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Year : 2017  |  Volume : 60  |  Issue : 4  |  Page : 533-540
Story of survival in anaplastic large cell lymphoma - sometimes more than the anaplastic lymphoma kinase status: An evaluation of pathologic prognostic factors in 102 cases

1 Department of Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
3 Department of Pediatric Hemato-Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
4 Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

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Date of Web Publication12-Jan-2018


Introduction: Systemic anaplastic large cell lymphoma (ALCL) accounts for 5%–10% of adult non Hodgkin's lymphoma (NHL) and 10%–30% of childhood NHL. Owing to significant differences in survival and gene expression profile, current WHO classifies ALCL into two distinct entities as anaplastic lymphoma receptor tyrosine kinase (ALK) positive and ALK negative ALCL with ALK expression by tumour as a good prognostic indicator. However, in our institute which is a cancer referral institute, our preliminary experience was that even ALK positive tumours did not fare well as compared to ALK- negative ALCL. So, the current study aims at exploring more clinical and pathological factors impacting survival in ALCL patients. Objective: To study clinical and pathological prognostic factors in cases of ALCL. Methods: 102 cases of ALCL were retrieved from pathology database. Pathological features and clinical features of these cases were recorded and factors found to impact overall survival (OAS) and disease-free survival (DFS) curves were identified based on univariate and multivariate analysis. Results: ALK 1 expression was seen in 71/102 (69.6%) cases and was not found to impact OAS or DFS. The 2 year OAS rate for ALK positive patients was 63.5% and DFS rate was 54.4%, while for ALK negative patients, the OAS was 60.5% and DFS was 43.5%. The Ann Arbor stage, performance status, international prognostic index, histological subtype, and the degree of the background inflammatory infiltrate were found to impact the OAS significantly. Increased reactive inflammatory component also negatively impacted DFS. In the multivariate analysis, only the histologic type emerged as significant for OAS. Conclusion: Though ALK plays a role in prognostication of systemic ALCL, advanced stage disease and an inflammatory milieu may modulate the final outcome. We report a study of clinical and pathologic prognostic features in 102 cases of anaplastic large cell lymphoma (ALCL) from a cancer referral institute in India. Anaplastic lymphoma receptor tyrosine kinase (ALK-1) expression was seen in 71/102 (69.6%) cases and was not found to impact overall survival (OAS) or disease-free survival (DFS). The 2-year OAS rate for ALK-positive patients was 63.5% and DFS rate was 54.4%, while for ALK-negative patients, the OAS was 60.5% and DFS was 43.5%. The Ann Arbor stage, performance status, international prognostic index, histological subtype, and the degree of the background inflammatory infiltrate were found to impact the OAS significantly. Increased reactive inflammatory component also negatively impacted DFS. In the multivariate analysis, only the histologic type emerged as significant for OAS. Thus, though ALK plays a role in prognostication of systemic ALCL, advanced stage disease and an inflammatory milieu may modulate the final outcome.

Keywords: Anaplastic lymphoma kinase, large cell lymphoma, non-Hodgkin's lymphoma

How to cite this article:
Agrawal K, Shet T, Sridhar E, Dhende S, Sengar M, Arora B, Laskar S, Gujral S, Menon H, Banavali S. Story of survival in anaplastic large cell lymphoma - sometimes more than the anaplastic lymphoma kinase status: An evaluation of pathologic prognostic factors in 102 cases. Indian J Pathol Microbiol 2017;60:533-40

How to cite this URL:
Agrawal K, Shet T, Sridhar E, Dhende S, Sengar M, Arora B, Laskar S, Gujral S, Menon H, Banavali S. Story of survival in anaplastic large cell lymphoma - sometimes more than the anaplastic lymphoma kinase status: An evaluation of pathologic prognostic factors in 102 cases. Indian J Pathol Microbiol [serial online] 2017 [cited 2023 Mar 30];60:533-40. Available from:

   Introduction Top

Systemic anaplastic large cell lymphoma (ALCL) accounts for 5%–10% of adult non-Hodgkin's lymphoma (NHL) and 10%–30% of childhood NHL.[1],[2],[3] The discovery of the novel chromosomal translocation t (2; 5)[4],[5],[6] gave an impetus to the accurate recognition of the disease pattern and clinical behavior.

