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ORIGINAL ARTICLE: LEUKEMIA AND LYMPHOMA
Year : 2017  |  Volume : 6  |  Issue : 3  |  Page : 129-131

Systemic and primary cutaneous anaplastic large cell lymphoma: Clinical features, morphological spectrum, and immunohistochemical profile


1 Department of Pathology, Christian Medical College and Hospital, Ludhiana, Punjab, India
2 Department of Clinical Hematology, Hemato-Oncology and Bone Marrow (Stem Cell) Transplant Unit, Christian Medical College and Hospital, Ludhiana, Punjab, India
3 Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA

Date of Web Publication14-Sep-2017

Correspondence Address:
Kanwardeep Singh Kwatra
Department of Pathology, Christian Medical College and Hospital, Ludhiana, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-330X.214575

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  Abstract 

Background: T-cell lymphomas with anaplastic morphology typically comprise of anaplastic lymphoma kinase positive, anaplastic large cell lymphoma (ALK+ ALCL), ALK-negative ALCL (ALK- ALCL), and primary cutaneous ALCL (PC-ALCL). However, other entities such as diffuse large B-cell lymphoma, peripheral T-cell lymphoma, Hodgkin lymphoma, and undifferentiated carcinoma can also show similar anaplastic features. Aims: To study the clinical features and histological spectrum of ALCL and emphasize the role of immunohistochemistry (IHC) in their diagnosis and categorization. Setting and Design: Eight cases of ALCL diagnosed over a period of 4 years were selected for the study. Materials and Methods: Histopathological review and IHC was performed on all cases. Two ALK+ ALCL cases were tested by fluorescent in situ hybridization (FISH) for t(2;5)(p23;q35). Results: There were four cases of ALK+ ALCL and two each of ALK- ALCL and PC-ALCL. Histologically, all the subtypes showed pleomorphic and “hallmark” cells with strong CD30 expression and variable loss of T-cell antigens. One case of PC-ALCL was leukocyte common antigen (LCA) negative. Epithelial membrane antigen was positive in all the six systemic ALCL cases. Two cases tested for t(2;5)(p23;q35) by FISH were positive. Conclusions: Diagnosis of ALCL is based on recognizing the key morphological features, especially the presence of “hallmark” cells. IHC is essential for confirmation of diagnosis and excluding other malignancies with anaplastic morphology. The inclusion of CD30 in the initial IHC panel will help identify LCA negative cases and avoid misdiagnosis.

Keywords: Anaplastic large cell lymphoma, anaplastic lymphoma kinase-1, CD30, epithelial membrane antigen, immunohistochemistry, non-Hodgkin lymphoma, T-cell


How to cite this article:
Kwatra KS, Paul PA, Calton N, John JM, Cotelingam JD. Systemic and primary cutaneous anaplastic large cell lymphoma: Clinical features, morphological spectrum, and immunohistochemical profile. South Asian J Cancer 2017;6:129-31

How to cite this URL:
Kwatra KS, Paul PA, Calton N, John JM, Cotelingam JD. Systemic and primary cutaneous anaplastic large cell lymphoma: Clinical features, morphological spectrum, and immunohistochemical profile. South Asian J Cancer [serial online] 2017 [cited 2017 Dec 17];6:129-31. Available from: http://journal.sajc.org/text.asp?2017/6/3/129/214575


  Introduction Top


Anaplastic large cell lymphomas (ALCLs) are a group of T-cell lymphomas composed of anaplastic large lymphoid cells which show diffuse CD30 positivity. It includes three entities, namely anaplastic lymphoma kinase positive, ALCL (ALK+ ALCL), ALK-negative ALCL (ALK− ALCL), and primary cutaneous ALCL (PC-ALCL).[1],[2],[3] ALCL should be distinguished from other lymphomas with anaplastic features which may also show CD30 expression, like diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma, and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). In this single institutional study of eight cases, we analyze the clinicopathological features and immunohistochemical (IHC) profile of ALCL with emphasis on diagnostic pitfalls.


  Materials and Methods Top


All cases diagnosed as ALCL over a period of 4 years in our institution (2011–2014), were included in the study. Hematoxylin and eosin sections and IHC sections were reviewed. All cases were stained with CD45, CD30, ALK-1, CD20, PAX5, CD15, epithelial membrane antigen (EMA), Epstein–Barr virus (latent membrane protein-1) and Ki-67 using standard IHC protocols. Fluorescent in situ hybridization (FISH) for ALK translocation t(2;5)(p23;q35) was carried out using Vysis ALK dual color LSI break apart FISH probe.


