ALK-positive large B-cell lymphoma: identification of EML4-ALK and a review of the literature focusing on the ALK immunohistochemical staining pattern

Abstract

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+LBCL) is a rare, aggressive B-cell lymphoma with ALK fusion genes. Histopathologically, the ALK immunohistochemical staining pattern is suggestive of the fusion partner of ALK. Here, we examined an ALK+LBCL case showing a unique diffuse cytoplasmic ALK staining pattern and identified EML4-ALK, which has not previously been reported in ALK+LBCL. Furthermore, to clarify whether the prognosis differs depending on the staining pattern, we reviewed 112 previously reported cases, and analyzed immunohistochemical markers and clinical data stratified by the staining pattern. We found that ALK staining can be classified into a granular cytoplasmic staining (GCS) or a non-GCS patterns. Sixty-four adult cases for which both the ALK staining pattern and survival time were reported were further analyzed for survival trends. The non-GCS pattern was significantly associated with inferior overall survival (P = 0.031). This difference remained significant after adjusting for age and clinical stage (hazard ratio 5.08, 95 % CI 1.88-13.7, P = 0.0013). Given that the ALK immunohistochemical staining pattern is associated with the ALK fusion partner, the present results suggest that the prognosis for ALK+LBCL differs depending on the ALK fusion partner.

Anaplastic lymphoma kinase positive large B‐cell lymphoma: Literature review and report of an endoscopic fine needle aspiration case with tigroid backgrounds mimicking seminoma

“…ALK is a tyrosine kinase of the insulin receptor superfamily. 27 Our patient showed a granular pattern of ALK1 immunoreactivity in the biopsy specimen. 20 ALK translocations were first described in LBCLs in the early 2000s, with these reports demonstrating resultant fusions of CLTC and ALK as well as NPM and ALK.…”

“…Other fusion partners for ALK genes in LBCLs have been reported, including but not necessarily limited to SEC31A, SQSTM1, RANBP2, and EML4. 8,9,13,[20][21][22][23][24][25][26][27] Of note, ALK1 immunohistochemical staining patterns have been reported to differ according to translocation partners with CLTC-ALK fusions and SEC31A-ALK fusions being associated with granular cytoplasmic staining, while EML4-ALK fusions and SQSTM1-ALK fusions are associated with diffuse cytoplasmic staining patterns. In cases with NPM-ALK fusions ALK1 staining patterns have been reported as mixed nuclear and cytoplasmic, while in RANBP2-ALK fusions, unique patterns of nuclear membrane staining have been described.…”

Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects

“…Additionally, a rare form of large B-cell lymphoma, called ALK-positive large B-cell lymphoma (ALK-positive LBCL), which is positive for the ALK fusion, has been reported and described as a distinct entity in the current WHO classification. 11,[40][41][42][43] CD30 is a type 1 transmembrane protein (595 amino acids, 120 kDa) encoded by a gene located at chromosome 1p36 and is also known as tumor necrosis factor (TNF) receptor superfamily 8 (TNFRSF8). In the extracellular domain, CD30 has six cysteine-rich pseudo-repeat motives that show structural characteristics of TNFSF 44 and a TNF receptor-associated factor (TRAF)-binding motif in the C terminus, mediating activation of nuclear factor-κB (NF-κB).…”

“…5 With regard to the clinical impact of the difference in partner genes of ALK, no significant differences in prognosis have been observed for NPM-ALK and other translocations in ALK-positive ALCL, 12,154 although the prognosis of ALK-positive large B-cell lymphoma (LBCL) differs depending on the ALK fusion partner. 43 In addition, some case reports have described patients with ALK-positive ALCL with concurrent rearrangement of MYC and aggressive clinical behavior. 155,156 Some additional factors have been suggested to predict poor outcomes in patients with systemic ALCL, including CD56 expression, 12 elevated pretreatment serum soluble CD30 levels, 157 and beta-2-microglobulin (≥ 3 mg/L).…”

Cytologic perspectives on neoteric B‐cell lymphoproliferative disorders

“…This may be particularly important for cytopathologists given that immunohistochemical studies often have a faster turnaround time than [38][39][40][41] Rare cases with Napsin A expression have also been described. 44 Confirmation of LBCLs allow for more exacting prognoses and may assist in tailoring disease specific therapies. With the exception of certain central nervous system cells, ALK protein expression is typically not demonstrable in normal postnatal human tissues including normal lymphoid cells.…”