The 10-year overall survival (OAS) (71% vs. 15%) and disease-free survival (DFS) (82% vs. 28%) of anaplastic lymphoma receptor tyrosine kinase (ALK)-positive ALCL are significantly better than that of ALK-negative ALCL.[7] Furthermore, gene-profiling data have confirmed that though morphologically similar, ALK-positive and ALK-negative ALCLs are two distinct diseases with the later being more heterogeneous.[8],[9],[10] Given the clearly disparate behavior, the WHO 2008 classification separates out the ALK-positive and ALK-negative groups of ALCL as two different entities. Recently, mutually exclusive chromosomal rearrangements of DUSP22 and TP63 were identified in 30% and 8% of ALK-negative ALCLs and these were absent in ALK-positive ALCLs.[10]

However, in our institute which is a large cancer center, our preliminary experience was that even ALK-positive tumors did not fare well, and hence, this study focused on comparing the pathological and immunohistochemical features of patients in ALK-positive and ALK-negative ALCL cases.

   Materials and Methods Top

A total of 135 patients of systemic ALCL were retrieved from the pathology database from the year 2002–2008. These cases were classified as ALCL according to the WHO 2008 criteria and a diagnosis of ALK-negative ALCL required typical morphology with hallmark cells, strong and uniform CD30 positivity, and negativity for B-cell transcriptional factors PAX5/Oct2 and BOB1. Coexpression of CD4 and cytotoxic granule protein with typical morphology and negative EBERISH were used to distinguish from peripheral T-cell lymphoma (PTCL). ALK-positive ALCL was diagnosed when any nuclear or cytoplasmic staining was seen in tumor cells, and in all cases, >25% of tumor cells stained with ALK.

The basic panel for immunohistochemistry which was done in all ALK-positive cases included leukocyte common antigen (LCA), CD20, CD30, CD3, ALK1, and MIb1. The panel done in ALK-negative cases included besides the above stains a PAX5, Oct2, BOB1, CD4, and TIA1 to rule out Hodgkin's lymphoma mimicking ALK-negative ALCL. A combination of CD4 and TIA1 and EBERISH is unique to ALCL and also helps in ruling out PTCL as CD4 expressing PTCL does not usually express TIA1.

Cases negative for CD3 were called null-cell ALCL as CD4 expression is ubiquitous in ALCL.

After review, 24 cases were deleted due to a changed diagnosis (11 ALCL-like Hodgkin's lymphomas, one CD30-positive NK/T-cell lymphoma, 8 PTCLs, 4 ALK-positive diffuse large B-cell lymphomas), and in 9 cases, the blocks were not available.

The selected 102 cases included in the study were categorized into different histological types (common, lymphohistiocytic [LH], small cell [SC], and mixed) as described in the literature. Tumors where a specific histological subtype could not be assigned were designated as not otherwise specified (NOS). Perivascular arrangement of tumor cells was noted. The total number of tumor cells and the percentage of hallmark cells were documented. The degree of background inflammatory infiltrate within the tumor was graded as 0 (absent), 1+ (<25% of tumor was formed by inflammatory infiltrate), 2+ (25%–50% inflammatory infiltrate), and 3+ (>50% of tumor showed inflammation). Two pathologists (KA/TS) scored the inflammation separately, and in cases where there was disagreement, a consensus result was taken as the final grade. Type of inflammation in background, namely, macrophage or granulocytes, neutrophils/eosinophils, lymphoid cells, or plasma cells were also documented. Immunohistochemistry was done on formalin-fixed paraffin-embedded tissues manually using Biocare Medical MACH 2 antigen retrieval polymer. Antibodies used for immunohistochemical evaluation were CD30 (BerH2, DAKO, 1:50), anaplastic lymphoma kinase (CD247, DAKO,1:100), leukocyte common antigen (LCA/2B11, DAKO, 1:200), CD3 (polyclonal, DAKO, 1:200), epithelial membrane antigen (EMA) (E29, DAKO, 1:200), CD56 (Diagnostic Biosystems, 1:20), CD138 (MI15, DAKO, 1:40), CD4 (Novocastra Leica, 1:10), and CD8 (1A5, Biogenex, 1:2). B-cell transcriptional factors PAX5 (BV6, Diagnostic Biosystems, 1; 40), OCT-2 (207, Novocastra Leica, 1:50), and BOB.1 (TG14, Biocare, 1:75) were done in ALK-negative ALCL to differentiate from Hodgkin's lymphoma. TIA 1 (Biocare, 1:40) and granzyme B (Novocastra Leica, 1:20) were used to document cytotoxic granule protein. The pattern of ALK-1 expression whether nuclear and cytoplasmic and cytoplasmic or both was noted. EBERISH was done in the 52 cases using the Novocastra EBER-ISH kit.

