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CASE REPORT Table of Contents  
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Small cell variant anaplastic large cell lymphoma presenting as leukemia: A case report and review of Literature

1 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Hematology, All India Institute of Medical Sciences, New Delhi, India

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Date of Submission06-May-2021
Date of Decision10-Dec-2021
Date of Acceptance11-Dec-2021
Date of Web Publication07-Jun-2022


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:

   Introduction Top

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.[1] Since its initial perception by Stein et al.[2] 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.[3],[4] Characteristically, though both nodal and extranodal sites like the skin, bone, soft tissue, lungs, and liver[3] are involved, however, the bone marrow involvement and leukemic presentation are rare and described usually with the small cell variant.[5] 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.[6] 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.[7] 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 Top

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 Top

Kinney et al.[4] 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.[7] The bone marrow involvement, using standard methods, is detected in only 10–14% of the cases.[8] In such cases, leukocytosis is invariably present with the infrequent presence of atypical lymphocytes in the form of cerebriform or flower-like cells.[7]

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.[1],[4],[9] 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.[1],[9] 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.[3] 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.[10] 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.[11]

As per studies, the 2-year overall survival rate has been predicted to be about 75–90% in ALK-positive ALCL.[12] However, the biological behavior of the small cell variant of ALCL is under speculation. Hodges et al.[13] 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.[13] 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,

Gurgaon, 122018

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.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Stein H, Foss HD, Dürkop H, Marafioti T, Delsol G, Pulford K, et al. HCD30+ anaplastic large cell lymphoma: A review of its histopathologic, genetic and clinical features. Blood 2000;96:3681-95.  Back to cited text no. 1
Stein H, Mason DY, Gerdes J, O'Connor N, Wainscoat J, Pallesen G, et al. The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: Evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 1985;66:848-58.  Back to cited text no. 2
Falini B, Lamant-Rochaix L, Campo E, Jaffe ES, Gascoyne RD, Stein H, et al. Anaplastic large cell lymphoma (ALCL), ALK-positive. In: Swerdlow SH, Campo E, Harris NL, et al., editors. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2017. p. 411-6.  Back to cited text no. 3
Kinney MC, Collins RD, Greer JP, Whitlock JA, Sioutos N, Kadin ME. A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma. Am J Surg Pathol 1993;17:859-68.  Back to cited text no. 4
Grewal JS, Smith LB, Winegarden JD, Krauss JC, Tworek JA, Schnitzer B. Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: A report of three cases and a review of the literature. Ann Hematol 2007;86:499-508.  Back to cited text no. 5
Duyster J, Bai RY, Morris SW. Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 2001;20:5623-37.  Back to cited text no. 6
Summers TA Jr, Moncur JT. The small cell variant of anaplastic large cell lymphoma. Arch Pathol Lab Med 2010;134:1706-10.  Back to cited text no. 7
Bayle C, Charpentier A, Duchayne E, Manel AM, Pages MP, Robert A, et al. Leukemic presentation of small cell variant anaplastic large cell lymphoma: Report of four cases. Br J Haematol 1999;104:680-8.  Back to cited text no. 8
Benharroch D, Meguerian-Bedoyan Z, Lamant L, Amin C, Brugières L, Terrier-Lacombe MJ, et al. ALK-positive lymphoma: A single disease with a broad spectrum of morphology. Blood 1998;91:2076-84.  Back to cited text no. 9
Nguyen JT, Condron MR, Nguyen ND, De J, Medeiros LJ, Padula A. Anaplastic large cell lymphoma in leukemic phase: Extraordinarily high white blood cell count. Pathol Int 2009;59:345-53.  Back to cited text no. 10
Sano F, Tasaka T, Nishimura H, Akiyama T, Kubo Y, Matsuhashi Y, et al. Small cell variant of anaplastic large cell lymphoma diagnosed by a novel chromosomal abnormality t (2;5;3)(p23;q35;p21) of bone marrow cells. Pathol Int 2008;58:494–7.  Back to cited text no. 11
Brugières L, Pacquement H, Le Deley MC, Leverger G, Lutz P, Paillard C, et al. Single-drug vinblastine as salvage treatment for refractory or relapsed anaplastic large cell lymphoma: A report from the French Society of Pediatric Oncology. J Clin Oncol 2009;27:5056–61.  Back to cited text no. 12
Hodges KB, Collins RD, Greer JP, Kadin ME, Kinney MC. Transformation of the small cell variant Ki-1+ lymphoma to anaplastic large cell lymphoma: Pathologic and clinical features. Am J Surg Pathol 1999;23:49-58.  Back to cited text no. 13

Correspondence Address:
Saumyaranjan Mallick,
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpm.ijpm_443_21


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