Anaplastic large cell lymphoma ALK-negative clinically mimicking alcoholic hepatitis - a review.

Aims—In anaplastic large cell lymphoma (ALCL), the site of origin has been described as an important prognostic factor. Recently, a fusion protein containing anaplastic lymphoma kinase (ALK) was described in...

Anaplastic large cell lymphoma (ALCL) was first described in 1985 as a large-cell neoplasm with anaplastic morphology immunostained by the Ki-1 antibody, which recognizes CD30. In 1994, the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK) fusion receptor tyrosine kinase was identified in a subset of patients, leading to subdivision of this disease into ALK-positive and -negative ALCL in the present World Health Organization classification. Due to variations in morphology and immunophenotype, which may sometimes be atypical for lymphoma, many differential diagnoses should be considered, including solid cancers, lymphomas, and reactive processes. CD30 and ALK are key molecules involved in the pathogenesis, diagnosis, and treatment of ALCL. In addition, signal transducer and activator of transcription 3 (STAT3)-mediated mechanisms are relevant in both types of ALCL, and fusion/mutated receptor tyrosine kinases other than ALK have been reported in ALK-negative ALCL. ALK-positive ALCL has a better prognosis than ALK-negative ALCL or other peripheral T-cell lymphomas. Patients with ALK-positive ALCL are usually treated with anthracycline-based regimens, such as combination cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOEP (CHOP plus etoposide), which provide a favorable prognosis, except in patients with multiple International Prognostic Index factors. For targeted therapies, an anti-CD30 monoclonal antibody linked to a synthetic antimitotic agent (brentuximab vedotin) and ALK inhibitors (crizotinib, alectinib, and ceritinib) are being used in clinical settings.

Recently, we demonstrated that the presence of high percentages of activated cytotoxic T-lymphocytes (CTLs) in biopsy specimens of both Hodgkin's disease (HD) and ALK negative anaplastic large cell lymphoma (ALCL) is associated with a poor prognosis. To test whether this biological prognostic factor is more important in predicting clinical outcome than histological diagnosis or clinical factors, we compared the prognostic value of these parameters in an expanded group of classical HD and ALK negative ALCL. Tumor biopsies of classical HD (n = 83) and ALK negative systemic nodal ALCL (n = 43) were investigated for the presence of activated CTLs by immunohistochemistry, using a monoclonal antibody directed against granzyme B. Percentages of activated CTLs were quantified using Q-PRODIT, and their prognostic value was compared to that of histological diagnosis and clinical parameters, including age and stage. Both in classical HD and ALK negative ALCL, a high percentage of activated CTLs (ie > or = 15%) identified a group of patients with poor overall and progression-free survival time, even when adjusted for stage. In multivariate analysis, percentage of activated CTLs remained a strong independent prognostic marker, and was more sensitive than histological diagnosis or clinical factors in predicting overall survival time. We conclude that a high percentage of activated CTLs in the reactive infiltrate of ALK negative ALCL and classical HD is a strong indicator for an unfavorable clinical outcome, regardless of histological diagnosis or clinical parameters. As such, this biological parameter may be an especially helpful tool to determine therapeutic strategies in cases in which the differentiation between ALK negative ALCL and HD remains difficult.

Differential Expression of BCL-2 Family Proteins in ALK-Positive and ALK-Negative Anaplastic Large Cell Lymphoma of T/Null-Cell Lineage

