| Abstract|| |
Anaplastic large cell lymphoma (ALCL) is a subcategory of the mature T-cell neoplasm characterized by sheets of cluster of differentiation (CD)30-positive pleomorphic large cells mostly present as lymphadenopathy. Here, we describe a case of Small cell variant ALCL with leukemic presentation without lymphadenopathy. A 68-year-old male presented with fatigue and weakness; examination revealed a total leukocyte count of 295,000/uL. The peripheral smear showed cells having cerebriform nuclei comprising 90% of the leukocytes. The flow cytometry showed that the cells were immunopositive for CD3 (weak), CD4, CD7, and negative for the rest of the markers. The cell blocks from the peripheral blood showed cells with immunopositivity for CD30, anaplastic lymphoma kinase (ALK), and Epithelial membrane antigen (EMA). A diagnosis of the small cell variant of ALK-positive ALCL was made. Due to the presence of atypical pleomorphic cells without lymphadenopathy, the case has a diagnostic dilemma with differential diagnosis of Sezary syndrome, T-cell prolymphocytic leukemia, and adult T-cell leukemia/lymphoma. Karyotyping and additional immunohistochemistry help for the confirmation of the diagnosis.
Keywords: ALK-positive, leukemia, lymphoma, small cell variant
|How to cite this URL:|
Dutta R, Ramteke P, Mathur SR, Saxena R, Pati Hp, Mallick S. Small cell variant anaplastic large cell lymphoma presenting as leukemia: A case report and review of Literature. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Jan 29]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=346848
| Introduction|| |
Anaplastic large cell lymphoma (ALCL) is one of the subcategories of mature T-cell neoplasms accounting for about 3% of adult lymphomas and 10–20% of childhood lymphomas. Since its initial perception by Stein et al. in 1985, many histomorphological and clinical subtypes were described. All the morphological patterns show the presence of signature neoplastic (anaplastic or embryo-like) cells called “hallmark” cells in a polymorphous background usually comprising of eosinophil, mature lymphocytes, and histiocytes. The wide array of histologic variants documented in the literature include common pattern (60%), lymphohistiocytic (10%), small cell (5–10%), Hodgkin-like (3%), composite (15%), and rare patterns as giant cell-rich, neutrophil-rich, and sarcomatoid type., Characteristically, though both nodal and extranodal sites like the skin, bone, soft tissue, lungs, and liver are involved, however, the bone marrow involvement and leukemic presentation are rare and described usually with the small cell variant. In about 75% of the cases, ALCLs are associated with a balanced chromosomal translocation t(2;5)(p23;q35), involving the genes encoding anaplastic lymphoma kinase (ALK), located at chromosome 2p23 and nucleophosmin (NPM) located at chromosome 5q35. Usually, the small cell variant of ALCL follows the same dictum in terms of presentation as the classical ALK-positive ALCL but poses a diagnostic challenge in scenarios of atypical presentation like isolated leukemic involvement. We, hereby, like to highlight a case of a small cell variant of ALCL with de novo leukemic presentation in the absence of clinically recognizable lymph node involvement. This type of presentation is rare and augments diagnostic perplexity.
| Case Report|| |
A 68-year-old male presented with symptoms of generalized weakness and easy fatigability. The clinical examination revealed pallor, however, there was no icterus, hepato-splenomegaly, or lymphadenopathy. The hemoglobin level was around 10.7 g/dL with a markedly raised total leukocyte count of 295,000/uL. The peripheral smear examination revealed lymphocytosis with the presence of atypical lymphoid cells having irregular nuclear contours (cerebriform nuclei) comprising 90% of the circulating leukocytes. A subsequent bone marrow aspiration and biopsy showed the presence of an atypical lymphoid population. The cytochemistry exhibited dot-like positivity with non-specific esterase (NSE). Flow cytometric immunophenotyping revealed the cells to be positive for CD45, CD2, CD3 (weak), CD4, CD7, and negative for CD13, CD33, CD10, CD19, CD34, CD117, Myeloperoxidase (MPO), CD79a, terminal deoxynucleotidyl transferase (Tdt), CD5, CD64, CD8 [Figure 1]. Immunohistochemistry on the clot core biopsy specimen showed that the atypical cells were immunopositive for ALK-1, CD30, and EMA [Figure 2]. To confirm the diagnosis, karyotyping was performed which showed balanced translocation t(2:5). Thus, a final diagnosis of the small cell variant of ALK-positive ALCL was rendered. The patient was managed accordingly, however, the patient succumbed due to the disseminated nature of the disease.
