive in ALCL.

Approximately 40 percent of primary systemic ALCL cases fail to express either B or T cell antigens (null cell type) [53,54]. Overall, the primary systemic ALCL tumors can be divided into the following immunophenotypic subtypes:

●T cell type – CD3+ and/or other T cell markers positive, clonal T cell receptor (TCR) rearrangements present (60 percent)

●Null cell type – All lineage markers negative, but clonal TCR rearrangements present (30 percent); all lineage markers negative, no TCR or IgH rearrangements present (10 percent)

The expression of surface receptors on ALCL was described by the International T cell Lymphoma Project, which assessed 1314 cases of peripheral lymphoma of T cell or NK cell origin, 159 of which were ALCL [7,8]:

●ALK-positive ALCL demonstrated universal expression of CD30 (100 percent); frequent expression of EMA (83 percent), TIA1, granzyme B, or perforin (80 percent); variable expression of CD43 (44 percent), CD4 (40 percent), and CD2 (23 percent); and low rates of expression of CD3 (12 percent), CD56 (7 percent), and CD8 (5 percent).

●ALK-negative ALCL demonstrated universal expression of CD30 (100 percent); frequent expression TIA1, granzyme B, or perforin (66 percent) and CD2 (59 percent); variable expression of CD43 (50 percent), CD3 (45 percent), EMA (43 percent), and CD4 (35 percent); and low rates of expression of CD8 (10 percent) and CD56 (4 percent). Down-regulation of TCR signaling molecules (eg, TCR, CD3) appears to be the result of epigenetic silencing mediated by ALK signaling [55].

ALK expression — By definition, all cases of ALK-positive ALCL have a rearrangement involving the anaplastic lymphoma kinase (ALK) gene [43]. Immunohistochemistry demonstrates expression of ALK, with variable subcellular distribution depending on the partner protein that is fused to ALK. Since ALK expression is normally confined to the central nervous system, immunoreactivity of a lymphoma with an ALK-specific antibody is a reliable predictor of the presence of a chromosomal rearrangement involving the ALK gene. ALK-negative ALCL does not have rearrangements of the ALK gene or express the ALK protein. Depending on the fusion partner, ALK staining may be seen in various subcellular locations.

Molecular genetics — Molecular genetic studies can aid in the diagnosis of ALCL by detecting clonal TCR gene rearrangements. However, the most important genetic finding in ALCL is ALK rearrangement, which is present in all cases of ALK-positive ALCL.

T cell receptor genes — The majority of ALCL have clonally rearranged T cell receptor (TCR) genes; roughly 10 percent have no rearrangement of TCR or immunoglobulin genes and belong to the null group [53,54]. Detection of ALK staining by immunohistochemistry is a highly reliable surrogate for the presence of an ALK gene rearrangement; in such cases, it is not necessary to assess the rearrangement status of the TCR genes.

ALK gene rearrangements — By definition, all cases of ALK-positive ALCL have a rearrangement involving the anaplastic lymphoma kinase (ALK) gene on chromosome 2p23 [43]. Several recognized translocations and inversions involve ALK [16,56-58]:

●t(2;5), encoding a nuclear phosphoprotein (NPM)/ALK fusion protein (70 to 75 percent of cases)

●t(1;2), encoding a tropomyosin3 (TPM3)/ALK fusion protein (10 to 20 percent of cases)

●t(2;3), encoding a TRK fused gene (TFG)/ALK fusion protein (2 to 5 percent of cases)

●inv(2), encoding a ATIC (Pur H gene)/ALK fusion protein (2 to 5 percent of cases)

●t(2;17), encoding a clathrin heavy (CLTC)/ALK fusion protein (2 to 5 percent of cases)

●t(2;17), encoding a RNF213/ALK fusion protein (2 to 5 percent of cases)

●t(2;19), encoding a tropomyosin 4 (TPM4)/ALK fusion protein (<1 percent of cases)

●t(2;22), encoding a non-muscle myosin (MYH9)/ALK fusion protein (<1 percent of cases)

●t(2;X), encoding a moesin/ALK fusion protein (<1 percent of cases)

●t(2;11), encoding a EEF1G/ALK fusion protein (<1 percent of cases)

●t(2;9), encoding at TRAF1/ALK fusion protein (<1 percent of cases)

ALK-negative ALCL — Patients with ALK-negative ALCL frequently have genetic aberrations, such as DUSP22 or TP63 rearrangements, but no single change is diagnostic of this disease. (See 'Pathogenesis' above.)