Simple SummaryAnaplastic large cell lymphoma (ALCL) is a lymphoid malignancy considered to be derived from T cells. Currently, two types of systemic ALCL are distinguished: anaplastic lymphoma kinase (ALK)-positive and ALK-negative ALCL. Although ALK+ and ALK− ALCL differ at the genomic and molecular levels, various key biological and molecular features are highly similar between both entities. We have developed the concept that both ALCL entities share a common principle of pathogenesis. In support of this concept, we here describe a common deregulation of CD74, which is usually not expressed in T cells, in ALCL. Ligation of CD74 induces cell death of ALCL cells in various conditions, and an anti-CD74-directed antibody-drug conjugate efficiently kills ALCL cell lines. Furthermore, we reveal expression of the proto-oncogene and known CD74 interaction partner MET in a fraction of ALCL cases. These data give insights into ALCL pathogenesis and might help to develop new treatment strategies for ALCL.In 50–60% of cases, systemic anaplastic large cell lymphoma (ALCL) is characterized by the t(2;5)(p23;q35) or one of its variants, considered to be causative for anaplastic lymphoma kinase (ALK)-positive (ALK+) ALCL. Key pathogenic events in ALK-negative (ALK−) ALCL are less well defined. We have previously shown that deregulation of oncogenic genes surrounding the chromosomal breakpoints on 2p and 5q is a unifying feature of both ALK+ and ALK− ALCL and predisposes for occurrence of t(2;5). Here, we report that the invariant chain of the MHC-II complex CD74 or li, which is encoded on 5q32, can act as signaling molecule, and whose expression in lymphoid cells is usually restricted to B cells, is aberrantly expressed in T cell-derived ALCL. Accordingly, ALCL shows an altered DNA methylation pattern of the CD74 locus compared to benign T cells. Functionally, CD74 ligation induces cell death of ALCL cells. Furthermore, CD74 engagement enhances the cytotoxic effects of conventional chemotherapeutics in ALCL cell lines, as well as the action of the ALK-inhibitor crizotinib in ALK+ ALCL or of CD95 death-receptor signaling in ALK− ALCL. Additionally, a subset of ALCL cases expresses the proto-oncogene MET, which can form signaling complexes together with CD74. Finally, we demonstrate that the CD74-targeting antibody-drug conjugate STRO-001 efficiently and specifically kills CD74-positive ALCL cell lines in vitro. Taken together, these findings enabled us to demonstrate aberrant CD74-expression in ALCL cells, which might serve as tool for the development of new treatment strategies for this lymphoma entity.

The anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is a clinically distinct but heterogeneous entity and lacks the specific immunophenotypic or genetic features compared with the ALK-positive ALCL. Recent molecular studies have provided genetic landscapes of ALK-negative ALCL that have prognostic significance. In this study, we subtyped ALK-negative ALCL based on DUSP22 rearrangements and TP63 expression and also looked for mutations in JAK-STAT pathway. The subtyping of the ALK-negative ALCL in relation to DUSP22 rearrangement and TP63 expression was done using fluorescence in situ hybridization and immunohistochemistry, respectively. The hotspot JAK-STAT mutations were analyzed using Sanger sequencing and amplification refractory mutation system polymerase chain reaction (PCR) and Signal transducer and activator of transcription 3 (STAT3) expression by immunohistochemistry. Forty-eight cases of ALCL were included with median age of 30 years and sex ratio of 1.8:1. The p63 expression was detected in 26.7% of ALK-negative ALCL cases. DUSP22 rearrangement was noted in 12.5% cases of p63-negative ALK-negative ALCLs. DUSP22 rearranged cases had better overall survival in contrast to p63 expressing and triple negative ALCLs. Triple negative ALCLs showed inferior overall survival rate. STAT3 expression was evident in 61.1% and 60% of ALK-positive and ALK-negative ALCLs, respectively. None of the cases subjected to Sanger sequencing as well as amplification refractory mutation system PCR for hotspot mutation analysis of JAK1 (exon 24) and STAT3 (exon 21) revealed any mutation. ALK-negative ALCL is a genetically heterogeneous disease with widely disparate clinical outcomes. Subtyping of ALK-negative ALCL based on DUSP22 rearrangement and p63 expression provides prognostic information.

Anaplastic large cell lymphoma (ALCL) has a characteristic feature that distinguishes it from the other types of non-Hodgkin lymphomas (NHLs) - the presence of a marker on its surface called CD30. It can be either cutaneous, systemic, or around breast implants. The systemic type of ALCL can be further classified based on the presence or absence of an abnormal protein, anaplastic lymphoma kinase (ALK), as ALK-positive or ALK-negative ALCL, respectively. We are presenting a case of a 35-year-old male who presented to the emergency department with an acute episode of abdominal pain. He underwent emergency laparotomy with ileal resection and anastomosis, as he was diagnosed with perforation peritonitis. Histological and immuno-histochemical reports of the specimen showed a lymphoproliferative lesion, and it helped reach the diagnosis of ALK-negative ALCL. ALK-negative ALCL can be diagnosed by using multidisciplinary investigation techniques, including radiological imaging, histopathological examination along with immunohistochemical staining. Prompt diagnosis helps in distinguishing ALK-negative ALCL from other lymphomas as well as solids tumors of the small bowel.