After the histopathological review, the clinical details and follow-up of these patients were retrieved from medical records and case files. The chemotherapy protocol used at our institute to treat ALCL, namely, MCP842 has been validated and published in an earlier study.[11] In addition, as a revision a weekly dose of 4 mg/m2, vinblastine (Velbe) is added instead of vincristine to reduce neuropathy in patients. Responses to treatment were evaluated during therapy by clinical examination and with a whole-body positron emission tomography scan/computed tomography scan at completion of therapy for the presence or absence of disease. OAS was measured from the time of diagnosis till death or last date of follow-up for patients who were alive. DFS was defined as time from completion of therapy to the first occurrence of relapse or event. In patients having progression on therapy, DFS was calculated as 0. The OAS and DFS rates were estimated using Kaplan–Meier analysis, SPSS Statistics for Windows, version 18.0 (SPSS Inc., Chicago, Ill., USA). Survival curves were compared and significance (P value) assessed using the Log Rank Mantel Cox test. Factors significant in the univariate analysis were run through for a multivariate analysis by applying Cox regression model.

   Results Top

Accurately classified systemic ALCL comprised 2.7% of all non-Hodgkin lymphomas and 26.9% of T-cell non-Hodgkin lymphoma during the study period.

Clinical features

The patients ranged from 3 to 73 years of age with a median age of 21 years and mean age of 27 years. There were 76 (74.5%) male and 26 (25.5%) female patients, with a male:female ratio of 2.9:1. In the 100 patients where exact site was known, 43 patients had nodal disease at presentation, 12 had pure extranodal disease, and remaining 45 patients had nodal as well as extranodal disease. More than half (58.2%) of the patients presented with “B” symptoms and 4 patients were hepatitis B surface antigen (HBsAg) positive. In four patients, bone marrow involvement was documented during staging. The extranodal site involvement included soft tissue (24 patients), bone (21 patients), pleura (14 patients), lung (6 patients), liver (12 patients), spleen (10 patients), peritoneum (2 patients), gastrointestinal tract (four esophageal, 3 gastric, 3 colonic, and 1 small intestine), and one each with central nervous system, pericardial, bladder, and breast involvement.

Out of the 99 patients where Ann Arbor stage could be recorded, 19 patients (19.2%) presented with stage I disease, 21 patients (21.2%) had stage II disease, 17 patients (17.2%) were stage III disease, and 42 (42.4%) had stage IV disease. A total of 71 (69.6%) tumors were ALK positive and 31 tumors were ALK negative. While every other site was involved with ALK-positive ALCL, spleen, gastrointestinal, and soft tissue involvement was less common in ALK-negative ALCL. [Table 1] summarizes the clinical differences in ALK-positive and ALK-negative ALCL. A statistically significant difference was seen in the age of occurrence, performance status (PS), and international prognostic index (IPI) between the ALK-positive ALCL and ALK-negative patients. Besides younger age, ALK-positive patients belonged to the low-risk IPI category while most of the ALK-negative patients were older with high-risk IPI (P = 0.008). A performance score (PS) of ≥2 was more frequently seen in ALK-negative as compared to ALK-positive patients.
Table 1: A summary of clinical findings in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative patients