DIAGNOSIS — The diagnosis of primary systemic ALCL is best made by excisional tissue biopsy, most commonly a lymph node. A discussion of lymph node and tissue biopsy, including the selection of a lymph node to biopsy, is presented separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymph node and tissue biopsy'.)

The pathologic diagnosis of ALCL is based on characteristic morphologic features and immunohistochemical patterns found on biopsy specimens in conjunction with the clinical features found on presentation [21,43]. On histology, the tumor is usually composed of large cells, often with horseshoe-shaped nuclei (so-called "hallmark" cells), prominent nucleoli, with or without a paranuclear hof. The tumor cells often grow in cohesive-appearing sheets and sometimes cluster within lymph node sinuses, appearances that can mimic metastatic solid tumors such as carcinoma. In the small cell variant, tumor cells have similar nuclear features but are substantially smaller in size and may be found mainly around blood vessels. In the monomorphic variant, the characteristic "hallmark" cells may be relatively few in number. On immunohistochemistry, there is a homogeneous and strong expression of CD30 in a membrane and Golgi pattern. There is also expression of T cell antigens or no lineage-specific antigens in the case of the null cell type. Systemic ALCL is further subclassified based on the presence or absence of ALK. ALK gene rearrangement can be inferred by immunostaining for ALK or detected directly using molecular genetics or cytogenetics and by definition must be present in ALK-positive ALCL.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of ALK-positive ALCL includes other lymphoid neoplasms of T or null cell origin and some B cell neoplasms, such as the anaplastic type of diffuse large B cell lymphoma and Hodgkin lymphoma, which may have similar morphologic features (table 2). A general approach to adults and children who present with lymphadenopathy is presented separately. (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach" and "Evaluation of peripheral lymphadenopathy in adults".)

Primary cutaneous ALCL — The broad clinicopathologic entity ALCL is comprised of two morphologically identical but clinically distinct subtypes referred to as primary systemic ALCL and primary cutaneous ALCL [43]. Primary cutaneous ALCL is confined to the skin in patients with no pre-existing lymphoproliferative disorder and does not contain translocations involving ALK [59]; instead, rearrangements involving the IRF4/MUM1 gene are common in this entity [60,61]. It is distinguished from other forms of ALCL by the absence of systemic, extracutaneous disease. (See "Primary cutaneous anaplastic large cell lymphoma".)

Most cases of primary cutaneous ALCL present as solitary or localized skin tumors or nodules, usually involving the trunk, face, extremities, or buttocks [43]. These lesions frequently demonstrate necrosis or ulceration. Tumors can show partial or complete spontaneous regression but have a tendency to relapse. The diagnosis of primary cutaneous ALCL is made based on a skin biopsy in a patient with disease confined to the skin and no pre-existing lymphoproliferative disorder. On histology, large lymphoid cells similar to those in primary systemic ALCL diffusely infiltrate the upper and deep dermis and often the subcutaneous tissue but lack epidermotropism. On immunohistochemistry there is a homogeneous and strong expression of CD30 in a membrane and Golgi pattern. There is expression of T cell antigens, but ALK is absent. Clonal T cell gene rearrangements are present. Unlike ALK-positive ALCL, 25 to 50 percent of cutaneous ALK-negative ALCLs have gene rearrangements involving the IRF4 gene (also known as MUM1) [41,60,61].

DLBCL, anaplastic type — In some cases of diffuse large B cell lymphoma (DLBCL), the cells are morphologically identical to those of ALCL, and strongly express CD30 as well as B cell antigens [43]. Although these have been called B cell anaplastic large cell lymphoma (B-ALCL) in the past, they are now considered to be a morphologic variant of DLBCL [62]. The key diagnostic criterion for such cases is the expression of B cell antigens, which are not expressed in ALCL. DLBCL is discussed in more detail separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)

DLBCL, plasmablastic type — Plasmablastic lymphoma is a heterogeneous category of DLBCL, some of which are associated with Epstein-Barr virus (EBV) infection, HIV infection, and/or other immunodeficiency states. A small minority of tumors with this morphology expresses ALK and also harbors ALK gene rearrangements. They are easily distinguished from ALCL by the absence of T cell markers and the expression of B cell markers. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Plasmablastic lymphoma'.)

Hodgkin lymphoma — In the past, some patients were diagnosed as having a variant of ALCL resembling Hodgkin lymphoma of nodular sclerosis type (NSHD), originally called ALCL Hodgkin's-related, and then called ALCL Hodgkin's-like (ALCL-HL) in the REAL classification [63-65]. This subtype was defined as having architectural features of Hodgkin lymphoma (nodularity and sclerosis) but cytologic features of ALCL (sheets of neoplastic cells and sinusoidal infiltration).