Activated c-Jun N-Terminal Kinase Is a Therapeutic Target in Advanced Stage ALK-Negative Anaplastic Large Cell Lymphoma.

Background Central nervous system (CNS) lymphomas frequently pose a diagnostic challenge to physicians. CNS anaplastic large cell lymphoma (ALCL) is a rare condition. A majority (80%) of ALCLs harbour anaplastic lymphoma kinase 1 (ALK-1) mutation with only a minority testing negative for this mutation. Methods Here we report a rare case of ALK-negative CNS ALCL with dural involvement. We conducted a literature search using PubMed for published studies in English on cases of patients with ALCL of the brain. The keywords used were ‘anaplastic large cell lymphoma’, ‘ALK’ and ‘primary central nervous system lymphoma’. Results A 63-year-old man presents with waxing and waning cranial nerve and spinal cord symptoms. MRI revealed multiple intracranial and intra-spinal lesions that were highly steroid responsive. A wide range of serum and CSF tests were non-diagnostic during three months of workup before a lesion appeared in the cervical spine that required decompression and allowed us to obtain a tissue sample. Final pathology revealed ALK-negative ALCL. There are only 24 reported adult cases to date of CNS ALCL in the English literature. To our knowledge, this is the first case of ALK-negative ALCL with primarily CNS and meningeal involvement. Conclusions ALK-negative ALCL with CNS involvement is extremely rare, which frequently results in delayed diagnosis (average 40.5 days). The diagnostic challenge posed by this case highlights the importance of a team approach to workup and diligent patient follow-up for such a rare disease.

Anaplastic large cell lymphoma (ALCL) can be divided into two major groups. The first is a spectrum of CD30+ T-cell lymphoproliferative disorders including primary cutaneous ALCL and lymphomatoid papulosis, usually affecting older patients but characterized by an excellent prognosis. The second is systemic nodal ALCL, which on the basis of genetic and immunophenotypic features combined with clinical parameters can be divided into two subgroups: anaplastic lymphoma kinase (ALK)-positive and ALK-negative systemic ALCL. ALK expression, usually the result of a t(2;5) translocation, correlates with the expression of other markers such as EMA and a cytotoxic phenotype, and is strongly related to younger age groups, lower international prognostic index (IPI) risk groups, and a good prognosis. ALK-negative ALCL, however, shows a more heterogeneous immunophenotype and clinical behaviour, and prognostic parameters are needed to determine treatment strategies in individual patients. Besides clinical parameters included in the IPI, recent studies have pointed out several biological prognosticators of potential value, such as the percentage of tumour-infiltrating activated cytotoxic T-lymphocytes. The expression of proteins involved in the execution or regulation of apoptosis, such as activated caspase 3, Bcl-2, and PI9, was also found to be strongly related to clinical outcome. These studies indicate that inhibition of the apoptosis cascade in particular is an important mechanism that can explain the poor clinical outcome in therapy refractory ALCL. Functional studies are required to investigate whether disruption of one or more of the apoptosis pathways is the major factor in the fatal outcome of the disease and whether apoptosis resistance based on inhibition of one pathway can be overcome by activating another pathway that is still intact.

Primary systemic anaplastic large cell lymphoma (ALCL) is divided into two entities according to the expression of anaplastic lymphoma kinase (ALK). We investigated (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) findings in primary systemic ALCL according to ALK expression. Thirty-seven patients who had baseline PET before CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone)-based chemotherapy were enrolled. Among them, patients who underwent interim and/or post-therapy PET were further investigated for the treatment response and survival analysis. Baseline PET was analyzed visually and semi-quantitatively using peakSUV, and interim and post-therapy PETs were visually analyzed. All cases were (18)F-FDG-avid on baseline PET. The peakSUV of ALK-positive ALCL (n = 16, 18.7 ± 10.5) was higher than that of ALK-negative ALCL (n = 21, 10.0 ± 4.9) (P = 0.006). In ALK-negative ALCL, complete response (CR) rate in negative-interim PET was higher than positive-interim PET (100% vs 37.5%, P = 0.02); however, there was no such difference in ALK-positive ALCL (100% vs 75%, P = 0.19). The 3-year progression-free survival (PFS) was not significantly different between ALK-positive and ALK-negative ALCL (72.7% vs 47.6%, P = 0.34). In ALK-negative ALCL, negative interim and post-therapy PET patients had better 3-year PFS than positive interim (83.3% vs 25.0%, P = 0.06) and post-therapy PET patients (70.0% vs 20.0%, P = 0.04). In contrast, ALK-positive ALCL had no such differences between PFS and PET results. On baseline PET, all cases showed (18)F-FDG-avidity, and ALK expression was related to higher (18)F-FDG uptake. ALK-positive patients tend to have better PFS than ALK-negative patients. Negative-interim PET was a good indicator of CR, and interim or post-therapy PET was helpful for predicting the prognosis only in the ALK-negative group.

