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We report detailed clinical and pathologic features of cases of anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma (ALK-DLBCL), a rare entity with only 33 currently reported cases. This reported case. Biopsies from adult male patients aged, 44 years (three lymph nodes And one skin lesion) the lymph node exhibited immunoblastic/plasmablastic morphology. By immunohistochemistry and they expressed cytoplasmic ALK-1, CD138, VS38 (3/3), monoclonal cytoplasmic light Chain, CD45, CD19, CD79 and were negative for CD3, CD30, CD20 and EMA. Showed rare CD43 (.) reactivity.
Keywords: ALK positive, difuuse large B-cell lymphoma, lymphoplasmoblastic pattern, anaplastic lymphoma
A 44 years old male patient initially presented to King Abdulaziz Specialist hospitall, Taif with Bronchopneumonia of the middle lung zone) & renal impairment. Sputum analysis showed gram positive (+ve) cocci and gram negative (-ve) bacilli with no AFB. Two months later, patient presented to KAASH with hoarseness of voice and mild dysphagia. Clinical examination showed left vocal cord paralysis. Ct scan neck showed left pyriform lesion with cervical lymphadenopathy. Bronchoscopy, esophagoscopy, and laryngoscopic biopsy were performed. Histopathology showed non-specific infection with no malignancy. A month later, patient presented with disseminated herpes zoster. Patient given. Acyclovir for 5 days and referred to Oncology Surgeon. Clinical examination showed a right outer canthus deep ulcer and wound, generalized lymphadenopathy (cervical, axilla and inguinal). Left thigh ulcerated lesion was also present. Patient was tested for HIV, II, P24 Ag in serum HCV, HBV all are negative. Again total protein in serum was high (13gm/dl) while serum albumin is low (2gm/dl). Excision biopsy of right cervical lymph node together with biopsies from right outer canthus ulcer and left thigh lesion were performed. The lymph node showed high grade ALK +ve large B-cell lymphoma with plasmablastic differentiation, skin biopsies from right canthus and left thigh showed chronic non–specific infections. Ct chest and abdomen showed nodular lung lesions involving both lungs, hepato-splenomegaly, para-aortic and Mesenteric lymph node enlargement. Patient gives history of fever and weighs loss. A staging bone marrow showed low level involvement by chronic lymphocytic leukemia, but no evidence of large cell lymphoma. The patient received CHOP and neck Irradiation for stage IV disease. Patient currently alive.
Immunohistochemical result
Punnel of immuno stain are preformed showing the atypical Lymphoid cell are positive for B cell marker CD79 (Figure 1) and CD19. About 30% of the cells are positive for CD 43 and CD4. Plasma cell marker show 40% positivity with CD 138 (Figure 2) as well as VS38 (3/3). Kappa and Lamda show restriction with 100% positivity with Lamda stain. ALK antibody show strong granular cytoplasmic positivity (Figure 3). K167 is > than 80% EBV is strong positive (Figure 4). White negative result are observed with Cd20, BCL6, CD10, CD3, Cyclinc D, CD23, EMA, and CD30 (Figure 5).
Figure 1 : High power examination, original magnifcation x40. CD79, with a moderate and focal membrane pattern.
Figure 2 : High power examination, original magnifcation x40. CD138, with week and focal nuclear and cytoplasmic pattern.
Figure 3 : High power examination, original magnifcation x40. The cells are strongly expresses ALK, with a diffuse cytoplasmic and nuclear pattern.
Figure 4 : High power examination, original magnifcation x40. The tumor show focal strong nuclear stain with EBV stain.
Figure 5 : High power examination, original magnifcation x40. CD30 for the tumour cell are negative.
Histological examination of the lymph node
The lymphoid tissue showing partial effaced architecture with vague nodular pattern accompanied by sclerosis and star sky appearance. The neoplastic infiltrate is composed of intermediate nuclei, prominent multiple nucleoli and abundant amorphelic cytoplasm, with focal area showing plasmocytoid differentiation (Figure 6). Frequent Mitotic figures are seen.
Figure 6 : High power examination, original magnifcation x40. Morphologic features of ALK-positive large B-cell lymphoma. Characteristic plasmablastic and immunoblastic morphology (H&E staining).
FISH for ALK gene rearrangement
FISH demonstrated an ALK gene rearrangement (Figure 7). Demonstrates a clearly separated. Orange and green signal indicating rearrangement of the ALK gene, (arrow) the normal ALK gene signal is seen as overlapping/fusion of the orange And green signals (yellow). As the ALK probe is a break Apart probe.
Figure 7 : Fluorescence in situ hybridization (FISH) of ALKDLBCL Showing ALK gene rearrangement using the ALK break Apart probe from Vysi Inc. The FISH pattern is positive for rearrangement involving the ALK gene locus (arrows). The typical abnormal pattern would be expected to show 1R1G1F (one red and one green signal (abnormal) and one fused (yellow) (the remaining normal allele)). In this particular case, the majority of neoplastic cells also demonstrate an additional fused (yellow), signal indicating either a duplication of the ALK gene region or an additional copy of chromosome 2.
We report A cases of plasmablastic lymphoma kinase positive diffuse large B-cell lymphoma (ALK-DLBCL) based on morphologic and immunophenotypic similarity to those previously described [1-6]. ALK-DLBCL was initially described by [1]. Our study of cases brings the total number of 33 reported cases of ALK-DLBCL in the literature to 34.