The current consensus is that the majority of these cases can be resolved by a combination of morphologic and immunophenotypic features as either:

●Hodgkin lymphoma (CD15+, CD30+, PAX/BSAP+, T cell antigen–, ALK–), or

●Anaplastic large cell lymphoma (CD15–, CD30+, PAX5/BSAP–, T cell antigen +/–, ALK+/–)

Thus, this separate category has been eliminated from the World Health Organization classification [21]. Nonetheless, there are occasional cases in which the combination of morphology, immunophenotype, and even genetic studies may not resolve ALCL and Hodgkin lymphoma with certainty [66]. The diagnosis of Hodgkin lymphoma is presented in detail separately. (See "Hodgkin lymphoma: Epidemiology and risk factors".)

PROGNOSIS — While ALCL has been historically grouped as an aggressive non-Hodgkin lymphoma, the clinical course varies considerably among subtypes [63,67,68]. The main predictors of survival are ALK status and the International Prognostic Index (IPI). Other predictors of worse outcome include older age (≥40 years) and increased beta-2 microglobulin (≥3 mg/L) [69].

In children with ALCL, identification of circulating tumor cells in the peripheral blood or bone marrow at the time of diagnosis or mid-treatment appears to be associated with a poor prognosis [70,71].

Other features may also affect prognosis. In one study, patients with ALK-negative ALCL containing a DUSP22 rearrangement had a five-year overall survival (OS) of 90 percent, which was comparable to the 86 percent five-year OS in patients with ALK-positive ALCL in the same cohort [26]. In contrast, the same study demonstrated the patients with a TP63 rearrangement have a five-year OS rate of only 17 percent while patients who lacked ALK, DUSP22, and TP63 rearrangements had a five-year OS of 42 percent. These data must be validated before they are used to stratify treatment decisions.

ALK status — Patients with ALK-positive primary systemic ALCL generally have better OS than those with ALK-negative disease, based on retrospective studies [7,69,72,73]. This prognostic advantage is present in both children and younger adults with ALCL, although it has been questioned in older adults with ALCL [74]. One of the initial retrospective analyses of 57 patients with T cell/null primary systemic ALCL found that patients with ALK-positive tumors had significantly higher rates of five-year OS (93 versus 37 percent) when compared with patients with ALK-negative tumors [72].

The largest retrospective analysis of the effect of ALK positivity on outcome was the International Peripheral T cell lymphoma (IPTL) Project [7]. This project studied outcomes in 159 systemic ALCLs and 22 primary cutaneous ALCLs. Primary cutaneous ALCL behaved indolently, having a five-year OS of 90 percent, but with a high propensity for cutaneous relapse. Systemic ALK-positive ALCL pursued an aggressive course but responded well to therapy, having an overall five-year survival of 70 percent. Systemic ALK-negative ALCL had a five-year survival that was significantly worse than that of ALK-positive ALCL (49 versus 70 percent), but significantly better than other peripheral T cell lymphomas (49 versus 32 percent). As a result, the IPTL determined that each of these variants deserved to be maintained in a separate diagnostic group.

Some studies have suggested that age is a more important prognostic factor than ALK expression, and one large study demonstrated that the presence of ALK imparted a more favorable prognosis only in patients under the age of 40 years [69]. In this study, more patients younger than 40 years old were ALK-positive than ALK-negative (66 versus 23 percent, respectively). ALK-negative cases were more likely to have an IPI of 3 to 5 (48 versus 23 percent), were less likely to have a complete response to first-line treatment (68 versus 86 percent) and had inferior OS rates at eight years (49 versus 82 percent).

International Prognostic Index — The IPI is an independent predictor of outcome in patients with ALCL. The IPI was originally devised to predict survival of patients with clinically aggressive non-Hodgkin lymphoma following treatment with doxorubicin-containing chemotherapy regimens (table 3). It incorporates the patient's age, serum lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group (ECOG) performance status, Ann Arbor clinical stage, and the number of involved extranodal sites. Patients are then divided based on these factors into four risk groups with significantly different outcomes. The details of the IPI are discussed separately. (See "Prognosis of diffuse large B cell lymphoma", section on 'International Prognostic Index'.)