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Pathological findings

The cases studied included 75 cases of common variant [Figure 1]a,[Figure 1]b,[Figure 1]c,[Figure 1]d, 3 LH variants (LH), 2 SC variants (SC), 12 mixed (tumors with admixture of the above patterns), and 10 ALCLs could not be slotted into any histological subtypes - NOS. In the LH variant, hallmark cells were less in number and background infiltrate of macrophages dominated the histology [Figure 2]a and [Figure 2]b. In the SC variant of ALCL, though tumors cells were small and not very anaplastic like a common variant, the ALK1 staining was seen in more cells than LH variant [Figure 2]c and [Figure 2]d.
Figure 1: (a) The common variant of anaplastic large cell lymphoma with typical hallmark cells (arrow) (H and E, 400). (b) Strong CD30 staining with membrane and Golgi zone accentuation (ABC, 400). (c) Nuclear and cytoplasmic staining for anaplastic lymphoma receptor tyrosine kinase in common variant. (d) Leukocyte common antigen staining was weaker in tumor cells as opposed to background (ABC, 200)

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Figure 2: (a) The lymphohistiocytic variant of anaplastic large cell lymphoma with scanty tumor cells (arrow) (H and E, 200). (b) Anaplastic lymphoma receptor tyrosine kinase staining highlights these tumor cells (ABC, 400). (c) Small cell anaplastic large cell lymphoma reveals a lack of typical anaplastic cells (H and E, 200). (d) Anaplastic lymphoma receptor tyrosine kinase staining reveals more highlighted tumor cells as opposed to lymphohistiocytic variant (ABC, 200)

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Five cases had no inflammatory infiltrate, 55 cases had minimal (1+) inflammatory infiltrate, 37 cases had moderate inflammation (2+), and five cases had an intense (3+) inflammation surrounding tumor cells. Forty-five patients had few number of hallmark cells (≤40%) and the remaining cases had >40% hallmark cells.

All 102 cases showed strong and homogeneous CD30 expression in membranous and Golgi zone pattern. ALK-1 expression was nuclear and cytoplasmic in 50 tumors and only cytoplasmic in 21 tumors. More than three-fourths of ALK-positive ALCL (83.3%) expressed LCA. LCA staining pattern was weaker than the background reactive cells [Figure 1]d. In 84 tumors, a CD3 was done and 17 (20.2%) ALCLs showed a T-cell immunophenotype, while remainder was null-cell (non-T) phenotype. EMA expression was seen in 45/63 (71.4%) tumors. Only 3/59 (5%) (2 ALK + and 1 ALK negative) were CD56 positive and 4/60 (6.6%) were CD138 positive (1 case diffuse and 3 focal). Of the ALK-negative cases, 9/27 (33.3%) had T-cell phenotype (P = 0.02). Strong association between ALK and EMA expression was observed (P = 0.002). EBERISH was done in 52 ALCLs and all were negative.

Follow-up and survival studies

Out of 102 patients, 13 patients were lost to follow-up and ten patients died before receiving any chemotherapy. In the 79 patients with follow-up, 57 patients (72.2%) were ALK positive and 22 patients (27.8%) were ALK negative. Histological subtypes in cases with follow up included, 57 common variant, 10 mixed types, 3 LH variant, 2 SC variant, 7 NOS subtypes. Among the 57 ALK-positive patients, 38 (66.6%) achieved complete remissions, of whom 31 are alive without relapse and all others either died or are alive with relapsed disease.

Among 22 ALK-negative patients, after therapy, 16 (72.8%) achieved complete response, 3 (13.6%) had PR, and 3 (13.6%) died of progression progressive disease. The therapy regimens used were MCP842 or cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) with addition of vinblastine (Velbe) in some. Ten out of fifteen patients (66.7%) receiving MCP842, 14/26 (53.8%) given CHOP, 22/27 (81.5%) with MCP842 Velbe and 4/6 (66.7%) with CHOP Velbe had complete response.

The 2-year DFS rate for all patients was 59% and OAS was 63.7%. The 2-year DFS for pediatric patients (≤15 years) was 63.5% and 2-year OAS rate was 74.8%. The 2-year OAS rate for ALK-positive patients was 63.5% and DFS rate was 54.4%, while for ALK negative, OAS was 60.5% and DFS was 43.5%.

