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Anaplastic large cell lymphoma: twenty-five years of discovery.

During the last 25 years, anaplastic large cell lymphoma (ALCL) has evolved from a tumor often misdiagnosed as metastatic carcinoma, melanoma, or malignant histiocytosis to a distinct molecular pathologic entity. Although initially recognized by relatively simple morphologic observations and immunophenotypic studies, ALCL has proved to be a model for investigating T-cell activation and signal transduction, lymphomagenesis, and oncogenesis in general.

In 1985, Harald Stein and Karl Lennert with colleagues (1) identified a unique large cell lymphoma with anaplastic cytology, an unusual sinus growth pattern, and strong expression of the antigen Ki-1 recognized by an antibody developed in Kiel, West Germany. (2) Subsequently, Ki-1 was identified as an activation antigen (now designated CD30) and a member of the tumor necrosis factor receptor family. The rather broad expression of CD30 in reactive processes and other tumors led many individuals to question whether ALCL was a distinct entity. In the late 1980s and early 1990s, a recurrent chromosomal translocation t(2;5) was described. (3-6) In 1994, the translocation was cloned by Steve Morris and others7 at St Jude Children's Research Hospital in Memphis, Tennessee, and was found to involve a receptor tyrosine kinase called anaplastic lymphoma kinase (ALK) on 2p23 and nucleophosmin (NPM) on 5q35. Because ALK is not normally expressed in lymphoid tissue, anti-ALK antibodies can be used as a surrogate method for detecting t(2;5). After widespread immunohistochemical analysis with antiALK antibodies, (8,9) ALK+ ALCL was defined as a specific entity that typically affects children and young adults, has a morphologic spectrum that includes small cell and lymphohistiocytic variants, and in most cases has a better prognosis than ALK- ALCL. (10-16)

Currently, 3 distinct T-cell tumors (ALK+ ALCL, ALK- ALCL, and primary cutaneous [C-ALCL]) are described in the 2008 World Health Organization (WHO) classification. (17-19) Although ALK+ ALCL and C-ALCL are well characterized, diagnostic pitfalls remain. In particular, recognition of ALCL with variant histology is difficult, and distinction of C-ALCL from lymphomatoid papulosis (LyP) and from systemic ALCL may be challenging. In addition, ALK dysregulation is not unique to ALCL and has been detected in inflammatory myofibroblastic tumors, carcinoma, tumors of neural origin, and in the peripheral blood cells of healthy people by sensitive, nested reverse transcription-polymerase chain reaction. (20) Despite considerable progress, questions remain regarding the biology of the ALK+ and ALK- groups and their relationship to one another. With sophisticated molecular genetic in vitro studies and correlation with clinical samples, the story continues to unfold and to shed light on the mechanisms of chromosomal translocation, oncogenic pathways, and novel therapies for treating this lymphoma and other tumors with ALK dysregulation. Despite some differences, clinical, immunohistochemical, and molecular data support the notion that ALK+ and ALK- ALCL are more closely related to each other than to peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). (21-23) Limited numbers (as few as 14) of genes may potentially be used to distinguish ALK+ or ALK- ALCL from PTCL-NOS. (24)


Clinical Features of ALK+ and ALK- Systemic ALCL

Anaplastic large cell lymphoma is most common in children and young adults but has a bimodal age distribution and can occur in older adults. (14,25) Anaplastic large cell lymphoma represents approximately 10% to 15% of pediatric/adolescent non-Hodgkin lymphomas, as compared to 2% of adult non-Hodgkin lymphomas and 30% to 40% of pediatric large cell lymphomas. The median age at diagnosis for pediatric patients is approximately 10.2 to 11.0 years, (26-28) and ALCL rarely occurs in infants. (15,28-30) Most patients with ALK- ALCL are adults (age range, 40-65 years), with a slight male predominance. (21) In the pediatric age group (fewer than 10%), ALK- ALCL is limited to single case reports or small numbers of patients in larger series.

Approximately 60% to 70% of patients have advanced stage III/IV disease due to peripheral and abdominal lymphadenopathy. Mediastinal adenopathy is present in approximately 5% to 40% of patients. Extranodal disease is frequent (approximately 40% to 50% of ALK+ and ALK- ALCLs) with skin, bone, and soft tissue being the most common sites. (21,31,32) Involvement of the central nervous system and gastrointestinal tract is rare. (33-37) ALK- ALCL tumors arising in the skin and gastrointestinal tract must be distinguished from C-ALCL and enteropathy-associated T-cell lymphoma. Uncommon extranodal presentations of ALK+ ALCL in pediatric patients include masses in the perirectal and buttock soft tissue/muscle, (38,39) hard palate and nasal cartilage, (40) stomach (polypoid lesion), (41) ovary, (42) bronchus, (43) and psoas muscle. (44) Other unusual sites of ALK+ and ALK- ALCL are ocular adnexa, primarily eyelid, (45) pleural effusion, (46) and as a pediatric ALK- ALCL, in the testis. (47) ALK- ALCL limited to the oral cavity behaves most like C-ALCL. (48) Breast involvement has been described in adults and a few pediatric ALCLs, with most cases being ALK- and seen in adults in association with breast implants. (49-52) A subset of patients with breast ALCL have an indolent course despite the ALK- status, suggesting some represent an unusual T-cell lymphoproliferative disorder rather than a frank malignancy. (51) A very unusual presentation of intravascular ALK+ ALCL mimicking inflammatory breast carcinoma has also been described in a patient with disseminated nodal disease. (53)

The bone marrow is involved in approximately 10% to 30% of cases, by morphology and immunohistochemistry, and in up to 61% of cases by molecular studies, (54,55) a finding that is most common in the small cell variant. Peripheral blood involvement is rare and is most often seen in pediatric small cell variant ALK+ ALCL but has been reported in adults and ALK- tumors. (15,56-58) Patients with peripheral blood involvement have a poor prognosis irrespective of ALK status. Patients may have an elevated white blood cell count owing to neutrophilia59 associated with granulocyte-colony stimulating factor production by the tumor. (60) Rare patients with ALCL have a hemophagocytic syndrome. (30,61) Both systemic ALK- ALCL and CALCL have rarely been described in the posttransplant setting, with a predominance of the latter. (62-64) Most cases occur 2 to 10 years after transplant, with Epstein Barr virus (EBV) expression in most nodal cases and approximately 30% of cutaneous cases. (64)

Prognosis in ALK+ ALCL is good overall, except for the small cell variant or the subset (~15%) that expresses CD56. (15,21,65-67) The 3- to 5-year event-free survival in pediatric series ranges from 65% to 85% with conventional chemotherapy. (26,27,68) Five-year overall survival of approximately 80% is reported in adolescents and young adults. (14) The survival data for ALK+ ALCL versus ALK- ALCL from the recent International T-cell Lymphoma Project has shown a 5-year failure-free survival of 60% versus 36% and a 5-year overall survival of 70% versus 49%, respectively. (21,69) The favorable prognosis of ALK+ ALCL may be somewhat related to the younger age of patients, as there was no significant outcome difference between ALK+ and ALK- ALCL for patients older than 40 years. Compared to the 5-year overall survival associated with PTCL-NOS, that of ALK- ALCL is superior (32% and 49%, respectively). Prior studies (13,14) have shown a 5-year overall survival for ALK+ ALCL versus ALK- ALCL of 71% to 79% versus 15% to 46%, respectively. Other adverse prognostic features include a high-intermediate or high International Prognostic Index and expression of survivin70 and epithelial membrane antigen (EMA/MUC-1). (71)

Challenges in the Diagnosis of ALK+ and ALK- Systemic ALCL

ALK+ and ALK- ALCL have similar histologic features (Figures 1, A through F, and 2, A through D), with cohesive clusters of pleomorphic large cells with a high mitotic rate (Figures 1, A and B, and 2, A). Both tumors have a CD4+, CD30+ (Figure 1, C) phenotype, with expression of EMA (Figure 1, D) and cytotoxic granule proteins (Figure 1, E) being somewhat less frequent in ALK- ALCL. (72) A prominent sinus growth pattern is often present, suggesting the possibility of a metastatic large cell neoplasm such as carcinoma, melanoma, or malignant histiocytosis (Figure 1, A). The large, somewhat eccentric nuclei have characteristically indented, horseshoe, kidney-shaped, or embryoid-appearing features and have been called "hallmark cells," as they are present to a certain degree in all the histologic variants of ALCL (Figure 1, B). The nuclear chromatin is partially dispersed with multiple, somewhat small basophilic nuclei. Multinucleated large cells (often wreathlike) are frequently present and can have larger, more eosinophilic nuclei, thus resembling Reed-Sternberg cells. The cytoplasm is abundant and often has denser focal staining in the perinuclear, Golgi region of the cytoplasm. Other large cell morphologic variants include sarcomatoid, (73) monomorphic, (74) and very rare signet ring-like75 and hypocellular types. (76) Approximately 3% of ALK+ ALCLs have a nodular growth pattern mimicking nodular sclerosing Hodgkin lymphoma (HL). (77,78)


Diagnosis of ALK+ ALCL of the common type has become straightforward owing to the widespread availability of reliable anti-ALK antibodies. (8) However, ALK+ ALCL includes a morphologic spectrum with small cell and lymphohistiocytic variants that represent approximately 10% to 20% of cases and can be easily confused with reactive lymphadenopathy (Figure 3, A through C). (15,79-81) The patients are often young, with symptoms of viral infection (fever, adenopathy); morphologically, there is a mixture of small and large cells and the initial biopsy site may be extranodal. (15) Staining for ALK-1, along with CD30, should be performed in lymph node biopsy specimens with paracortical expansion and sinus infiltrates, particularly from children and young adults, to help determine if more subtle involvement by a variant ALCL or focal involvement by classical ALCL is present. Although CD30+ large cells are virtually always present and surround B-cell follicles in reactive adenopathy, the presence of any ALK+ cells is abnormal. A particularly useful diagnostic feature in the small cell variant is the tendency of ALK+, CD30+ large cells to be distributed in a perivascular pattern (Figure 3, B and C) rather than randomly scattered. The large cells are usually EMA+ and T-cell intracellular antigen 1 (TIA-1)+ in the small cell and lymphohistiocytic variants, as is typically seen in ALK+ ALCL, common type. The small cell variant is frequently associated with widespread disseminated disease, and initial biopsies may be from sites such as skin or liver, or cytology fluids from body cavities, thus contributing to the difficulty in making this diagnosis. (15) The Wright-stained cytology, with very basophilic cytoplasm and fine cytoplasmic vacuoles, is characteristic and may be helpful in identifying peripheral blood, bone marrow, or body fluid involvement (Figure 4, A). (82) Bone marrow involvement, although relatively infrequent in ALCL (and more common in the small cell variant), is often subtle, without mass lesions; in many cases, immunohistochemical staining for CD30 and ALK-1 and careful examination of Wright-stained aspirate smears or touch preparations is necessary to detect involvement (Figure 4, A through D). (82,83)


The most important diagnostic feature of ALK- ALCL is the strong membrane and Golgi expression of CD30 in virtually every cell, which is only rarely seen in other

lymphomas (Figure 2, B).18 A diagnosis of ALK- ALCL also requires morphologic features compatible with ALCL and exclusion of other lymphomas with CD30+ large cells. In ALK- ALCL, the large cells may be more pleomorphic and are more often multinucleated than seen in ALK+ ALCL. It should be noted that ALK- ALCL with variant morphologic features is not recognized in the current WHO classification, as the small cell and lymphohistiocytic variants may be difficult to distinguish from other PTCL-NOS.