Several retrospective studies have found the IPI to be an independent predictor of outcome in patients with ALCL, and especially in ALK-positive ALCL [7,72,73,75]. Prognostically, the IPI score can be at least as important as the presence or absence of ALK, and even patients with ALK-positive ALCL have a poor outcome if the IPI score is ≥3 [7,69,72,73,75]. However, the independent value of each component of the IPI is not entirely clear. Age at diagnosis has been recognized as a prognostic factor. ALCLs that arise during childhood, the vast majority of which are ALK-positive, are characterized by high-stage but therapy-responsive disease; OS is excellent [76-79]. In adults, the tumor is clinically aggressive but potentially curable, having an OS similar to that of diffuse large B cell lymphoma [7,65,80,81].

The International Peripheral T cell Lymphoma Project, described above, reported estimated five-year OS rates for patients with ALK-positive ALCL of 90, 68, 23, and 33 percent for patients with an IPI of 0 or 1, 2, 3, and 4 or 5, respectively [7]. Corresponding estimates of five-year survival in patients with ALK-negative ALCL were 74, 62, 31, and 13 percent, respectively. Poor performance status, high stage, and elevated LDH were also predictive of lower survival in patients with ALCL. In addition, increased age, multiple extranodal sites, and anemia were poor prognostic factors in ALK-positive, but not ALK-negative, ALCL.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging".)

SUMMARY

●Description – Anaplastic large cell lymphoma (ALCL) is one of the most common forms of peripheral T cell lymphoma. There are four subtypes of ALCL:

•Primary systemic ALCL (sALCL), anaplastic lymphoma kinase (ALK) positive

•sALCL, ALK negative

•Breast implant-associated ALCL (BI-ALCL) (see "Breast implant-associated anaplastic large cell lymphoma")

•Primary cutaneous ALCL (PC-ALCL) (see "Primary cutaneous anaplastic large cell lymphoma")

●Epidemiology – ALCL is most often seen in children and young adults, and it has a male predominance. (See 'Epidemiology' above.)

●Pathogenesis – Differs between ALK-positive and ALK-negative subtypes:

•ALK-positive sALCL – By definition, there is rearrangement of ALK that causes constitutive activation; most often this involves rearrangement with nucleophosmin (NPM) to generate NPM::ALK. (See 'ALK expression and activation in ALK-positive ALCL' above.)

•ALK-negative sALCL – Up to one-third of cases of ALK-negative sALCL are associated with t(6;7), a translocation that markedly decreases expression of DUSP22, which encodes a dual specificity phosphatase that regulates mitogen-activated protein kinase signaling. (See 'DUSP22 in ALK-negative ALCL' above.)

●Presentation – Most patients present with rapidly progressive, painless lymphadenopathy, with or without constitutional symptoms. Most have advanced-stage disease, and many have extranodal involvement (eg, skin, liver, lung, bone, central nervous system). (See 'Clinical features' above.)

●Pathology – Excisional lymph node biopsies are preferred. (See 'Pathologic features' above.)

•Morphology – Large pleomorphic cells, some with horseshoe-shaped nuclei, that often manifest as a sheet of abnormal cells. Most cases have this classic appearance, but up to one-fifth of cases are atypical variants. (See 'Morphology' above.)

•Immunohistochemistry – Strong and homogeneous CD30 expression in the cell membrane and Golgi. T cell antigens are expressed variably, but there is no expression of B cell markers. (See 'Immunophenotype' above.)

•ALK expression – There is also expression of T cell antigens or no lineage-specific antigens as in the case of the null cell type. The presence of an ALK rearrangement can be inferred by immunostaining for ALK (indirectly) or detected directly by molecular genetics or cytogenetics. (See 'Pathologic features' above.)

●Diagnosis – The diagnosis should be suspected in patients with rapidly progressive peripheral and/or retroperitoneal adenopathy, with or without constitutional symptoms (eg, fevers, night sweats, weight loss) and/or extranodal findings (eg, involving skin, liver, lung, bone, or central nervous system).

Diagnosis is based on the pathologic features of lymph node or other tissue and should define the subtype as ALK positive or ALK negative. (See 'Diagnosis' above.)

●Differential diagnosis – Includes other lymphomas (eg, diffuse large B cell lymphoma, Hodgkin lymphoma) and solid tumors that may have similar morphology (table 2). (See 'Differential diagnosis' above.)

●Prognosis – ALCL often has a clinically aggressive course. ALK-positive sALCL is more responsive to therapy and is associated with a better prognosis than ALK-negative ALCL. The International Prognostic Index is useful for assessing prognosis for individual patients. (See 'Prognosis' above.)