The clinical factors adversely impacting OAS included a high Ann Arbor stage (P = 0.007), high/high-intermediate IPI (P = 0.001), and low PS (P = 0.017). Although age did not impact survival (P = 0.282), a pairwise stratification revealed that there was statistically significant OAS difference between patients aged ≤15 years and 16–30 years of age (P = 0.051). Other factors that did not influence OAS were an extranodal versus nodal location (P = 0.437), gender (P = 0.630), presence of A or B symptoms (P = 0.074), presence of a bulky disease (>7 cm as per our institute guidelines) (P = 0.095), hemoglobin levels (P = 0.172), serum albumin levels (P = 0.270), serum lactate dehydrogenase (LDH) (P = 0.308), serum β2-microglobulin (P = 0.373), and T-type of chemotherapy. Amongst the pathological features which were evaluated, the histological subtype was found to significantly impact the OAS whereby prognosis of SC/ LH variants was worst followed by ALCL- NOS while the common and mixed type had best prognosis [Figure 3]. Another histological feature impacting OAS was the extent of background inflammatory cells with tumors having intense inflammation behaving worse and tumors with absence of background inflammatory cells behaving best [P = 0.004, [Figure 4]. In tumors with + 2/+3 inflammation, tumors with mixed inflammation had better OAS curve than the macrophage or granulocyte (neutrophil or eosinophil)-rich tumors though these differences were not statistically significant.
Figure 3: Significant differences in survival between different histological subtypes of anaplastic large cell lymphoma

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Figure 4: Adverse impact of inflammatory background on overall survival of anaplastic large cell lymphoma patients

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The histological features that did not impact OAS were percentage of hallmark cells (P = 0.062), mitotic counts (P = 0.136), perivascular distribution of neoplastic cells (P = 0.136), degree of apoptosis (P = 0.889), and presence of necrosis (P = 0.638). Among the immunophenotypic features, the presence of T-cell immunophenotype (P = 0.924), LCA expression (P = 0.969), CD56 (P = 0.258), and CD138 (P = 0.593) staining did not impact OAS. The ALK status (P = 0.723) and the pattern of ALK expression cytoplasmic or nuclear and cytoplasmic did not impact OAS (P = 0.369).

The extent of background inflammation continued to have a negative impact on DFS, with best DFS for tumors lacking inflammation and worst for those with intense inflammation (P = 0.024). A similar trend toward better curves with a mixed inflammation rather than macrophages and granulocytes (neutrophil/eosinophils) was observed in tumors with + 2/+3 inflammation [Figure 5]. Among the pathologic features evaluated the histological subtype (P = 0.073), the percentage of hallmark cells (P = 0.071), necrosis (P = 0.754), perivascular distribution of neoplastic cells (P = 0.854), extent of apoptosis (P = 0.527) and mitotic count (P = 0.300), LCA (P = 0.696), T-cell immunophenotype (P = 0.466), CD138 (P = 0.266), and CD56 (P = 0.409) did not affect DFS in patients with ALCL. In ALK-positive patients, however, histologic subtype (P = 0.010), high IPI (P = 0.006), high Ann Arbor stage (P = 0.043), and poor Eastern Co-operative Oncology Group PS (P = 0.041) adversely impacted DFS. None of the factors impacted DFS (including histologic type), significantly in the ALK-negative group.
Figure 5: Impact type of inflammatory background on disease-free survival in anaplastic large cell lymphoma

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Although IPI did not impact DFS (P = 0.104), a pairwise stratification revealed that ALCL patients with low-risk IPI did remarkably well as compared to patients in the high-risk category (P = 0.012). A pairwise stratification revealed that patients with stage I disease have better DFS as compared to those with stage IV disease (P = 0.029). Factors not affecting DFS were age group of patients (P = 0.698), gender (P = 0.686), presence of “B” symptoms (P = 0.508), bulky “T” size >7 cm (P = 0.160), low hemoglobin level (P = 0.397), low serum albumin (P = 0.848), elevated serum LDH (P = 0.386), and serum β-2 microglobulin levels (P = 0.684). Type of chemotherapy did not impact DFS (P = 0.286); however, a pairwise stratification revealed that patients with CHOP vinblastine did significantly worse than patients with MCP842 vinblastine (P = 0.025).