ALK-DLBCL has a distinct morphologic appearance with immunoblastic/plasmablastic cytology with round, centrally to eccentrically located nuclei, prominent single central nucleoli, and moderate amounts of variably eosinophilic cytoplasm A sinusoidal growth pattern may be seen Immunohistochemically, ALK-DLBCL shows features suggesting plasmacytic differentiation, with positivity for CD138, VS38c, and monotypic cytoplasmic light chain. The characteristic ALK staining is usually cytoplasmic and coarsely granular Occasional cases with nuclear and cytoplasmic positivity have also been reported. CD4, and CD43 are variably positive, while CD30, B-cell related antigens (CD20), and T-cell related antigens (CD3) are negative.
Although, a fairly typical immunohistochemical (plasmacytic) profile has been established for ALK-DLBCL, it is clear that some immunophenotypic heterogeneity exists. As in some reported case in the review literature.
CD 20 highlighted rare positive tumor cells, providing a helpful clue to the underlying B cell lineage. CD20 positivity, even focal, is distinctly unusual. Also some cases been reported to show scattered cytokeratin (AE1/AE3)-positive tumor cells, which in conjunction with EMA positivity may lead to an erroneous interpretation of carcinoma. In addition, although usually negative [3], report one of their cases as being CD30 positive. The overall morphologic and immunohistochemical features should allow for distinction of ALK-DLBCL from other entities including ALCL, plasmablastic lymphoma, plasmablastic myeloma, anaplastic variant of diffuse large B-cell lymphoma, and carcinoma. ALCL is typically CD30 (+), of T-cell phenotype and would be negative for plasma cell markers (CD138) and immunoglobulin light chain. Plasmablastic lymphomas often occur in the oral region of human immunodeficiency virus-infected individuals, and are EBER positive and ALK negative [15]. The anaplastic variant of DLBCL is usually strong CD20 (+) and ALK (-). Plasmablastic myeloma has not been reported to be ALK positive, and would be associated with other features such as lytic bone lesions and a monoclonal protein in serum and/or urine.The clinical features from the 33 reported cases of ALK-DLBCL are all summarized in. ALK-DLBCL (Table 1) spans age groups with an overall male predominance (M: F ratio of 3:1). The M: F ratio is similar in children (7:3) and adults (18:5). Commonly reported clinical features included lymphadenopathy (27 cases), hepato- and/or splenomegaly (four cases), bony/CNS extension (four cases), mediastinal mass (four cases), and laryngeal/oral mass (three cases). Although only 33 cases of ALK-DLBCL have been reported thus far, higher stage disease at presentation (III–IV) appears to correlate with a poor Response to multi-agent lymphoma Chemotherapy and an aggressive Clinical course. The overall median survival of high stage III/IV patients (N=13) was 11 months. Of the 11 patients reported as low stage I/II with at least 14 months follow-up, the average disease-free survival was 41 months (N=10). Only one was dead of disease after 14 months. The recent discovery of underlying ALK rearrangement in ALK-DLBCL.
Table 1 : Comparison of selected clinical features of the 33 reported cases of ALK-DLBCL.
Is an important advance in our understanding of the pathogenesis of this lymphoma [2-6]. The ALK gene located on chromosome 2p23 may be translocated to either the Clathrin (LCTC) gene on chromosome 5q35, resulting in CLTC-ALK and NPM-ALK fusion products, respectively [2-6,8-11]. Both of these rearrangements were originally identified in classic ALK (+) ALCL, with NPM-ALK being distinctly more common (70-80% of cases). 16 As in ALCL, the ALK staining pattern in ALK-DLBCL appears to correlate with the type of underlying rearrangement. Cases with CLTC-ALK/t (2; 17) rearrangement show a dinstinctly cytoplasmic and granular ALK staining pattern. Whereas those cases with an NPM-ALK/t (2; 5) rearrangement show both cytoplasmic and nuclear staining [2-6,8-11,16]. However, this correlation may be imperfect, as [5], reported on case of ALK–DLBCL with NPM-ALK fusion that showed cytoplasmic ALK staining only. Thus, ALK gene rearrangements, originally thought to be uniquely associated with T-/null cell ALCL, have now been convincingly shown to occur in rare cases of B-cell lymphoma [2-13]. Of note, prior to the initial series by [1,17] in 1996 reported NPM/ALK fusion transcripts (by RT PCR) in four of 33 cases of large B-cell lymphoma. Interestingly, and in contrast to the cases of ALK-DLBCL reported thus far, this case had a conventional B-cell immunophenotype (CD97+). Was EMA (-) and CD30 negative result. ALK aberrations, specifically involving rearrangements of the CLTC gene, have also been identified in some cases of inflammatory myofibroblastic tumors (IMT) [18]. Thus, ALK over expression likely contributes to the pathogenesis of a Variety of otherwise unrelated neoplasms, ALK-DLBCL, ALCL, and IMT.
The authors declare that they have no competing interests.
| Authors' contributions | EMJ | DMN | JMJ | AAS | SMA | AMM | HB |
| Research concept and design | √ | √ | -- | √ | -- | -- | -- |
| Collection and/or assembly of data | √ | √ | -- | √ | -- | -- | -- |
| Data analysis and interpretation | √ | √ | -- | -- | -- | -- | -- |
| Writing the article | √ | -- | -- | -- | -- | -- | -- |
| Critical revision of the article | √ | √ | √ | -- | √ | -- | √ |
| Final approval of article | √ | √ | √ | -- | √ | √ | √ |
| Statistical analysis | √ | √ | -- | -- | -- | -- | -- |
Editor: Takuji Tanaka, Gifu University, Japan.
Received: 20-Oct-2013 Revised: 23-Nov-2013
Re-Revised: 02-Dec-2013 Accepted: 08-Dec-2013
Published: 20-Dec-2013
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