Distinction of ALK- ALCL from HL may be problematic, particularly in HL with numerous large dysplastic cells. In the small number of CD15+ ALK- ALCLs, testing for EBV, PAX-5, and T-cell receptor gene rearrangement is useful for ruling out HL. Hodgkin lymphoma is a tumor of defective B cells that often express PAX-5, and PAX-5 expression would usually exclude ALCL. (84) The presence of a T-cell receptor gene rearrangement would strongly support ALCL, as only very rare cases of HL with a T-cell genotype have been described. (85-88) Hodgkin lymphoma may express T-cell antigens, (89,90) but even in most of these tumors, the genotype is that of a B cell. (86-88) BCL6 can be expressed in approximately 50% of ALCLs and HLs and is of little use in the differential. Expression of cytotoxic granule proteins would favor ALCL, but ALK- ALCL more frequently lacks these antigens, and TIA-1 expression has been reported in a small percentage (fewer than 15%) of HLs. (91) Fascin and clusterin can be expressed in both ALCL and HL92; however, clusterin expression in HL usually shows a membranous pattern rather than the punctate, cytoplasmic pattern seen in ALCL. (93)

Distinction of ALCL from T- or natural killer (NK)-cell lymphoma is occasionally difficult. Epstein-Barr virus expression is very rare in ALCL and, if present, T/NK-cell neoplasm or HL should be considered. CD30+ large cells are present in angioimmunoblastic T-cell lymphoma (AITL) but are usually few in number and randomly scattered without perivascular accentuation or sinus involvement. The presence of EBV+ B cells, expanded follicular dendritic cell meshworks, and expression of BCL6, CD10, CXCL13, and PD-1 are useful in diagnosing AITL. (94) Peripheral T-cell lymphoma, not otherwise specified, has fewer CD30+ cells and more abnormal small to medium-sized cells than typically present in the more homogeneous large cell population in ALCL. The presence of perivascular lymphocytes with some infiltration of the vessel wall and CD56 expression in a small percentage of ALCLs may suggest extranodal NK/T-cell lymphoma, nasal type; however, the lack of angiodestruction, zonal necrosis, and EBV and the presence of CD5 expression and a T-cell receptor gene rearrangement would favor ALCL. In cytologic preparations, the perivascular distribution of ALCL may mimic a soft tissue sarcoma. (95)

Anaplastic large cell lymphoma is predominantly an activated CD4+ T-cell tumor with an unusual cytotoxic TIA-1+, granzyme B+, perforin+, granulysin+, EMA+, punctate cytoplasmic clusterin+ phenotype (93,96-101) (Figure 1, D and E). Defects in T-cell signaling often lead to loss of pan-T-cell antigens; in particular, CD3 and the [alpha][beta] T-cell receptor complex are often decreased or absent. (102) Immunostaining for CD43 and CD45RO in addition to CD2, CD4, CD5, CD7, and CD8 are useful in demonstrating T-cell lineage. (103) Rare ALCLs have a CD8+ phenotype. Approximately 85% to 90% of ALK+ and ALK- ALCLs have a detectable clonal T-cell receptor (TCR) gene rearrangement; the remainder is considered "null" (104,105) if the tumor cells do not express T-cell antigens. A small percentage (9%-11%) of ALK+ and ALK- ALCLs have shown a simultaneous B-cell clone. (105) The immunoglobulin heavy locus clone is most frequently detected in DH1-6 and FR3 BIOMED-2 primer sets.


Certain immunophenotypic features of ALCL potentially lead to confusion with other neoplasms if limited immunohistochemical panels are performed. (106) CD45RB (LCA [leukocyte common antigen]) expression may be weak to absent in up to 40% of ALCLs. The presence of EMA, and in rare cases, expression of keratin (particularly with immunostaining for KL-1), are features that suggest a carcinoma. (107,108) Approximately 70% to 80% of ALK+ ALCLs express CD99, an antigen also present in Ewing sarcoma and acute lymphoblastic leukemia; ALCL should be considered in the differential diagnosis of "small round blue cell tumors." (109-111) Expression of the (subunit of human chorionic gonadotrophin is present in rare ALK+ ALCLs. (112) Despite the CD4+, CD25+ phenotype in ALCL, there is no evidence of involvement by human Tlymphotropic virus (HTLV-1). (113)

Flow cytometric detection of ALCL can be problematic. Due to few large cells (focal nature of tissue involvement in some cases, fragility of large cells in processing, etc.) and scattering outside of the lymphocyte gate, flow cytometry results may be falsely reported as negative. (114,115) Myeloid antigen expression (CD13 and/or CD33) is detected in up to 90% to 100% of ALK+ ALCLs (approximately 33% have both) and in approximately 10% to 15% of ALK- ALCLs (58,115-119); along with the decreased expression of pan-T-cell antigens and weak expression of CD45RB (LCA), this finding may suggest the possibility of acute leukemia. Expression of other myeloid antigens, such as CD15 and CD11b, has been reported in fewer cases.

Diagnosis of Primary Cutaneous CD30+ Lymphoproliferative Disorders

Although skin involvement is a relatively frequent extranodal manifestation of systemic ALCL, by the late 1980s and early 1990s it was apparent that ALCL could be limited to the skin (primary cutaneous ALCL, C-ALCL), usually had an indolent course, and shared overlapping features with LyP. Owing to overlapping clinical and pathologic features, such as large cells with CD30 expression, C-ALCL and LyP are grouped together in the current WHO classification as CD30+ lymphoproliferative disorders (LPDs) and represent the second most common clonal T-cell proliferations in the skin. (19) The WHO and antecedent European Organization for Research and Treatment of Cancer classifications include LyP in the "T-cell lymphoma category," as clonality can be detected in approximately 60% of LyP cases and 5% to 15% can evolve to ALCL or mycosis fungoides (MF). (19,120,121) However, from the clinical perspective, LyP is not considered "malignant" and has an indolent course. Integration of clinical and pathologic features is essential in distinguishing ALCL and LyP. (122) Expression of ALK in CALCL is exceptional, is rarely reported, and has a cytoplasmic distribution. (123-126)

Clinical Features of C-ALCL.--Primary cutaneous ALCL is predominantly a disorder of adults, with a median age at diagnosis of approximately 50 to 60 years and a wide age range. (19) Most patients are older than 50 years. Primary cutaneous ALCL is rare in children, with an age range of approximately 13 months to 17 years at diagnosis. (127-131) Most of the cases previously diagnosed as regressing atypical histiocytosis are C-ALCLs. (132) Primary cutaneous ALCL usually presents as a solitary tumor or nodule that is often ulcerated and present on the extremities, face, or less frequently, the trunk. Presentation as eyelid masses in adolescents and children and facial lesions masquerading as posttraumatic maxillary sinusitis have been described (.45,133) Multifocal lesions are present in approximately 20% of cases and, more frequently, have extracutaneous spread (approximately 10% of patients). Spontaneous regression occurs in approximately 25% of patients with C-ALCL. Young adults with C-ALCL may have a history of childhood chronic atopic eczema. (134)

Treatment of C-ALCL is complete excision and/or local irradiation; low-dose methotrexate (10-25 mg weekly) is usually effective in persistent or multifocal disease. (135) The course is indolent with a 5-year disease-specific survival of 90% or more, but with a 30% to 40% relapse rate (5-year failure-free survival of 55%). (21) The new TNM classification of malignant tumors, as applied to 135 patients with CALCL, showed that the 5-year disease-specific survival was stage dependent: 93% for T1 (localized), 93% for T2 (regional), and 77% for T3 disease (generalized). Patients with generalized disease or T2 or T3 leg involvement had significantly worse 5-year disease-specific survival. (136) Rare C-ALCL with extensive limb disease--defined as disease involving a circular area of 15 to 30 cm, or greater than 30 cm in 1 or more contiguous body regions, or generalized multiple lesions involving at least 3 body regions--appears to have an aggressive course, with overall 5-year survival of 50%.137 Systemic disease must be ruled out with careful staging, as most skin lesions in systemic ALCL are associated with an aggressive course with a 5-year survival of approximately 30% to 45% (138,139;) however, rare patients with long-term survival and relapsing disease have been reported. (140) There are no specific or reliable tumor markers to distinguish systemic and C-ALCL. Some studies suggest that draining lymph node involvement by ALCL is not aggressive; nonetheless, most patients have received systemic chemotherapy. (141,142) Pediatric C-ALCL also has a high relapse rate, even in patients who have received chemotherapy; the course is still favorable without systemic spread. (127,129,141) Optimal therapy for pediatric C-ALCL is not known. Rare cases of cutaneous ALK+ ALCL with negative initial staging are ultimately associated with disseminated disease. (143) Long-term follow-up of patients with C-ALCL is necessary owing to the high relapse rate and the rare evolution to systemic disease. CD30+ LPDs of the oral mucosa include those with ALCL and LyP morphology and show overlap with traumatic eosinophilic granuloma; if limited to the oral cavity, CD30+ LPDs have an indolent course similar to that of C-ALCLs. (48,144)