To investigate whether MUC1 mucin, a high molecular weight transmembrane glycoprotein, also known as epithelial membrane antigen (EMA), differs in its expression and degree of glycosylation between anaplastic large cell lymphoma (ALCL) and classic Hodgkin's disease (HD), and whether MUC1 immunostaining can be used to differentiate between CD30 positive large cell lymphomas. Using five different monoclonal antibodies (E29/anti-EMA, DF3, 139H2, VU-4H5, and SM3) that distinguish between various MUC1 glycoforms, high MUC1 expression (50-95% of tumour cells positive) was found in 13 of 17 anaplastic lymphoma kinase (ALK) positive systemic nodal ALCLs, and in one of 20 cases of classic HD. Scattered or focal staining (< 25% of tumour cells) was seen in two additional ALK positive systemic ALCLs, two additional classic HD cases, and in three of 20 cases of ALK negative systemic nodal ALCL. Primary cutaneous ALCL showed no staining with the anti-MUC1 antibodies. Antibodies detecting hypoglycosylated MUC1 were found to be absent in all lymphomas (SM3) or present in only six of 15 ALK positive ALCLs (VU-4H5). MUC1 is preferentially expressed by a subtype of systemic nodal ALCL, characterised by ALK expression, but is found in only a few cases of classic HD and ALK negative ALCL. Therefore, although MUC1 could be used in a panel of markers for CD30 positive lymphomas, it is probably not a valuable tool to differentiate between ALK negative CD30 positive large cell lymphomas. Finally, the degree of MUC1 glycosylation in lymphomas is relatively high, compared with the aberrant hypoglycosylation found in adenocarcinomas.

In the 3rd edition of the WHO Classification of Hematopoietic Neoplasms, anaplastic lymphoma kinase-positive (ALK+) and anaplastic lymphoma kinase-negative (ALK–) anaplastic large cell lymphoma (ALCL) were considered as a single disease entity and defined as lymphomas consisting of lymphoid cells that were usually large with abundant cytoplasm and pleomorphic, often horseshoe- shaped nuclei.1 The cells are CD30-positive2 and most cases express cytotoxic granule-associated proteins3,4 and EMA.5 It became clear that while ALCL expressing ALK constituted a relatively homogeneous entity, cases with similar morphology and phenotype but lacking ALK expression were much more heterogeneous. In the 4th WHO classification, ALCL, ALK+ is a distinct entity and ALCL cases without ALK expression are a provisional entity.6 ALK+ ALCL are associated with a chromosomal abnormality, the t(2;5)(p23;q35), that fuses part of the nucleophosmin (NPM) gene on chromosome 5q35 to a portion of the ALK (anaplastic lymphoma kinase) receptor tyrosine kinase gene on chromosome 2p23, resulting in the expression of a unique chimeric NPM-ALK protein.7,8 Besides the t(2;5), at least eleven variant translocations involving ALK gene at p23 have been recognized. All result in upregulation of ALK fusion protein. Primary systemic anaplastic large cell lymphoma, both ALK+ and ALK–, must be distinguished from ALCL of primary cutaneous type and from other subtypes of T or B-cell lymphoma with anaplastic features and/or CD30 expression (Jaffe 2001).

