|Year : 2013 | Volume
| Issue : 4 | Page : 649-652
Anaplastic large cell lymphoma: A single institution experience from India
KC Lakshmaiah1, B Guruprasad1, Ashish Shah2, S Kavitha3, Linu Jacob Abraham1, K Govindbabu1, BS Aruna kumari3, L Appaji3
1 Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India
2 Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, India
3 Department of Paediatric oncology, Kidwai Memorial Institute of Oncology, Bangalore, India
|Date of Web Publication||11-Feb-2014|
PG Hostel Room Number 108, Kidwai Memorial Institute of Oncology, Dr. M. H. Marigowda Road, Bangalore
Source of Support: None, Conflict of Interest: None
Background: Systemic anaplastic large cell lymphoma (ALCL) accounts for 2-8% of non-Hodgkin's lymphoma in adults and 10-15% in children. While there is ample data in the world literature about the clinical features and outcome of this disease, prognosis in Indian patients is largely unknown.
Objective: To study the clinical, pathologic profile and outcome ALCL.
Materials and Methods: Fifty patients who had pathologically proven diagnosis of systemic ALCL at our institute from June 2003 to May 2011 were included for retrospective analysis. This included 30 cases of anaplastic lymphoma kinase+ (ALK+), ALCL and 20 cases of anaplastic lymphoma kinase- (ALK−), ALCL. The hospital protocol for treatment of these patients included CHOP chemotherapy regimen in >15 years of age and MCP842 protocol with vinblastine for 1 year in <15 years of age. Event free survival was noted. These outcomes were correlated with ALK status, International Prognostic Index (IPI) score, and stage at presentation.
Results: At a median follow-up of 36 months (range: 6-72 months) ALK− ALCL had a poor outcome. The 3 year event free survival in pediatric ALCL was 66.7%. In adults, this was 60% ALK+ ALCL was 60% and 20% in ALK− ALCL.
Conclusions: Systemic ALCL is an aggressive disease. CD3 + positivity is commonly seen in ALK− ALCL and ALK+, epithelial membrane antigen + positivity is seen in ALK+ ALCL. ALK− ALCL, advanced stage III, IV and high IPI score were associated with poor prognosis. The demographic profile and outcome in our study was similar to the world literature. With new drugs like crizotinib and brentuximab vedotin the future looks very promising.
Keywords: Anaplastic large cell lymphoma, anaplastic lymphoma kinase positive/negative, chemotherapy
|How to cite this article:|
Lakshmaiah K C, Guruprasad B, Shah A, Kavitha S, Abraham LJ, Govindbabu K, Aruna kumari B S, Appaji L. Anaplastic large cell lymphoma: A single institution experience from India. J Can Res Ther 2013;9:649-52
|How to cite this URL:|
Lakshmaiah K C, Guruprasad B, Shah A, Kavitha S, Abraham LJ, Govindbabu K, Aruna kumari B S, Appaji L. Anaplastic large cell lymphoma: A single institution experience from India. J Can Res Ther [serial online] 2013 [cited 2020 Feb 28];9:649-52. Available from: http://www.cancerjournal.net/text.asp?2013/9/4/649/126468
| > Introduction|| |
Anaplastic large cell lymphoma (ALCL) is a rare T cell lymphoma. It was first identified by Stein et al. in 1985 as tumor, which are strongly CD (cluster of differentiation) 30 positive; after discovery of CD30 in 1982 by Schwab et al.  The first step in elucidating the pathobiology ALCL was taken in the early 1990 when the recurrent t (2;5)(p23;q35) was described.  This chromosomal translocation leads to the generation of the chimeric protein NPM (nucleophosmin)- anaplastic lymphoma kinase (ALK), which helped in the identification of the two subtypes of systemic ALCL. Since, the last two decades there is ample data in world literature regarding the demographic profile and outcome of this rare disease, outcome in Indian patients is largely unknown due to the paucity of data.
In this study, we have compared the clinical, histological, immunohistochemical (IHC), and outcome of the two subtypes of ALCL. To the best of our knowledge, this is the largest study of the demographic profile and outcome of systemic ALCL in India.
| > Materials and Methods|| |
sixty five patients were diagnosed to have systemic ALCL during June 2003 to May 2011 at our institute based on the diffuse unequivocal CD30 positivity and immunophenotypic features of mature activated T cell. Fifty of these patients received treatment at our institute and were considered for the study. Patients with primary cutaneous ALCL were excluded from the analysis. The case records of these 50 patients were analyzed in detail for demographic profile, clinical features, treatment given and outcome.
The major clinical parameters studied were age, sex, tumor stage at presentation, B symptoms, site of disease (nodal; extranodal), performance status (ECOG-Eastern cooperative oncology group- scale), no of extranodal sites, and LDH (lactate dehydrogenase) value more than the upper limit of the normal range in our institute). The staging work up for all patients included chest X-ray, ultrasound abdomen, computed tomography scan neck, thorax, abdomen, and bone marrow examination. PET (positron emission tomography) scan was used only in affordable patients for staging. Ann Arbor staging system was used to stage the disease. Based on the above parameters the patient was divided into risk groups, by using the international prognostic index (IPI). After lymph node biopsy, morphological subtype of ALCL was noted. IHC markers were further used for confirmation of diagnosis and sub classification of ALCL; these markers included CD30, ALK, LCA (leukocyte common antigen), CD3, epithelial membrane antigen (EMA), LMP (latent membrane protein), CD4, and CD8. Cytogenetics was not routinely studied in all patients. In the absence of standard protocol for treatment of ALCL, the hospital protocol for treatment of these patients included CHOP (Cyclophosphamide, adriamycin, vincristine and prednisolone) chemotherapy regimen in >15 years of age and MCP (multicentric protocol) 842 protocol with vinblastine maintenance in <15 years of age. Radiotherapy was given for bulky lymphadenopathy. The patients were followed-up every 3 monthly for initial 2 years and 6 monthly thereafter.