Pathologic Features of C-ALCL.--Primary cutaneous ALCL is a CD4+ T-cell tumor composed of cohesive large anaplastic cells, with indented to slightly irregular nuclei and abundant pink cytoplasm, that are similar to those observed in systemic ALCL (Figure 5, A and B). (145) Approximately 20% of C-ALCLs have non-anaplastic large cell or variant morphology (including rare small cell variant). (139,141,145,146) Tumor cells spread diffusely throughout the dermis into the subcutaneous tissue, often showing a perivascular distribution with some infiltration and expansion, but not destruction, of the vessel wall. Reactive lymphocytes may be prominent, particularly at the periphery of the infiltrate, and acute inflammatory cells are often admixed, particularly with ulcerated lesions. Neutrophil-rich (or pyogenic) and eosinophil-rich variants with fewer large cells may be confused with a reactive process. (147-149) Approximately 25% to 30% of CALCLs are associated with pseudoepitheliomatous hyperplasia and have been initially misdiagnosed in adults as squamous cell carcinoma. (150,151)

Primary cutaneous ALCL has strong Golgi and membrane expression of CD30 in virtually every cell (Figure 5, C), with variable loss of pan-T-cell antigens and expression of cytotoxic proteins (TIA-1, granzyme B, and perforin). Primary cutaneous ALCL expresses cutaneous lymphocyte antigen, but even this marker is not specific, as recent studies152 have shown that cutaneous lymphocyte antigen can be present in the cutaneous lesions associated with systemic ALCL, even when the nodal tumor is negative for this antigen. Approximately 20% to 30% of C-ALCLs express EMA, (153) but expression is usually more focal and weak than typically seen in ALK+ ALCL. Anaplastic lymphoma kinase expression is highly associated with systemic disease; however, as mentioned earlier, rare cases of ALK+ C-ALCL have been reported. (123,125,126,154) Nuclear survivin expression seen in systemic ALK- ALCL is absent in C-ALCL (in the small number of cases tested) and could potentially be useful in distinguishing C-ALCL and systemic disease, (70,155) but the staining pattern may be antibody dependent. Punctate clusterin expression is seen in 41% to 100% of C-ALCLs (Figure 5, D). (93,98) CD56 expression is present in a subset of cases (wide range from 12% to 75%) but is not necessarily associated with a worse prognosis. (96,156) Approximately 65% to 80% of C-ALCLs, LyPs, transformed MFs, and cases of secondary skin involvement in systemic ALK- ALCL express TRAF1 and 70% to 100% express MUM1; therefore, these antigens have limited usefulness in distinguishing CALCL from LyP or systemic disease. (157-159) Fascin is expressed in 69% of C-ALCLs but also in 24% of LyPs and 60% of cutaneous lesions in systemic lymphoma. (160) CD30 may be strongly expressed in viral infection, and rare reports of patients with early varicella zoster infection and CD30+ pseudolymphomatous infiltrates have been described. (161) Destruction of the hair follicle with necrotic keratinocytes should prompt examination for multinucleated giant cells with ground-glass nuclei. (162) Clusters of CD30+ large cells are also present in drug eruptions, scabies infestation, and other reactive processes. (163)



An important consideration in the differential diagnosis of C-ALCL is transformed MF, which is CD30+ in approximately 20% to 25% of cases. (164,165) Anaplastic large cell lymphoma is principally distinguished by the lack of antecedent patch and plaque lesions and the absence of background cerebriform lymphocytes. If the clinical history is incomplete regarding the presence of MF type lesions, or if staging studies have not been performed, the diagnosis should be descriptive: "CD30+ lymphoproliferative disorder" with a comment stating the features are suggestive of C-ALCL; however, staging studies must be performed to rule out systemic disease, and the possibility of transformed MF should be mentioned.

Differentiating C-ALCL and LyP may be difficult and is principally based on clinical features (number and size of the lesions and time course) (122,166,167) and morphology, including the number and distribution of CD30+ large cells and the depth of invasion of the infiltrate. Lymphomatoid papulosis usually has crops of small papules and nodules that ultimately ulcerate and heal with a hyper-pigmented scar, usually within 1 to 3 months. The infiltrate is perivascular, wedge-shaped, and usually does not involve the subcutaneous tissue. In LyP, the CD30+ large cells are scattered or in small clusters of 5 to 10 cells. However, in LyP type C, larger clusters of CD30+ cells are present, and the lesions tend to be more persistent. If there is history of similar lesions with regression, a diagnosis of LyP type C should be strongly considered. (166) Primary cutaneous ALCL is more often solitary and larger than LyP (often greater than 2 cm) and shows progressive enlargement. Sheets and large clusters of CD30+ large cells are present in C-ALCL and often invade the subcutaneous tissue. Lymphomatoid papulosis rarely occurs in children, is often associated with atopy, and occurs earlier in boys but otherwise is similar to LyP in adults. (168) Approximately 5% to 15% of patients with LyP develop lymphoma, predominantly C-ALCL but also systemic ALCL. Differences in chemokine expression (CXCR3 [chemokine (C-XC motif) receptor 3] in 85% of LyPs and 8% of C-ALCLs and CCR4 [C-C chemokine receptor, type 4] in 92% of CALCLs and 15% of LyPs) may also be potentially useful in distinguishing C-ALCL and LyP but have not been evaluated in large numbers of cases. (169)


Dysregulation of ALK Tyrosine Kinase Through NPM and Other Variant Translocations

Anaplastic lymphoma kinase (CD246) is a transmembrane receptor tyrosine kinase (RTK) belonging to the insulin receptor superfamily. (170) Receptor tyrosine kinases contain a YXXXYY motif within the activation loop of their kinase domains, and phosphorylation of these tyrosines is essential for autoactivation and induction of downstream signaling. Anaplastic lymphoma kinase contains Tyr1278, Tyr1282, and Tyr1283, and NPM-ALK contains Tyr338, Tyr342, and Tyr343.171 Activation of the first tyrosine of the YXXXYY motif in the ALK activation loop is necessary for autoactivation of the ALK kinase domain and the transforming ability of NPM-ALK. Anaplastic lymphoma kinase is normally expressed in the central and peripheral nervous system and is involved in neuron differentiation, mitogenesis, and in midgut and neural tissue development. (172-174) The distribution overlap of ALK with members of the TRK neurotrophin RTKs suggests that ALK may be a receptor for neurotrophic factors such as the related proteins midkine and pleiotrophin. (170) However, there is evidence that ALK may be indirectly activated by pleiotrophin via inhibition of receptor protein tyrosine phosphatase ([beta]/[zeta] rather than by direct ligand binding to ALK. (175)

Aberrant expression and/or function of the ALK tyrosine kinase is known to promote tumorigenesis in several cancers. In addition to ALCL, ALK dysregulation has been reported in a rare, aggressive, large, EMA+, CD138+, CD20--, CD30--, EBV--, ALK+ diffuse large Bcell lymphoma, (176,177) a subset of non-small cell carcinomas, breast cancers,178 rhabdomyosarcomas, neuroblastomas, glioblastomas,170,175,179-182 a rare ALK+ systemic histiocytosis of uncertain malignant potential in infants, (183) and approximately 30% to 60% of inflammatory myofibroblastic tumors. (181,184-188) In malignant tumors, ALK is expressed as a mutated or amplified full-length protein. As seen in ALCL, ALK is more commonly expressed as a chimeric fusion protein created as a result of chromosomal translocation. (170) A recent study189 suggests that dysregulation of several genes (FRA2, ID2, and the CSF1 receptor gene), through unknown mechanisms, may create conditions favorable for the occurrence of translocations and contribute to lymphomagenesis. For example, ID2 regulates the expression of activation-induced cytidine deaminase, which mediates somatic hypermutation and classswitch recombination by introducing single-strand breaks into target DNA. Since ID2 is overexpressed in 70% to 80% of ALK+ and ALK- ALCLs, possibly via upregulation by myelocytomatosis oncogene MYC, (190) it is possible that ID2 stimulates aberrant expression of activation-induced cytidine deaminase, which would promote chromosomal translocations.

In approximately 80% to 85% of ALK+ ALCLs, an ALK translocation (2p23) occurs with NPM, a gene on 5q35 that encodes a carrier protein involved in shuttling newly synthesized proteins between the cytoplasm and the nucleolus. (191-193) Other translocation partners include non-muscle tropomyosin (TPM3, 1q25 and TPM4, 19p13.1); amino-terminus of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase gene (ATIC, 2q35); TRK-fused gene (TFG, 3q21), with 3 variants depending on the length (short, long, extra-long); clathrin heavy polypeptide gene (CLTC, 17q23); moesin gene (MSN, Xq11-12); myosin heavy chain 9 gene (MYH9, 22q11.2); and ALK lymphoma oligomerization partner on chromosome 17 (ALO17, 17q25). (17) An additional translocation, dic(2;4)(p23;q33) (dicentric), involving an unknown gene, has recently been described. (194) Inflammatory myofibroblastic tumors express ALK fusions with tropomyosin genes TPM3 and TPM4, CLTC, ATIC, and less frequently, RANBP2 (RAN-binding protein 2), CARS (cysteinyl-tRNA synthetase), and SEC31A (SEC-like 1) that are not expressed in ALCL. (181,184-187,195-197) A novel echinoderm microtubule-associated protein-like 4 (EML4)ALK fusion and a kinesin family member 5B (KIF5B)-ALK fusion have been identified in approximately 2% to 6% of non-small cell lung carcinomas. (180,198-203) However, recent studies204 have identified EML4-ALK transcripts, but not the fusion protein, in 5.9% of reactive lymphoid tissues and 20.7% of lymphomas that include diffuse large B-cell lymphoma, follicular lymphoma, and HL, indicating that these transcripts are not specific for non-small cell lung carcinoma.

The ALK genomic breakpoints in ALK translocations are almost invariably located in the intron flanked by exons 16 and 17, with exons 17 to 26 encoding the intracytoplasmic domain. The fusion gene is composed of the 5' end of the partner gene fused to proximal flanking regions and the ALK tyrosine kinase domain at the 3' end. The translocation partners provide a dimerization domain for homodimerization or heterodimerization, resulting in transphosphorylation-induced activation of the ALK catalytic domain, and thereby in the phosphorylation of adaptor proteins involved in multiple signaling pathways. The pattern of ALK expression correlates with the translocation genes involved, such that NPM-ALK, for example, is expressed in the nucleus (and nucleolus) (Figures 1, F, and 3, C) and cytoplasm, while CLTC-ALK staining is granular cytoplasmic (clathrin-coated cytoplasmic vesicles) (Figure 6, A and B) and TPM3-ALK is diffuse cytoplasmic with peripheral intensification, and MSN-ALK is membranous; the others show predominantly diffuse cytoplasmic staining.