   Discussion Top

In the international T-cell lymphoma study (ITLS) project involving 22 countries with 1314 eligible patients, 181 (13.8%) had ALCL.[7] As documented in the above study and present study, the overall incidence and the relative frequency of ALCL in Asia is lower. Two prior studies from our institute have reported an incidence of 4.3%[12] and 4.8%,[13] respectively, for ALCL (among all NHL). A lowered frequency in the current study could be because we have excluded referral cases and used an expanded immunohistochemistry panel for diagnosis. A fourth of our cases of Hodgkin's or PTCL-NOS had been misdiagnosed as ALCL as was also observed in the non-Hodgkin lymphoma classification project.[14]

In the current study, the median age of presentation was 16 years for ALK-positive patients and 48 years for ALK-negative patients and this is concordance with the other studies.[6],[7],[14] Systemic ALCL is notorious for a high incidence of extranodal site predilection, and the same was seen with two-thirds of patients showing some extranodal site involvement (including bone marrow). The pattern of extranodal site involvement in the ALK-positive and ALK-negative group in the present study parallels that reported by the ITLS project report.[6]

The frequency of ALK expression depends on age and stringency of the pathologic criteria used for the diagnosis.[6],[7],[14] The 69.6% ALK expression reflects the preponderance of pediatric patients in our study. Although age did not emerge as a significant factor, patients ≤15 years in our study had 75% OAS at par with rates reported in literature. In the present study, in spite of higher proportion of pediatric patients, ALK status did not impact OAS, and while we cannot exclude a referral bias, few other studies have observed this too.[14],[15] The international T-cell lymphoma project observed that ALK-positive and ALK-negative ALCLs seem to have a similar prognosis (in terms of both DFS and OAS) when patients are stratified according to the clinical parameters (i.e., age and/or stage).[6] This hints that the survival in ALK-positive ALCL is beyond its ALK status and is influenced by clinicopathological features.

Most studies on ALCL focus on clinical factors impacting survival and very few studies in literature stress on the histopathological features and background microenvironment.[15],[16],[17] The histological subtypes significantly impacted survival in our study, whereby the SC and LH variant, followed by ALCL-NOS, behaved much aggressively as compared to the common variant. The SC variant of ALCL in notorious for a leukemic presentation [18],[19] and advanced stage with an overall poor prognosis.[20] Likewise, LH variant of ALCL also has poorer prognosis.[21] The ALCL99 study launched by the European Intergroup for Childhood NHL documented that the presence of a SC/LH component was significantly associated with a high risk of failure in a large series of 365 pediatric cases.[15] The SC and LH variants are closely related, and cases containing a mixture of these two patterns can be seen.[22] Although the number of SC and LH in the present study is very small for definite conclusion, SC and LH fared poorly. In addition, we uniquely report that ALCL where the tumor lacks typical hallmark cells and often shows prominent nucleoli (ALCL-NOS) emerged as an adverse histological type too. The reason for the poorer prognosis for some variants of ALCL is unknown, but it probably is related to the poorer immune response to these deviations from common type.[15],[23] Thus, the histological subtypes appear to be relevant to the prognosis in ALCL and should be indicated in the pathology report. In the multivariate analysis in the ALCL 99 study controlling for clinical characteristics, besides the histologic subtype, a perivascular pattern and CD3 positivity were significantly associated with a high risk of relapse.[24] The perivascular distribution of neoplastic cells and CD3 did not emerge as a significant factor in our study as we had lesser SC/LH cases. Interestingly, transition from one histologic subtype to the other type in ALCL is at times recorded indicating modulation based on different interaction between the tumor and microenvironment.[24]