The event free survival (EFS) was evaluated for all patients using the Kaplan Meier curve (SPSS 19 - SPSS Inc., USA). These outcomes were correlated with ALK status, IPI score, and stage at presentation.
| > Results|| |
The clinical features are shown in [Table 1]. In the ALK+ subgroup, median age of the presentation was 14 years (range: 1-45 years, 92% cases ≤ 30 years of age) whereas in the ALK− subgroup, the median age of the presentation was 37.5 years (range 15-75 years, only 10% cases less than 20 years). There was a male preponderance in both the subgroups. Swelling due to lymphadenopathy was the most common presenting complaint seen in 60% of cases in both subgroups, with the mean duration of symptoms being 3 months. The most common lymph node groups involved were cervical (ALK+, 13 cases; ALK−, 10 cases), inguinal (ALK+, 12 cases; ALK−, 8 cases) and axillary (ALK+, 9 cases; ALK−, 6 cases) in that order. Among the total number of cases exhibiting lymphadenopathy, a major proportion of cases (ALK+, 64%; ALK−, 52%) presented with involvement of >1 lymph node region. Splenomegaly was seen in 12 cases (ALK+, 9; ALK−, 3).
Extranodal involvement was seen in 24 (48%) cases; of which 11 cases (ALK+, 7; ALK−, 4) presented as a primary extranodal disease. The details of the extranodal sites involved are given in [Table 2].
In the morphological subtypes, the classic pleomorphic pattern was the most common histological subtype noted in both ALK+ and ALK− groups, as shown in [Table 3].
[Table 4] shows the IHC marker positivity in both the subtypes of ALCL, with CD3 positivity more common in ALK− ALCL, and EMA positivity more common ALK+ ALCL.
These patients were treated by two team of specialist; one by pediatric oncology team in less than 15 year, another by medical oncology team in >15 years. Both used different protocols. The outcomes in both these patients are given in [Figure 1] and [Figure 2] respectively. At the median follow-up of 36 months, the EFS in pediatric ALCL was 66.7%, 60% in adult ALK+ ALCL and 20% in adult ALK− ALCL. Advanced stage (P = 0.01), ALK− ALCL (P = 0.001) and high IPI score (P = 0.03) correlated with poor outcome.
|Figure 1: Event-free survival in patients <15 years of age, where all patients were ALK+ anaplastic large cell lymphoma|
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|Figure 2: Event free survival in >15 years, which included both subgroups|
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| > Discussion|| |
ALCL represents 2% of all non-Hodgkin's lymphoma.  There is scarcity of data in Indian context about this disease. Little is known about the clinical, hematological profile and outcome in our setting.
Compared to patients hailing from China and Pakistan, the median age of the presentation was lower with ALK+ ALCL, but similar to those reported in world literature for patients with ALK− ALCL. ,,
The incidence of nodal disease versus extranodal disease was similar world literature, with involvement of bone being the commonest extranodal site in ALK+ ALCL and skin involvement in ALK− ALCL. However, involvement of bone marrow and central neural system was not seen in our series compared to world literature. 
Systemic ALCL is generally aggressive with the majority of patients presenting with stage III or stage IV disease at the onset. Other larger case series also have shown similar data. 
Among ALK+ ALCL, the incidence of small-cell variant and lymphohistiocytic variants were similar to world series, which comprised around 6% of all cases.  Comparing the IHC marker, ALCL has the immunophenotype of mature activated T cells with CD30 positivity. A greater proportion of ALK− ALCL tumors were CD3+ (59% vs. 19%; P < 0.001), and ALK+ ALCL tumors were more often EMA+ (EMA; 86% vs. 47%; P = 0.002), consistent with a prior report. 
The outcomes in these patients are given in [Figure 1] and [Figure 2] respectively. Effectiveness of vinblastine maintenance has been shown by various trials, both in upfront and relapsed pediatric ALCL. , Vinblastine was given at the dose (6 mg/m 2 ) with one vinblastine injection during each course followed by weekly vinblastine to complete a total of 1 year of treatment. The 3 year EFS was 66.7% in pediatric ALCL with a median duration of event free interval being 30 months, which was similar to other larger reported studies. , In adults, the 3 year EFS in ALK+ ALCL was 60% and median duration of event free interval being 24 months, whereas in ALK− ALCL it was 20% and median duration of event free interval being 16 months, which were similar to the outcome from other large series.  The limitations of our study are the lack of cytogenetics and a short follow-up interval.
Advanced stage (P = 0.01) ALK− ALCL (P = 0.001) and high IPI score (P = 0.03) correlated with poor outcome, similar to data from other larger studies. 
Newer therapy used in ALCL includes brentuximab vedotin and crizotinib. brentuximab vedotin is immune-conjugate that combines an anti-CD30 antibody with monomethylauristatin E, a potent antimicrotubule agent. Crizotinib is an inhibitor of ALK tyrosine kinase that has been approved for the treatment of ALK non-small cell lung cancer.  Ongoing trials are evaluating the role of these drugs both in the first line and recurrent setting.
| > Acknowledgments|| |
We are grateful to the faculty of Department of Medical and Pediatric Oncology, KMIO, Bangalore, 560029. We extend our heartfelt thanks to all the faculty of the department of pathology especially Dr. Clementina Rama Rao, Professor, Department of Pathology.
| > References|| |
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]