NPM-ALK Affects Multiple Signaling Pathways and Cellular Processes

Signal transduction through NPM-ALK, the most well-studied ALK fusion protein, leads to proliferation, prolonged tumor cell survival, cytoskelet al rearrangement, and cell migration through activation of multiple pathways including JAK/STAT (Janus kinase/signal transducer and activator of transcription), PI3-K/AKT (phosphatidylinositol-3 kinase/AKT), MAPKs (mitogenactivated protein kinases), and PLCg (phospholipase C g) (Figure 7). (181,205-209) The interaction of NPM-ALK with these signaling pathways is either direct or through adaptor proteins containing SH2 (SRC homology 2) or phosphotyrosine-binding domains. (210,211) NPM-ALK has been shown to interact with insulin receptor substrate-1 (through Tyr156), SH2 domain-containing transforming protein (SHC) (through Tyr567), growth factor receptorbound protein 2 (GRB2), and CRK-like protein (CRKL), and p130CAS (CRK-associated substrate). (212,213) NPM-ALK also associates with Src kinase [pp60.sup.src,] although the downstream targets of NPM-ALK [pp60.sup.src] are unclear. (214) Proliferative effects are primarily the result of activation of cyclins and enhanced expression of genes such as FOS, JUN, and MYC. Activation of PLC[gamma] generates soluble inositol-1,4,5-triphosphates and membrane diacylglycerol, which activates protein kinase C (PKC) and leads to calcium mobilization and transmission of mitogenic signals. (210) However, the mechanism by which the PLC[gamma]/ PKC pathway signals proliferation remains to be elucidated. NPM-ALK signaling involves significant functional redundancy and cross-talk. For example, mutation of docking sites within NPM-ALK for SHC binding sites and insulin receptor substrate-1 does not affect transformation in vitro, and mutation of the PLC[gamma] docking site inhibits mitogenesis but not antiapoptotic signaling. (210)

NPM-ALK and JAK/STAT Signaling

JAK/STAT signaling mediates several cytokine-regulated functions such as cell growth, differentiation, and survival. Phosphorylated JAK proteins activate STATs, which, as transcription factors, mediate many of the mitogenic and antiapoptotic effects of ALK. (211,215) STAT3 is directly activated by NPM-ALK through JAK3. (216-218) Phosphorylated STAT3 dimerizes and translocates to the nucleus, where it increases the transcription of antiapoptotic molecules (B-cell lymphoma 2 [BCL2], B-cell lymphoma-extra large [BCL-xL], survivin, myeloid cell leukemia sequence 1 [MCL1]) and cell cycle regulators such as cyclin D3. (219-221) STAT3 also appears to regulate MYC, a potent oncogenic transcription factor that drives the expression of multiple genes associated with proliferation and survival. (222) Activation of MYC has been demonstrated in ALCL. (223,224) A role for NPM-ALK in regulating MYC is supported by a previous report, (225) which demonstrated that transfection of rat fibroblasts with NPM-ALK resulted in elevated expression of MYC. The importance of all of these downstream mediators (BCL2, BCL-xL, cyclin D3, survivin, MCL1, and MYC) was demonstrated in a study (222) that showed apoptosis and cell cycle arrest of ALK+ ALCL cells, with decreased expression of the mediators when STAT3 was selectively inhibited. STAT3 also upregulates the transcription factor CCAAT/enhancer-binding protein [beta] (C/EB[beta]), which is critical to NPM-ALK-driven proliferation and possibly survival. (219,226,227) C/EBP[beta] also promotes Th2 differentiation (228) and is involved in terminal differentiation of the monocyte/macrophage lineage, perhaps contributing to the aberrant expression of myeloid and histiocytic antigens such as clusterin, CD68, CD13, and CD33, as reported for ALCL. (99,106,119) STAT3 also promotes angiogenesis through expression of vascular endothelial growth factor-1. (229) Interestingly, activation of STAT3 has also been reported to occur through an autocrine stimulatory loop involving interleukin (IL)-22. ALK+ ALCL cells produce IL-22--which can activate STAT3, MAPKs, and AKT--as do normal activated T cells, but ALCL cells appear to also aberrantly express the IL-22 receptor, which is not present in normal lymphocytes. This pathway may also be operative in ALK- ALCL, as the IL-22 receptor 1 is expressed in the ALK- C-ALCL cell line MAC-2A. (230) STAT5B, which promotes cell growth, is also activated by NPM-ALK via JAK2, although the downstream mediators have yet to be elucidated. (215,231) Importantly, STAT5A (a potent tumor suppressor) (232) and the negative regulator of the JAK/STAT pathway, SHP1 (SH2 domain-containing protein tyrosine phosphatase 1), are epigenetically silenced via DNA methylation. (233,234)

NPM-ALK and PI3-K Signaling

Activation of PI3-K generates phosphoinositol 3,4,5-triphosphates, which ultimately activate PKB/AKT signaling. The PI3-K/AKT pathway regulates diverse cellular processes, such as growth factor signaling, cell growth, and apoptosis, through the mammalian target of rapamycin (mTOR), cyclin-dependent kinase (CDK) inhibitors p21 and p27, cyclin D1, p53, and by direct inhibition of proapoptotic molecules (BCL2 agonist of cell death [BAD] and the forkhead family of transcription factors). (235) For example, PI3-K/AKT pathway activation by NPM-ALK inhibits FOXO3A (forkhead box O3A), leading to increased cyclin D2 expression and decreased transcription of genes that promote apoptosis [BCL2-like 11 (BIM)] and that negatively regulate the cell cycle (p27). (236,237) The dual-specificity phosphatase CDC25A, which activates CDK2, a key regulator of the G1 phase and the G1/S transition, also appears to be activated through PI3-K/AKT or STAT3. (238) PI3-K/AKT- and MEK/ERK- induced activation of mTOR, particularly mTORC1 in ALCL, results in inhibition of proapoptotic BAD and also increases proteasomal degradation of p27. mTORC1 acts by directly activating p70S6 kinase 1 (a serine/threonine kinase that phosphorylates an S6 protein of the 40S ribosomal subunit to stimulate protein translation and ribosome biogenesis) and by phosphorylating/inactivating eukaryotic translation initiation factor 4E-binding protein 1 (a translational repressor that negatively regulates eukaryotic initiation factor 4E/4G). (237,239-241) The importance of PI3-K/AKT signaling in ALCL is underscored by studies demonstrating that PI3-K inhibition induces the apoptosis of lymphoma cells. (211,242)


PI3-K/AKT activation by ALK also induces signaling through the sonic hedgehog (SHH) pathway, which has been implicated in the pathogenesis of several malignancies including medulloblastoma, basal cell carcinoma, rhabdomyosarcoma, B-cell tumors, and ALCL. (243) Sonic hedgehog is a regulator of T-cell differentiation, T-cell receptor repertoire selection, peripheral T-cell activation, and an inhibitor of apoptosis in germinal center B cells. Sonic hedgehog interacts with 2 transmembrane proteins, patched and smoothened, which mediate ligand binding and signal transduction, respectively. Patched normally inhibits smoothened until it binds with SHH. The SHH signal is transmitted by the glioma-associated oncogene homologue (GLI) transcription factors, which can increase the expression of cyclin D2. Protein expression of SHH has been detected in 100% of ALK+ ALCLs and 85% of ALK- ALCLs, and GLI in 82.1% of ALK+ ALCLs but only 10% of ALK- ALCLs. (243) Amplification of SHH but not GLI1 has been detected by quantitative reverse transcription-polymerase chain reaction in 75% of ALK+ ALCLs and 60% of ALK- ALCLs, with fluorescence in situ hybridization confirmation of multiple copies of the SHH locus (7q36.2). The expression of GLI1 (12q13), without gene amplification, may be related to AKT-induced inactivation of glycogen synthase kinase 3 [beta] (GSK-3[beta]), which prevents proteasomal degradation of GLI1. Whatever the mechanism of increased GLI1, it most likely results in enhanced cyclin D2 expression and proliferation of lymphoma cells. The importance of the PI3-K/AKT/SHH signaling axis in ALCL is supported by the observation that inhibition of signaling through SHH results in decreased cell viability and induces cell cycle arrest in ALK+ ALCL cell lines. (243)


The MAPK signaling pathways are activated by RTKs and play a role in cell growth and differentiation. Although the specific components that trigger signaling vary according to the receptor, in general they include adaptor molecules linking the receptor to guanine nucleotide exchange factors (such as son of sevenless), which transduce signals from the receptor to small guanosine triphosphate (GTP)-binding proteins such as RAS, which then activate the core signaling mediators MEK1/2 and ERK1/2 (extracellular signal-regulated kinases 1/2). ERK1/2 appears to play a critical role in

the proliferation of ALCL cells. (209,244) NPM-ALK acts as a docking molecule for downstream adaptors--including insulin receptor substrate-1, SRC (sarcoma), SHC, and PLC[gamma]--that activate the RAS-ERK pathway. One of the key steps in lymphomagenesis appears to be the interaction of the SHP2 (PTPN11)/GRB2 complex with ALK through SHC to enhance phosphorylation of ERK1/2 via SRC and son of sevenless. (210,244,245) In addition, SNT-1/FRS-2[alpha] and SNT-2/FRS-2[beta] (Suc-1 and Suc-2-associated neurotrophic factor-induced phosphorylated target/fibroblast receptor substrates) are membrane docking proteins that normally mediate signaling from fibroblast growth factor receptor and nerve growth factor receptor TrkA to RAS and MAPK; NPM-ALK physically associates with SNT-1 and SNT-2. (246) Thus, it appears there is a redundant array of adaptor proteins that can mediate NPM-ALK-induced MAPK signaling.