e19563 Background: Anaplastic large cell lymphoma (ALCL) is a CD30+ T-cell lymphoma that is generally unrelated to EBV in the non-HIV setting. Based upon anaplastic lymphoma kinase (ALK) expression, the new WHO classification provisionally distinguishes between ALK+ (favorable) and ALK- (unfavorable) ALCL. The characteristics of ALCL, such as ALK expression and EBV coinfection, in individuals with HIV infection have not been adequately evaluated. The aim of this study was to investigate these features in HIV-associated ALCL cases. Methods: A MEDLINE search for all cases of HIV-associated non-cutaneous ALCL was undertaken. Data regarding patient age, gender, HIV status (CD4 count, viral load, opportunistic infections), HAART, lymphoma features (B symptoms, stage, sites of involvement, immunophenotype, ALK expression, molecular studies), EBV coinfection, therapy and outcome (survival, cause of death) were extracted and analyzed. Results: A total of 23 cases were included. Patients were of median age 39 years with a male:female ratio of 7:1. Median CD4+ count was 76 cells/mm3 and HIV viral load 416,500 copies/ml. Most (67%) patients had an opportunistic infection, although only 3 (17%) were on HAART. ALCL was extranodal in 22 cases (96%) affecting most commonly lung, soft tissue and liver. Many (78%) patients had stage IV disease and B symptoms were reported in 9 cases (50%). T-cell receptor gene rearrangement was present in all cases, CD30 was positive in 22 (96%), and the vast majority (90%) were ALK-negative. EBV was identified in 8 (35%) cases. Therapy for ALCL was documented in 15 (67%) cases; 64% received CHOP. In 2 of the 3 patients who were on HAART, long-term survival was achieved. Many (68%) patients died, with a median survival of 9 months. Death was caused by either lymphoma progression (42%) or infection (58%). Conclusions: HIV-associated non-cutaneous ALCL appears to affect younger individuals and is associated with EBV infection in a subset of cases. Apart from marked immunosuppression, the poor prognosis of HIV-associated ALCL appears to be related to the absence of ALK expression, advanced stage at presentation with prominent extranodal disease, inadequate therapy including HAART, and poor response to CHOP. Further research is needed to better understand and treat this unique HIV-associated lymphoma. No significant financial relationships to disclose.

Simple SummaryALK- anaplastic large cell lymphoma (ALK- ALCL) is a rare subtype of CD30+ large T-cell lymphoma that typically affects older adults and has a poor prognosis. Recognition of its histopathologic spectrum, subtypes, and of other tumors that can resemble ALK- ALCL is crucial to avoid making a wrong diagnosis that could result in inappropriate treatment for a patient. In recent years, several important studies have identified recurrent molecular alterations that have shed light on the pathogenesis of this lymphoma. However, on the other hand, putting all this vast information together into a concise form has become challenging. In this review, we present not only a more detailed view of the histopathologic findings of ALK- ALCL but also, we attempt to provide a more simplified perspective of the relevant genetic and molecular alterations of this type of lymphoma, that in our opinion, is not available to date.Anaplastic large cell lymphoma (ALCL) is a subtype of CD30+ large T-cell lymphoma (TCL) that comprises ~2% of all adult non-Hodgkin lymphomas. Based on the presence/absence of the rearrangement and expression of anaplastic lymphoma kinase (ALK), ALCL is divided into ALK+ and ALK-, and both differ clinically and prognostically. This review focuses on the historical points, clinical features, histopathology, differential diagnosis, and relevant cytogenetic and molecular alterations of ALK- ALCL and its subtypes: systemic, primary cutaneous (pc-ALCL), and breast implant-associated (BIA-ALCL). Recent studies have identified recurrent genetic alterations in this TCL. In systemic ALK- ALCL, rearrangements in DUSP22 and TP63 are detected in 30% and 8% of cases, respectively, while the remaining cases are negative for these rearrangements. A similar distribution of these rearrangements is seen in pc-ALCL, whereas none have been detected in BIA-ALCL. Additionally, systemic ALK- ALCL—apart from DUSP22-rearranged cases—harbors JAK1 and/or STAT3 mutations that result in the activation of the JAK/STAT signaling pathway. The JAK1/3 and STAT3 mutations have also been identified in BIA-ALCL but not in pc-ALCL. Although the pathogenesis of these alterations is not fully understood, most of them have prognostic value and open the door to the use of potential targeted therapies for this subtype of TCL.