The immunophenotypic features we report showed mild variations with what is reported in literature. CD3 expression was seen in only 20% ALK-positive ALCL in the present study. Although only half of ALCL express T-cell markers on immunohistochemistry, up to 90% reveal a clonal T-cell origin in both T- and null-cell subtypes on molecular analysis and in both ALK-positive and ALK-negative phenotypes.[25] In our study, LCA expression was seen in 82.5% cases of ALCL (both ALK positive and ALK negative) which is more compared to the 60% rate reported in literature.[7],[26] Although an earlier study in our institute reported EBV in ALCL,[27] we found no association and agree that strictly defined ALCL is “consistently negative for EBV.”[28] We did not come across any immunophenotypic marker in ALCL that was associated with poorer prognosis. A minority of ALCL may be derived from NK/T cells, and in a study, CD56 expression was seen in 16% ALK-positive and 20% ALK-negative ALCL, and this had adverse impact on prognosis in both groups.[29] CD56 expression was seen only in 5% cases in our study and did not emerge as a significant prognostic factor.

Besides the histological type, the degree of background inflammation emerged as a factor impacting OAS and DFS in the univariate analysis. While many studies are focusing on the microenvironment in NHL, very few address this issue in ALCL. An inflammatory background in ALCL is variable and is usually more evident in SC/LH histologic variants.[22] Tamiolakis et al. reported a neutrophil-rich variant of ALK-positive ALCL with an aggressive outcome,[30] but no report has documented aggressive behavior of type of inflammatory cell background in ALCL. A high percentage of activated cytotoxic T-lymphocytes (≥15%) was also shown to be an unfavorable prognostic marker in the ALK-negative group.[16] One recent study documented that high content of intratumoral macrophages in ALK-negative ALCL resulted in inferior outcome, and a similar trend was observed in ALK-positive ALCL though the differences were not statistically significant.[17] It appears that prominence of inflammatory infiltrate promotes aggressive behavior in ALCL. The process of quantification we used is simple and less subject to interobserver variation as tumors with no inflammation versus >50% inflammation are the groups with maximum impact. Interestingly, in our study, though no such statistical significance was reached, tumors with macrophages had better DFS/OAS curves than neutrophil rich or eosinophil-rich tumors indicating that the result may be cytokine modulated. It is known that macrophages have different immune functions with pro-inflammatory and immunosuppressive types,[17] and this could explain the contrast of unfavorable impact of LH subtype but better prognosis with tumor rich in macrophages. While tumor-associated macrophages are immunosuppressive types, in the LH variant, they probably are pro-inflammatory and derogatory.

OAS and DFS rates in our study for ALK-positive tumors are lower than those reported by many large trials (70%–92%).[31],[32] NHL-BFM90 study involving 12 different countries recorded a 2-year DFS and OS rates of 71% and 92%, respectively, for the whole ALCL trial population.[32] While the rate of DFS and OAS for ALK-positive patients was lower, the survival rates for ALK-negative ALCL are more comparable.[31],[32] We found that the IPI was very effective in defining different risk categories, especially for ALK-positive patients in our study as has been documented in several studies before.[6],[7],[32],[33] Both the NHL-BFM90[32] and ALCL99[33] have demonstrated that adding vinblastine to standard chemotherapy for total treatment duration of 1 year in children with high-risk ALCL significantly delayed the occurrence of relapse but did not reduce the risk of failure, resulting in no benefit in the 2-year event-free survival or OAS curves.[28],[29] Likewise, type of chemotherapy did not impact DFS, but a significantly higher response was observed with MCP842 vinblastine/Velbe as compared to other regimens in our study. We speculate that poorer survival of ALK-positive patients in study could either be due to high-risk factors such as IPI and advanced stage in our patients coupled with poorer nutrition and a possibility of impact of histological microenvironment on tumor growth.

   Conclusion Top

Survival story of ALCL is complex and influenced by a volley of clinical factors, histologic subtype, and tumor microenvironment. The inflammatory milieu seems a promising feature and should be evaluated in larger future studies.

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Conflicts of interest

There are no conflicts of interest.

   References Top

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Correspondence Address:
Dr. Tanuja Shet
Department of Pathology, 8th Floor, Annexe Building, Tata Memorial Centre, Dr. E Borges Road, Parel, Mumbai - 400 012
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_778_15

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