Stress-activated protein kinases/C-JUN N-terminal kinase (JNK) are members of the MAPK family that are activated by environmental stress, inflammatory cytokines, and growth factors and play a role in cell growth/ survival; they have also been implicated in oncogenesis. Stress signals are transmitted through small GTPases of the Rho family (RHO, RAC, CDC42) to a membrane-proximal MAPK kinase, with ultimate activation of JNK and translocation to the nucleus, and subsequent activation of various transcription factors including C-JUN and JUNB. Introduction of NPM-ALK into HEK (human embryonic kidney)-293T cells has been reported to activate JNK. (247) C-JUN and JUNB are members of the JUN family of AP-1 (activator protein 1) transcription factors and are expressed in CD30+ LPDs including ALK+ and ALK- ALCL, C-ALCL, LyP, and HL. (248-250) Upregulation of AP-1 transcription factors induced by NPM-ALK via ERK1/2 and JNK leads to decreased p21 and increased cyclin levels, resulting in uncontrolled cell proliferation. (247) In addition, JUNB binds to an AP-1 site that normally represses the CD30 promoter, and it appears to relieve inhibition of expression and increase CD30 expression. (251) Recent studies (252) have shown that the CD30 promoter has a binding site for the transcriptional repressor YYI and that MYC can bind to YYI and prevent its repressive function; this may be the same mechanism JUNB uses to increase CD30 expression. Although it is unclear what role JUNB-mediated increases in CD30 expression play in the survival/proliferation of neoplastic cells, overexpression of NPM-ALK in mice results in B-cell lymphoma development, with marked JNK activation that appears to signal survival of neoplastic cells. (253) Constitutive ALK signaling may also lead to inactivation and/or JNK-induced MDM2 (murine double minute)-dependent degradation of p53 and the PI3-K-mediated exclusion of p53 from the nucleus. (254) Thus, reactivation of p53 by pharmacologic inhibition of JNK, PI3-K, and/or MDM2 activity may be a novel therapeutic modality for ALK+ ALCL.

WNT/[beta]-Catenin Signaling in ALCL

The WNT/ [beta] -catenin pathway regulates cell fate decisions during differentiation and development. Not many studies have investigated the role of the WNT/ [beta]-catenin pathway in T-cell lymphomagenesis. [beta]-Catenin is activated as a result of WNT binding to Frizzled receptors or by other pathways, such as through RTKs. b-Catenin accumulates in the cytoplasm and then is translocated to the nucleus, where it binds and activates members of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors, which upregulate the expression of genes involved in oncogenesis, such as MYC and CYCLIN D1. The tumor suppressor PTEN (phosphatase and tensin homolog) negatively regulates this pathway by inhibiting nuclear accumulation of [beta]-catenin and thereby, the activity of TCF/LEF; ablation of PTEN leads to increased nuclear accumulation of [beta]-catenin and TCF transcriptional activity. (255) Nuclear TCF-1/LEF-1 is expressed in T-lineage acute lymphoblastic leukemia (T-ALL) and some PTCLs-NOS, particularly those with a Th1 profile, (256) whereas T-cell lymphomas with a Th2 cell immunophenotype, such as ALK+ and ALK- ALCL, are TCF-1/LEF-1 negative. (256) Cutaneous ALCL is TCF/LEF negative but does have cytoplasmic expression of [beta]-catenin but no nuclear accumulation; it is unclear why this signaling pathway is disrupted. (257) The lack of nuclear accumulation of [beta]-catenin and loss of expression of TCF 1/LEF-1 is not likely due to PTEN, as 1 study (258) found partial or complete loss of PTEN in 66.7% of ALCLs compared to 12.5% of all other peripheral T/NK-cell tumors. Moreover, a small number of primary ALCLs and 4 ALCL cell lines were examined for PTEN deletions/ mutations and none were found. (259) Thus, the role that the WNT/ [beta]-catenin pathway plays in ALCL remains to be elucidated.

NOTCH Signaling in ALCL

NOTCH is a transmembrane heterodimeric receptor that plays an important role in thymic maturation and peripheral T-cell proliferation and survival. (260) NOTCH1, in response to binding its ligand Jagged1, enhances tumor cell growth and inhibits apoptosis. (261) Dysregulation of NOTCH is also prolymphomagenic. Approximately 50% of T-ALLs have mutations in NOTCH and 2% have t(7;9)(q34;q34.3) involving the TCR [beta] and NOTCH loci. NOTCH-1, and 1 of its ligands, Jagged, are strongly expressed in ALK+ and ALK- ALCLs and in HL, both in tumor cells and reactive bystander cells. This suggests that NOTCH signaling is activated by homotypic or heterotypic cell interactions. (261) One of the downstream targets of NOTCH is the HES (hairy enhancer of split) family of transcriptional repressors. Cell culture work has demonstrated activation of HES in ALCL and HL lines. Upregulation of NOTCH-1 leads to expression of D-type cyclins, which associate with CDK and facilitate cell entry into S phase. Normal activated T-cells upregulate cyclin D3, which targets CDK4 and CDK6 to drive the cells to proliferate. (262) T-ALL, MYC, TCF-1/LEF-1, and mTOR pathways have all shown cross-talk with NOTCH signaling; sustained activation of TCF/LEF target genes may push thymocytes to malignant transformation. (263-265) Indeed, there is evidence that NOTCH1 uses TCF/LEF to promote the survival of T-cell lymphomas. (263)

ALK+ ALCL and Epigenetic Silencing

Epigenetic silencing of various tumor suppressors and other genes by DNA methylation is a significant mechanism of malignant transformation in ALK+ ALCL. Silencing of p16(INK4a), a major inhibitor of cell cycle progression, promotes uncontrolled growth. (266) STAT3 promotes the epigenetic silencing, via enhanced expression of DNA methyltransferase, of the tumor suppressor SHP-1, a tyrosine phosphatase that regulates signaling through the TCR and cytokine/chemokine receptors, and fosters the ubiquitin-dependent degradation of ALK. (233,267,268) Although CD4+ T cells are normally a major source of TNF-[alpha], its expression is inhibited by promoter methylation that protects ALK+ ALCL from apoptosis despite the expression of TNFR1. (269) Interestingly, ALK- ALCL expresses TNF-a but lacks TNFR1, indicating that protection of ALCL from TNF-[alpha]-induced apoptosis may be critical to the development of this lymphoma. The nuclear factor of activated T cells (NFATC) family of proteins controls the transcription of cytokine genes and genes that regulate proliferation and apoptosis. NFATC1, which normally exerts a proapoptotic effect (but in the NFATC1/aA1 form is an oncogene), is silenced by promoter hypermethylation in ALCL. (270) NPM-ALK has also been shown to activate NFATC/AP-1 complexes (including C-JUN, FRA-1, JUNB, JUND, and C-FOS) that bind to a TRE (12-O-tetradecanoylphorbol-13-acetateresponsive element) region enhancer element in the promoter of genes such as IL-2, IL-4, IFN[gamma], CD25, CD40L, and FASL. (271) Thus, NPM-ALK induces a variety of effects via NFATC factors.

ALK-Mediated Cytoskelet al Abnormalities

Anaplastic large cell lymphoma is morphologically a very pleomorphic tumor with clinically high-stage disease affecting extranodal sites. This suggests that ALK may induce cytoskelet al abnormalities that lead to an abnormal cytologic profile and a propensity for tumor spread. For example, in ALK+ ALCL, upregulation of centrosome and microtubule-associated proteins (CEP250, mitotic kinesinlike protein, and microtubule-associated protein 4) and an abnormal centrosome size may be associated with large nuclei and frequent multinucleation. (272,273) Indeed, transfection of NPM-ALK into fibroblasts or lymphoma cells induces morphologic changes resembling ALCL or promotion of neurite growth, depending on the cell type. (173,274) Cytoskelet al changes are mediated through signaling to G protein-coupled receptors that relay signals from membrane receptors (such as integrins or RTKs) via proteins that exchange guanine nucleotides on RAS and activate signaling through the MAPK pathway. The VAV3 or VAV1 guanine nucleotide exchange factors may be a direct substrate for phosphorylation/activation by NPMALK or be indirectly phosphorylated by the NPM-ALK-associated adaptor molecules GRB2 and p130CAS. (213) Phosphorylated VAV then activates the RHO family of GTPases (RAC, RHO, and CDC42), resulting in changes in actin filament depolymerization and loss of cell-matrix adhesion, which may contribute to the unusual sinus growth pattern of this lymphoma. Indeed, RHO GTPases mediate many cellular effects including proliferation, cell survival, polarity, adhesion, membrane trafficking, and motility. (275) Vasodilator-stimulated phosphoprotein, a protein that appears to be involved in regulating actin polymerization, is also associated with and phosphory lated by ALK. (276)

Interestingly, various ALK fusion proteins have shown differences in invasive properties, which may be due to differences in signaling. (277) In particular, studies with the TPM3-ALK fusion protein have shown increased invasive properties and metastatic potential. TPM3-ALK apparently induces the strongest activation of the PI3-K/AKT pathway and migratory capacity in vitro; however, in vivo, tumorigenicity is less than with NPM-ALK. These variations in signaling and tumorigenicity may arise from variable subcellular localization of activated ALK, altered sequences of tyrosine autophosphorylation, differences in kinase substrate specificity, and other mechanisms. (278) More studies are needed to elucidate various signaling differences among ALK fusion proteins for therapeutic targeting.

Proteomic Studies of ALCL

Proteomic studies have identified alterations of proteins or adaptor molecules involved in ALK signaling. Changes in proteins may represent a neoplastic phenotype but may either lack a pathogenetic role (referred to as "passengers") or be pathogenetically relevant (referred to as "drivers"); the latter changes are ideal therapeutic targets. Proteomic strategies have validated previously recognized ALK signaling pathways and identified new interacting molecules that may mediate ALK signaling. These ALK interacting molecules modulate protein phosphatases, upregulate downstream targets of the mTOR pathway that are involved in ribosome biosynthesis and translation (ribosomal S6 kinase, translational initiation factor elF4, ribosomal protein L11, eukaryotic translation initiation factor 3, translation initiation factor IF-2 homolog, and translation initiation factor elF-2[alpha]), and regulate cytoskelet al molecules such as the focal adhesion protein paxillin as well as the adaptor scaffold GRB2. (272,279-286) NPM-ALK also directly interacts with and phosphorylates several RNA/DNA binding proteins such as polypyrimidine tract-binding protein-associated splicing factor (PSF), the nuclear RNA-binding protein 54 kDa ([p54.sup.nrb),] and EWS (expressed in Ewing sarcoma). (285) PSF forms multiprotein complexes involved in pre-RNA splicing, gene transcription, DNA repair, DNA recombination, and cytoplasmic RNA stability. (285) Tyrosine phosphorylation of PSF by NPM-ALK appears to inhibit its function. (285) Another molecule, nuclear interacting partner of ALK, is activated by NPM-ALK and other ALK fusion proteins and facilitates mitotic entry in the cell cycle. (287-289) Proteomic analysis has also shown association of NPMALK with molecules involved in DNA repair (Ku86, Ku70, PARP1 [poly(ADP-ribose) polymerase 1], MSH2, PCNA [proliferating cell nuclear antigen], and MCM6 [mini-chromosome maintenance deficient 6 homolog]) (283) and has revealed other new binding partners for NPM-ALK, including Nup98 and importin 8 (subcellular protein transport), Stim 1 (calcium signaling), and 82FIP (RNA regulation). (283) While proteomic studies have yielded a wealth of proteins that interact with ALK, considerable work remains to identify the key mediators that drive ALCL lymphomagenesis.