|Figure 1: (a) Microphotograph of the peripheral smear shows large atypical small cells with multilobate hyperchromatic nuclei. (b) Cytochemistry for non-specific esterase shows peripheral rim positivity. Flow cytometric evaluation of peripheral blood shows mature lymphoid cells [a] which are immunopositive for CD45 (c,f), CD3 [h], CD4 [k], and Alphabeta [l] and negative for CD19, CD10 [e], CD34, CD117 [g], TdT [h], MPO, CD79a [i], CD5, CD64 [j], CD8 [k], Gammadelta [l]|
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|Figure 2: Cell block from peripheral blood shows small cells [a x 200] which are immunopositive for ALK [d X 100], CD30 [e x200], EMA [f x100] and negative for CD3 [b x100], CD20 [c x100]|
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| Discussion|| |
Kinney et al. first recognized this unique morphological variant of ALCL in 1993, which nowadays account for approximately 5–10% of the total ALCL cases. Small cell ALCL shows varied clinical presentations ranging from macular eruptions to subcutaneous nodules in the skin with occasional involvement of the bone and soft tissues. The bone marrow involvement, using standard methods, is detected in only 10–14% of the cases. In such cases, leukocytosis is invariably present with the infrequent presence of atypical lymphocytes in the form of cerebriform or flower-like cells.
The neoplastic cells are immunonegative or weakly positive for leukocyte common antigen (LCA) and T-cell markers like CD3, CD2, CD5, and CD4. Though most cases are T-helper cell phenotype, the neoplastic cells also show cytotoxic markers like granzyme and perforin. The expression of CD30 is a defining feature even for the small cell variant of ALCL, however, staining patterns of the small, medium, and large cells are varied.,, The CD30 expression in the large cells is strong and seen in the cell membrane and Golgi region, whereas the small- and medium-sized cells which usually predominate in this entity exhibit weak or sometimes negative immunostaining for CD30. The EMA expression is seen in only a proportion of the neoplastic cells., Unlike other variants, the small cell types show nuclear ALK positivity. Thereby, CD30 coupled with ALK positivity essentially clinches the diagnosis in a typical case scenario. However, a dilemma arises in atypical presentations like in our case. In scenarios of high Total leucocyte count (TLC) count with cells having cerebriform (flower-like) nuclei and T-cell immunophenotype, the common differential diagnoses include (I) Sezary syndrome (II) Adult T-cell leukemia/lymphoma (ATLL), (III) T-prolymphocytic leukemia, etc. A detailed clinical history and immunophenotyping aids in the definitive diagnosis. Sezary syndrome is defined by the triad of erythroderma, generalized lymphadenopathy, and neoplastic cells in peripheral blood, unlike in our case. ATLL usually is associated with human retrovirus Human T-cell lymphotropic virus type 1 (HTLV-1) and presents with generalized lymphadenopathy and skin involvement seen in 20% of the cases, however, HTLV-1 serology was negative in this patient. In both the above differentials, large transformed cells may be positive for CD30 but are negative for ALK and EMA. About 5% of the T-cell prolymphocytic leukemia (T-PLL) can have very irregular nuclei, which may even be cerebriform-shaped and the neoplastic cells of T-PLL show dot-like positivity for alpha-naphthyl acetate esterase and acid phosphatase. Our case was a diagnostic challenge as the patient was an elderly man with a leukemic presentation without a typical history of lymph node involvement. Initially, the case was suspected to be T-PLL given the positivity for NSE. However, immunohistochemical positivity for CD30, EMA, and ALK helped in clinching the diagnosis. The final diagnosis was possibly based on the cumulative flow cytometry findings along with the immunohistochemistry and confirmation by ancillary molecular techniques.
Nguyen et al. noted that 85% of the small cell ALK+ ALCL cases showed the characteristic t(2;5)(p23;q35) translocation, which is defining for all morphological variants of ALCL. The rest of the cases showed variant translocation involving ALK and a few exhibited trisomies, deletions, and 3-break rearrangements in isolated cases but nothing paramounting to statistical significance.
As per studies, the 2-year overall survival rate has been predicted to be about 75–90% in ALK-positive ALCL. However, the biological behavior of the small cell variant of ALCL is under speculation. Hodges et al. in their review of 17 cases showed that 24% transformed to classical ALCL signaling a rapid clinical course with 75% of those transformed cases succumbing in less than a year. Owing to the leukemic involvement, the small cell variant usually has an unfavorable prognosis, with overall 2-year survival of 50% compared to about 75% in classical ALCL. Whether it is related to the definite molecular biology of this unique variant of ALCL or due to the disseminated nature of the disease, needs to be analyzed further.
To conclude, the small cell variant of ALCL often creates a diagnostic pitfall owing to its atypical clinical presentation, like our index case compounded by the unusual cell morphology, unlike typical ALCL. A high index of suspicion aided by ALK along with CD30 and EMA immunopositivity helps in raising the possibility of this entity as a differential, which can be confirmed by ancillary molecular techniques.
Contribution of Authors: Director and Head, Path and Lab Medicine, Medanta, The medicity, Gurgaon, 122018
Cell Block --- Dr Sandeep
Flowcytometry, PS - Dr Renu & Dr H P pati
Manuscript review- Dr saumyaranjan
Current affiliation of Dr Renu Saxena
Director and Head, Path and Lab Medicine,
Medanta, The medicity,
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]