ALK positive diffuse large B-cell lymphoma, lymphoplasmablastic differentiation

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.


Introduction
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.

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.

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.
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.