Additional Pathogenic Mechanisms in ALCL

Another potential oncogenic mechanism in ALK+ ALCL is the enhancement of ribosome stability, particularly for synthesis of molecules upregulated by ALK signaling, such as PLC[gamma], PI3-K, and STAT3. Anaplastic lymphoma kinase binds to and phosphorylates AUF1/ hnRNPD, a member of the AU-binding protein family, (284) which regulates the cellular half-life of many messenger RNAs (mRNAs) by directly interacting with an AU-rich element (ARE) located in the 3' untranslated regions of genes. Many ARE-containing RNAs are transcribed from proto-oncogenes (such as MYC), cytokines, cyclins, and growth factors. Thus, AUF1 phosphorylation by ALK can potentially result in the increased stability of mRNAs for a variety of oncogenes. NPM-ALK has also been shown to modulate or associate with molecules involved with the ubiquitin-proteasome machinery, such as heat shock protein 90, heat shock protein 70, RanBP2, SUMO E3 ligase (small ubiquitin-like modifier), BAG2 (BCL2-associated athanogene 2), and ubiquitin carboxy-terminal hydrolase. (272,283,290,291) Such associations may favor protumorigenic signaling. Indeed, NPM-ALK is unstable and rapidly undergoes proteasome degradation, but interaction with heat shock protein 90 is protective. (291)

NPM-ALK is entirely intracellular and lacks an extracellular domain. Recent evidence suggests that the IGF-1R (type 1 insulin-like growth factor receptor) tyrosine kinase may function as an extracellular domain for NPM-ALK that maintains its phosphorylation at Tyr646 and Tyr664, thereby sustaining its ability to transduce signals. (292) Indeed, inhibition of IGF-1R decreases STAT3 activation and induces apoptosis and cell cycle arrest. Interestingly, NPM-ALK phosphorylates IGF-IR, suggesting a novel reciprocal functional interaction between the 2 molecules. All ALK+ ALCL cell lines and approximately 60% of clinical ALCL samples express IGF-1R. (292)

Yet another ALK-mediated protumorigenic mechanism involves purine synthesis. Actively dividing neoplastic cells rely heavily on de novo purine synthesis to generate purine nucleotides for DNA synthesis rather than on the salvage pathway used by normal cells. AICAR transformylase IMP cyclohydroxylase is a bifunctional enzyme that catalyzes the final 2 steps of de novo purine synthesis. The cryptic inversion inv(2)(p23q35) results in an ATIC-ALK fusion in a small subset of ALCLs. ATIC is folate dependent and potentially a target of methotrexate therapy; however, phosphorylation by ALK would enhance ATIC enzymatic activity and increase methotrexate resistance. Interestingly, using a high throughput proteomic analysis of ALCL cell lines that focused on tyrosine phosphopeptides, Boccalatte et al (276) showed direct phosphorylation of ATIC by ALK as a general effect of ALK signaling and not just as it related to the specific inv(2)(p23q35).

Abnormal Immune Regulation in ALCL

ALCL Is an Activated T Cell With Aberrant Antigen Signaling.--Normal activated T cells regulate morphology and cytoskelet al rearrangement through a signaling cascade beginning with phosphorylation of the immunoreceptor Tyr-based activation motifs (ITAMs) present in the TCR-associated CD3 chains. The phosphorylated ITAMs recruit ZAP-70 ([zeta]-chain-associated protein kinase 70), which is then phosphorylated by LCK. ZAP-70 then phosphorylates SRC homology 2 domain-containing leukocyte proteins of 76 kDa (SLP76) and linker for activation of T cells (LAT). Ultimately, LAT and SLP76 complexes activate guanine nucleotide exchange factor VAV, which is linked to the activation of RHO family GTPases. Anaplastic large cell lymphoma is a tumor of activated (CD25+, CD30+, CD45RO+, HLA-DR+) T cells, with signaling through RHO-GTPases by ALK activation of VAV1 and CDC42. (213,293,294) Despite the T-cell genotype, many pan-T-cell antigens are not expressed (particularly CD3), and there is aberrant signaling through the T-cell receptor. In the early 1990s, decreased expression of CD3 and other T-cell antigens in ALCL was noted, leading to use of CD43 or CD45RO to confirm a T-cell phenotype. (103) Bonzheim et al (102) identified loss of the [alpha] [beta] T-cell receptor protein and signaling molecule ZAP-70. Recent studies have shown even broader defects in T-cell signaling, with decreased expression of other signaling molecules such as LAT (through DNA methylation and inhibition of transcription) and hypermethylation of CD3e, ZAP-70, and SLP76. (295) Normal activated effector T cells eventually undergo apoptosis through activation-induced cell death and the FAS-dependent pathway. Although ALCL shows strong expression of FAS, there is resistance to apoptosis, (296) which may be partially related to lack of an intact T-cell receptor signaling pathway.

CD30 Signaling Has Variable Effects on Apoptosis and Proliferation.--CD30, located at 1p36, codes for a member of the tumor necrosis factor receptor (TNFR) superfamily (TNFRSF8) that lacks the intracellular death domain. CD30 mediates signals through TNFR-associated factors (TRAFs). CD30 is normally expressed on activated T cells. The function of CD30 engagement is variable, with stimulation resulting in the induction of cell proliferation in some cell types and apoptosis in others. (297) Trimerization of CD30 leads to the activation of the MAPK pathway and NF-[kappa]B, resulting in expression of IL-2, IL-6, IL-8, IL-12, and granulocyte colony-stimulating factor and other proteins. The effects of CD30 stimulation on the apoptosis of ALK+ ALCL cells appears to depend on how CD30 is stimulated. In most studies, CD30 activation in ALCL decreases proliferation and induces cell cycle arrest (298-301) and apoptosis. However, CD30 stimulation triggers 2 competing effects: the upregulation of proteins involved in apoptosis and the activation of NF-[kappa]B. It was recently reported that genome-wide expression array analysis of CD30 activation in ALCL cell lines showed upregulation of genes involved in signal transduction, cytokine genes, and immune response/apoptosis-related genes; 41 of the top 208 upregulated genes are reported to be NF-[kappa]B related. (302) However, although apoptosis-inducing genes such as TNF-[alpha] and TNF-related apoptosis-inducing ligand are highly expressed, the cells are likely protected from apoptosis due to expression of the caspase-8 antagonist cFLIP (cellular FLICE inhibitory protein), the caspase inhibitor cIAP2, and the antioxidant enzyme manganese superoxide dismutase. (302) The same study demonstrated that stimulation of CD30, combined with stable transfection of a dominant negative NF-[kappa]B inhibitor, leads to the induction of caspase-3, caspase-8, caspase-9, and BID, resulting in massive apoptosis. This suggests a potential therapy that combines a stimulating anti-CD30 antibody with NF-[kappa]B inhibitors.

Suppression/Modulation of the Immune Response.--NPM-ALK signaling appears to have a negative regulatory effect on the immune system via inhibition of the antitumor inflammatory response. STAT3 activation by NPM-ALK leads to the binding of STAT3 to the CD274 (PD-L1, B7-H1) promoter, leading to the expression of this highly immunosuppressive protein. (303) CD274 and CD272 (PD-L2 or B7-DC) are ligands for PD-1 (programmed cell death-1) (CD279), which is expressed by activated CD4+ and CD8+ T cells and associates with the TCR-CD3 complex to transduce an inhibitory signal after ligand binding; this induces T-cell tolerance during the immune response. Therefore, activation of this pathway by NPMALK could be a mechanism by which ALCL tumor cells evade the immune system. Similarly, NPM-ALK has other immune inhibitory effects, including induction of the anti-inflammatory cytokines IL-10 and transforming growth factor b (TGF-b) (304) and inhibition of TNF-a production via methylation of its promoter. In addition, Gal-1, an immunoregulatory carbohydrate involved in T-cell survival, is expressed in an AP-1-dependent manner after activation of C-JUN in ALK+ and ALK- ALCLs. (305) Gal-1 appears to mediate its effects by inhibiting Th1- and Th17-mediated responses and favoring a Th2 response, which may inhibit the initiation of effective cellular immunity against ALCL. Serpin A1, a secretory glycoprotein involved in the modulation of inflammatory responses, is also expressed in ALK+ ALCL and can inhibit granzyme B-mediated killing, thereby protecting tumor cells from cytotoxic T and NK cells; expression of serpin A1 correlates with metastases and extranodal disease. (306)

Molecular Profiling of ALK+ and ALK- ALCL

Gene Expression Profiling.--Gene expression microarray profiling of ALK+ and ALK- ALCL has been performed by several groups. The initial study by Thompson et al (307) found that ALK+ ALCL overexpresses genes encoding signal transduction molecules such as SYK, LYN, and CDC37 and underexpresses transcription factors such as HOXC6 and HOXA3; both ALK+ and ALK- ALCL highly express kinase genes (LCK, protein kinase C, VAV2, and NKIAMRE) and antiapoptotic molecules. In addition, cyclin D3 was overexpressed in the ALK+ group, and the cell cycle inhibitor p19INK4D was decreased in the ALK- group, suggesting different mechanisms of cell cycle regulation (Gl/S transition). (307) French investigators demonstrated that nodal PTCL-NOS and ALCL could be distinguished at the molecular level (308) and found that BCL6, PTPN12, CEBPB, and SERPINA1 genes were differentially expressed in ALK+ ALCL, and CCR7, CNTFR, IL-22, and IL-21 in ALK- ALCL. (309) Gene ontology analysis of biologic processes, cellular components, and molecular functions associated with gene products demonstrated that the ALK+ ALCL profile was related to immunologic functions with overrepresentation of pathways involving leukocyte transendothelial migration, focal adhesion, and adherens junctions. The ALK+ tumors were also shown to have different expression profiles based on variant morphology (common versus small cell); in particular, ALCL with variant morphology overexpressed genes involved in cell cycle regulation and proliferation, and genes encoding proteins involved in adhesion and migration. The variant histology group also showed upregulation of biochemical pathways, reflecting a hyperactive metabolic state.

Using microdissected tumor cells, Eckerle et al (23) found that few genes were differentially expressed between systemic ALK+ and ALK- ALCL and primary cutaneous ALCL, suggesting that these tumors are pathogenetically related and that the microenvironment may influence the clinical course (aggressive versus indolent). Differentially expressed genes in ALK+ ALCL compared with ALK- ALCL were predominantly related to signaling pathways activated by ALK gene dysregulation. Numerous NF-[kappa]B genes were expressed at higher levels and many T-cell-specific molecules were down-regulated. Profiling of ALK+ ALCL and ALK- ALCL by The International T-Cell Lymphoma Project, and comparison with AITL, adult T-cell leukemia/lymphoma, and PTCL-NOS, revealed that ALK+ ALCL could be separated from these entities at the molecular level. (310) Differentially expressed genes in ALK+ ALCL included genes encoding classical ALCL markers (ALK, CD30, MUC1 or EMA), immunoregulatory cytokines (IL-26, IL-31RA, IL-9, IL-1R2), Th17 cell-associated molecules (IL-17A, IL-17-F, ROR[gamma]), proliferation associated molecules (CCNA1, AGT, PDE4DIP, UPK1B, CDC27), STAT3-regulated targets (SERPINB3, SERPINB4, SOCS1, SOCS3), genes identified in other tumors (RRAD, RAR[alpha], NRCAM, TMEM158, CA12), cytotoxic molecules (PRF1, GZMB), and immunosuppressive response molecules (LILRA3). Interleukin 26, IL-31RA, and IL-9 are immunoregulatory cytokines/receptors regulating STAT3 (IL-26, IL-31RA) and JAK3 (IL-9) activation. As noted in other studies, expression of TCR components and molecules involved in TCR signaling or activation was decreased. ALK- ALCL did not form a unique consensus cluster, although there were differences with ALK+ ALCL and PTCL-NOS. As with ALK+ ALCL, TCR signaling molecules were decreased and IL-20 and IL-9 were highly expressed, but the STAT3 target signature was not detected in ALK- ALCL. In contrast to ALK+ ALCL, there was also lower expression of cytotoxic molecules, cathepsins, and Th17 cell-associated molecules, and higher expression of some cytokines/receptors (CCL1, CCL22, CCR8, CCR4, IL-13RA2, CXCL14, TGF-bR1) and antiapoptotic molecules (BCL2, BIRC6, BIC), and lower expression of some proapoptotic genes (BAX, BCL2L1, BNPIP3). The authors of this study suggested that the Th17 differentiation profile might result from abnormal cytokine secretion.

Using ALK+ ALCL cell lines with silenced expression of ALK and STAT3, Piva et al (24) demonstrated that two-thirds of ALK-regulated genes were dependent on STAT3 expression. Gene expression microarray profiling of primary ALCL and other systemic primary T-cell lymphomas (AITL and PTCL-NOS) showed a distinct cluster for ALK+ ALCL. Cluster analysis revealed that a limited set of genomic classifiers (14 genes including IL-1RAP, GAS1, PRF1, TMEM158, and IL-2R) could distinguish ALCL from PTCL-NOS and normal T cells, regardless of ALK status. In addition, 30 genes (only a few were regulated or associated with ALK signaling) were differentially expressed in ALK+ and ALK- ALCL, which suggests a common pathogenesis for ALCL in general. Gene ontology and gene set enrichment analysis of commonly expressed genes in ALK- and ALK+ ALCL suggest common pathways of lymphomagenesis, including loss of T-cell signaling, hypoxia, and a mitochondrial signature. A subset of ALK- ALCLs expressed some ALK-associated proteins such as phospho-STAT3 and/or C/EBP[beta]. In the future, this "ALCL signature" may be useful in separating ALK- ALCL from PTCL-NOS. Taken together, gene expression microarray profiling data show that, regardless of ALK status, ALCL is different from PTCL-NOS. These data support the current WHO classification of ALCL.

Comparative Genomic Hybridization.--Conventional comparative genomic hybridization (CGH) analysis has identified secondary genomic imbalances in more than 50% of ALK+ ALCLs, with the specific chromosomal abnormalities being somewhat variable in the limited number of cases investigated. (311,312) Loss of 11q or 13q has been reported in ALK+ and ALK- ALCLs in approximately 15% to 30% of cases. Loss of chromosome 4q13q21313 and of chromosome arms 9p and 10p311 are reported in ALK+ ALCLs. (311-313) Gains of 7p and 6p (311) and 17p and 17q have been reported in ALK+ ALCL. (313) Although loss of 13q and gain of 17q are commonly present in other Tcell lymphomas, other numerical abnormalities, such as loss of 9p21-pter, 5q21, or 12q21-22 seen in approximately 30% of PTCLs-NOS, have been detected in fewer than 5% of ALK- or ALK+ ALCLs.

Submegabase resolution tiling array CGH performed on ALCL cell lines DEL and SR-786 revealed gains in 5p15.32 p14.3, 20p12.3-q13.11 and 20q13.2-q13.32 and losses in 18q21.32-18q23. (314) Using 1 megabase-resolution array CGH, a British study of pediatric ALK+ ALCL (315) revealed that regions of genomic gain were far more frequent than regions of loss and were most often found on chromosomes 1 to 4,5 to 12,14, and 17, with the highest number of gains (92.9%) seen in chromosome 11, predominantly in the 11q12-13 region and in chromosome 7q36.3 (66.7%). Regions of loss were not associated with known tumor suppressor genes, such as RB1 or TP53 or CDKN2A.In fact, TP53 at 17p13.1 was gained in 40% of cases; interestingly, most of these cases were associated with gain of the negative regulator of TP53, MDM4 on 1q32.1, and of the region encoding the retinoblastoma binding protein 5 (RBBP5). The median number of total genomic imbalances was 14, with a range of 2 to 40. Correlation with clinical data showed improved survival for pediatric patients with lower numbers of genomic imbalances (survival of 85% compared to 40% at 3 years, when tumors harbored less than 14 gains or more than 14 gains, respectively). In contrast, in 2008, using lower-resolution conventional CGH analysis of both adult and pediatric ALCL patients, Salaverria et al (313) did not find prognostic significance in copy-number abnormalities. Gains included regions containing genes previously described to be affected in ALCL, such as survivin (BIRC5) (17q25.3), HRAS (11p15.5), and HOXB (17q21.32). Patients whose tumors had gains containing the BIRC5 gene and the DNA damage-binding protein (DDB1) gene (11q12.2) had inferior survival, but the study was limited to small numbers of patients. Survivin, a member of the inhibitor of apoptosis family, is thought to be inhibited by TP53, and its increased expression may be due to inhibition of TP53 by NPM-ALK in a MDM2- and JNK-dependent manner. (254)


Primary cutaneous ALCL may arise de novo or as part of the spectrum of LyP. Studies have compared the 2 entities to gain insight regarding the pathogenesis of ALCL. Loss of TGF-[beta]-induced lymphocyte growth inhibition has been demonstrated in C-ALCL, due to a dominant negative mutation of the TGF-[beta] type II receptor or deletion of the initiating sequence for translation of the type I receptor transcripts; this observation suggests that altered TGF-b/SMAD signaling may play a role in the progression of LyP to ALCL. (316-318) NOTCH and its

ligand Jagged (but not Delta) are expressed in C-ALCL as well as in ALK+ and systemic ALK- ALCL, and to a lesser extent in LyP. (319) As mentioned earlier, NOTCH signaling upregulates D-type cyclins, which ultimately promotes proliferation. Thus, upregulation of NOTCH and Jagged may also play a role in the progression of LyP to ALCL.

Homing of T cells to the skin is mediated by interactions of chemokines and their receptors and by adhesion molecules; in particular, cutaneous lymphocyte antigen and CCR3 (and its ligand, eotaxin [CCL11]) are important mediators of homing. (320) Interestingly, chemokine/chemokine receptor interactions appear to also have roles in tumor survival. Anaplastic large cell lymphoma has a Th2 cytokine receptor profile with expression of CCR3 and CCR4 and production of IL-4 but not IFN[gamma]. The expression of CCR3 and its ligand, RANTES (regulated upon activation, normal T-cell expressed and secreted), in cases of C-ALCL without regression, suggests the presence of an autocrine loop that may play a role in tumor cell growth. In contrast, LyP, particularly type B, expresses chemokine receptor CXCR3, which is suggestive of a Th1 profile and is associated with spontaneous regression. (169,320,321) Modulation of HOX genes also affects the adhesive and homing properties of lymphocytes. Messenger RNA expression of all 3 HOX genes (HOXC4, HOXC5, and HOXC6) has been detected in ALCL and C-ALCL, with HOXC5 being most strongly expressed in C-ALCL, (322) suggesting a role in the cutaneous location of this tumor.

Analysis of death-receptor signaling in C-ALCL has revealed defects in the proapoptotic pathways of TNF-[alpha] and TRAIL (TNF-related apoptosis-inducing ligand), which promote the survival of this neoplasm. The loss of expression of TNFR1 explains TNF-[alpha] unresponsiveness, and resistance to TRAIL may be due to overexpression of the antiapoptotic protein c-FLIP and frequent loss of the proapoptotic protein BID. Indeed, CD30 ligation leads to an NF-[kappa]B-mediated increase in c-FLIP. (323) Although CD95 (FAS) is uniformly expressed in LyP and C-ALCL, (324) inhibition of this pathway may also be secondary to upregulation of c-FLIP. (296) Recent studies in cutaneous Tcell lymphoma cell lines325 have also demonstrated that defects in T-cell receptor signaling (in particular, phospholipase C-[gamma]1 activity) abrogate expression of CD95L (FAS ligand), which is normally induced as part of activation-induced cell death. BCL2 has been reported to be variably expressed in LyP (approximately 30%-40%), C-ALCL (approximately 20%-60%), and CD30+ transformed MF (approximately 70%). (155,157,324) On the other hand, CD30 ligation can also have antiproliferative effects. Indeed, CD30 ligand is expressed in C-ALCL and may play a role in LyP lesions that undergo regression. (326) The expression of certain proapoptotic proteins and lack of expression of antiapoptotic proteins in LyP and C-ALCL might also explain their low-grade behavior and tendency to undergo regression. For example, the expression of the proapoptotic BAX (BCL2-associated X protein) is higher in LyP and C-ALCL than in systemic ALCL, (327) and fewer than 5% of the cells in LyP and C-ALCL express the prosurvival proteins BCL-xL and MCL-1.

Elucidation of the role that viruses or other microbes, such as chlamydiae, play in the pathogenesis of C-ALCL, via their interaction with Toll-like receptors (TLRs), is in the early stages. However, TLR-2, TLR-4, and TLR-7, but not TLR-9, are strongly expressed by neoplastic cells in CALCL and LyP, in approximately 55% to 75% of cases. (328) Since recent studies suggest that Toll-like receptors can stimulate T-cell proliferation, (329,330) it is reasonable to speculate that microbes might play a role in enhancing the proliferation of C-ALCL and LyP. Although initial studies in the late 1980s and early 1990s suggested a role for EBV in the pathogenesis of ALCL, many of these studies were based on polymerase chain reaction assays that probably detected EBV latent infection or included cases of CD30+ diffuse large B-cell lymphoma. (331-334) It is unlikely that EBV has a role in the pathogenesis of ALCL in patients with a normal immune system. The CD4+, CD25+ phenotype of ALCL suggests the possibility of human T-lymphotropic virus type 1 infection, but recent analysis of childhood ALCL for this virus has yielded negative results. (113)

Recurrent translocations involving multiple myeloma oncogene 1/interferon regulatory factor 4 (MUM1/IRF4) (located on 6p25) have been detected by fluorescence in situ hybridization in C-ALCL (57% of cases tested), rare PTCL-NOS (5%), and systemic ALK- ALCL (4%). (335) In PTCL-NOS, IRF4 translocation involved the T-cell receptor [alpha] locus (14q11.2); the translocation partner was not identified in C-ALCL. Half of the patients with IRF4 translocation had lymph node disease 1 to 126 months after diagnosis and had persistent disease, with 1 death at follow-up. Only 1 case of C-ALCL with no IRF4 translocation was associated with nodal disease. As mentioned earlier, MUM1 protein expression is common in C-ALCL and ALK+ and ALK- ALCL, making the biologic significance of IRF4 translocation uncertain at the present time.

Molecular Profiling of C-ALCL

The genetic events involved in C-ALCL and other cutaneous lymphomas are largely unknown. Similar to systemic ALCL, C-ALCL is distinct from primary cutaneous PTCL-NOS. Cytogenetic analysis of C-ALCL has revealed recurrent copy-number alterations including gains on 6p, 7q, and 19 and losses on 6q, 9, and 18. (311,336-339) Array CGH studies have shown gains of large regions of chromosomes 7 (including 7q31, the location of the MET oncogene) and 17 (including 17p13, the location of TP53) in both C-ALCL and primary cutaneous PTCL-NOS. However, C-ALCL is distinguished by additional losses on chromosomes 6 (including 6q16-6q21, the location of PRDM1/BLIMP-1 that encodes a transcription factor involved in T-cell homeostasis and differentiation) and 13 (including FOXO1A and BRCA2 on 13q12-13q14). Peripheral T-cell lymphoma NOS is distinguished by gains on chromosome 8 (including 8q22-8q24.2 containing MYC) and losses on 9p21 (containing p16/CDKN2A, tumor suppressor gene) (336,340,341); concurrent gene expression analysis showed higher expression of skin-homing chemokine receptors CCR10 and CCR8 on C-ALCL, which potentially explains the lower tendency of C-ALCL to disseminate. In addition, compared to primary cutaneous PTCL-NOS, C-ALCL had high expression of IRF4/MUM1, TNFRSF8/CD30, and TRAF1, involved in regulation of apoptosis, and decreased expression of CDKN2C/p18. Although expression of TRAF protein was not detected in C-ALCL in a previous immunohistochemical study, (159) which suggested possible dysregulation of TRAF signaling and inhibition of NF-kB activation, a more recent study157 found TRAF expression in C-ALCL, LyP, transformed MF, and secondary skin involvement in systemic ALCL in 65% to 80% of the cases. Peripheral T-cell lymphoma NOS has higher expression of PRKCQ (protein kinase C 0), which regulates survival after T-cell activation) and FYN and decreased expression of FAS and Caspase 10, which would lead to proliferation and loss of apoptosis and a more aggressive disease course.

Amplification of JUNB (19p13) is reported in 70% of C ALCLs, and JUNB protein expression is present in virtually all cases, which might promote tumor cell survival via its upregulation of CD30 and thereby, NFkB activation. (337,342) JUNB protein expression may be further upregulated by constitutive CD30 signaling, which has been reported to induce a MAPK-mediated increase in JUNB that activates the CD30 promoter, creating an autocrine loop that is not present in normal cells owing to the weak expression of CD30. (251) Interestingly, overrepresentation of certain polymorphisms in the CD30 promoter microsatellite repressor element in patients with LyP and C-ALCL suggests a predisposition for developing CD30+ LPD in individuals carrying such genetic variations. (343)


Novel therapies for ALCL and other ALK+ tumors are being investigated. Small-molecule inhibitors of ALK are

in development. (170,278,344-346) PF-02341066, an inhibitor of cMET, has significant anti-ALK activity and is in clinical trials. (347) Potentially, mutations in the ALK kinase domain could confer resistance to tyrosine kinase inhibitors; therefore, mutant ALK molecules are being tested. (346) Targeting ALK signaling pathways is another avenue for therapeutic agents. Flavopiridol, an inhibitor of cyclindependent kinases that result from ALK activation, is effective against ALCL cell lines. (348) The monoclonal antiCD30 antibody-drug conjugate containing monomethyl auristatin E, SGN-30, has been tested in refractory/ relapsed ALCL and has shown little toxicity but, unfortunately, modest clinical activity. (349,350) A fully humanized anti-CD30-specific ribonuclease fusion protein has shown growth inhibition of the ALCL cell line Karpas 299. (351) Inhibition of the sonic hedgehog signaling pathway (SHH/GLI1) leads to apoptosis and cell cycle arrest; inhibition of SHH/GLI1 signaling would theoretically be effective in combination with ALK inhibitors. (278) ALK+ ALCL frequently expresses nonmutated p53, which is functionally inactivated or degraded in a JNK- and MDM2- dependent manner or excluded from the nucleus in a PI3-kinase-dependent manner. (254,352) Nutlin-3a, an MDM2 inhibitor, has shown apoptotic activity in ALK+ ALCL cell lines through reactivation of p53 or possibly other tumor suppressors such as p73. (254,352) Targeting of CDC25A phosphatase (an activator of CDK2) may provide another therapeutic approach. (238) Recently, a small-molecule kinase inhibitor (GSK 1838705A), which is a modulator of IGF-1R signaling, has been shown to inhibit ALK and promote complete regression of ALK-dependent tumors in vivo. (353) Pediatric ALCL is not associated with frequent activation of antiapoptosis genes, such as survivin, or expression of tissue inhibitor of met alloproteinase-1 inhibitors, as seen in adult ALCL, and different therapies may be indicated. (354)

Finally, vaccination of patients with a DNA-based vaccine against ALK would be potentially useful, as ALK is not normally expressed except in the central nervous system, an immunologically privileged site. Anaplastic lymphoma kinase is immunogenic, as demonstrated by the presence of anti-ALK antibodies in 95% of patients with ALK+ ALCL. (355,356)


Despite being an uncommon neoplasm, in just 25 years ALCL has emerged as a distinct entity and arguably the best characterized of the mature T-cell neoplasms. Initially defined by morphology and the presence of an activation antigen, CD30 (Ki-1), the discovery of a unique t(2;5)(p23;q35) chromosomal translocation and cloning of the ALK gene on chromosome 2p23 led to further definition of its morphologic (small cell and lymphohistiocytic) and clinical spectrum. Currently, the 2008 WHO classification divides ALCL into 3 groups including ALK+ and ALK- systemic ALCL and primary cutaneous ALCL. ALK- ALCL has been separated as a provisional entity to provide better definition (strong expression of CD30 in virtually every large cell, strict exclusion of other tumors with CD30+ large cells, often more pleomorphism in the large cells) of this tumor and to emphasize the closer relationship of ALK- ALCL to ALK+ ALCL than to PTCL-NOS.

Particularly during the last decade, the complex pathogenesis of ALCL has been revealed. Multiple signaling pathways affecting cell proliferation, cell fate, and cytoskelet al modeling are affected in a complex and redundant manner. Molecular genetic studies have shown overlap in gene expression and cytogenetic abnormalities in ALK- and ALK+ ALCL. Independent of ALK, this activated CD4+ T-cell tumor has aberrant signaling through the T-cell receptor and a propensity to maintain its activated state, proliferate, and escape death through inhibition of apoptosis and alteration of cytotoxic receptor signaling. In combination, clinical outcome, dysregulation of T-receptor signal transduction, and other cytogenetic and molecular abnormalities support the close association of ALK+ and ALK- ALCL.

The successes of the last 25 years have been very gratifying; however, diagnostic and therapeutic challenges remain. Border zones between ALCL and other CD30+ lymphoproliferations, such as HL and LyP and transformed MF, leave some skin-based and nodal CD30+ tumors poorly characterized and leave patients without a definitive diagnosis. There are no reliable methods, other than staging, to distinguish systemic ALCL from C-ALCL. Particularly problematic is the appropriate therapy in CALCL, when focal draining lymph node involvement is detected. Although many patients with systemic ALCL do well with current treatment, ALCL has a high relapse rate and approximately 20% to 50% of patients with systemic ALCL die from the disease. Anaplastic large cell lymphoma is predominantly a tumor of children and young adults. To avoid long-term complications of therapy, risk stratification is important to determine which patients will respond to minimal therapy versus those who have a poor prognosis and require more aggressive treatment. Identification of ALK dysregulation in other mesenchymal and epithelial tumors in children and adults extends the need for new, targeted agents. Better definition of signaling pathways and unique tumor-associated genetic abnormalities should resolve many of these issues, hopefully in the near future.


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Author:Kinney, Marsha C.; Higgins, Russell A.; Medina, Edward A.
Publication:Archives of Pathology & Laboratory Medicine
Date:Jan 1, 2011
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