  Results Top


Of a total of 246 cases of non-Hodgkin lymphoma (NHL) diagnosed over a period of 4 years, eight cases (3.3%) were categorized as ALCL. Of these, four were ALK+ ALCL, and there were two cases each of ALK− ALCL and PC-ALCL.

The clinical features and histopathological findings are summarized in [Table 1]. The age range was 15–72 years with an equal sex distribution in all the subtypes. B-symptoms were present in four cases, three of which were ALK+ ALCL. Extranodal involvement of the intestine was present in one case of ALK− ALCL. One case of PC-ALCL had multiple lesions on the thigh and gluteal region while the other had a solitary lesion on the face. Hepatomegaly was present in three cases, one ALK+ ALCL and two ALK− ALCL cases, while none had splenomegaly. Bone marrow (BM) involvement was present in one case of ALK+ ALCL. Serum lactate dehydrogenase levels were increased with a mean value of 407 U/L.
Table 1: Clinical profile and histopathological findings of patients with anaplastic large cell lymphoma

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All the cases showed diffuse sheets of large anaplastic lymphoid cells with interspersed scattered “hallmark” cells. The latter showed large kidney-shaped vesicular nuclei, conspicuous nucleoli, and abundant cytoplasm [Figure 1]. One case of ALK+ ALCL resembled syncytial variant of nodular sclerosis Hodgkin lymphoma. Mitotic activity was uniformly high. A polymorphous inflammatory background was present in one case of ALK− ALCL and one case of PC-ALCL, which was ulcerated.
Figure 1: Anaplastic lymphoid cells and “hallmark” cells (arrows) (H and E, ×800)

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IHC findings are shown in [Table 2]. All cases were strongly and uniformly positive for CD30. The pattern of staining of ALK-1 in all the four ALK+ ALCL cases was nuclear and cytoplasmic [Figure 2]. One case of PC-ALCL was leukocyte common antigen (LCA) negative. Aberrant loss of CD3 was present in 5/8 cases, CD5 loss in 3/8, and both CD3 and CD5 loss in 2/8 cases. Both the cases of PC-ALCL were EMA negative while all the six cases of systemic ALCL were positive. The mean Ki-67 proliferative index was 74%. Two cases of ALK+, ALCL tested for t(2;5)(p23;q35) by FISH were positive.
Table 2: Immunohistochemical profile of anaplastic large cell lymphoma cases

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Figure 2: Anaplastic lymphoma kinase-1 positivity, both nuclear and cytoplasmic (IHC, ×400)

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Complete staging and work up were possible in five of eight cases. Of these five cases, treatment was possible in three; 2 ALK+ ALCL (Case numbers 1 and 2) and 1 PC-ALCL (Case number 7). All were given six cycles of cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP) and were in clinical remission at their last follow-up of 3 years, 1 year, and 2 years 9 months, respectively. Two patients; one ALK+ ALCL (Case number 4) and one ALK− ALCL (Case number 5), expired at diagnosis, and the remaining three were lost to follow-up.


  Discussion Top


The rarity of ALCL was highlighted in our study which showed it to comprise 3.3% (8/246) of all NHL. A clinical evaluation of 1378 cases of NHL by International NHL Classification Project found ALCL to be comprising 2.4%.[4]

The clinical profile of our patients was similar to that described in literature. ALK+ ALCL mostly occurs in the first three decades of life with the male:female ratio ranging from 1.5 and 6.5.[1] This lymphoma is aggressive and frequently presents as Stage III–IV disease with systemic symptoms and extranodal involvement.[1] The frequency of BM involvement is 11%. Only one case of ALK+ ALCL in our series had BM involvement. ALK− ALCL occurs in older patients, peak age of incidence being in the sixth decade of life, with a lower male predominance when compared to ALK+ ALCL. Advanced-stage disease and B-symptoms are relatively less common.[2],[5] Primary cutaneous CD30-positive T-cell lymphoproliferative disorders include PC-ALCL and lymphomatoid papulosis (LyP). The median age at diagnosis for PC-ALCL is 60 years with a male:female ratio of 2–3:1.[3],[6] Common sites of involvement are the face, trunk, extremities, and buttocks. They commonly present with solitary nodules that may ulcerate. In 20% of cases, the lesions are multiple while in 10% cases there may be regional lymph node involvement.[3],[6]

Histologically, all types of ALCL are characterized by sheets of large pleomorphic cells with a variable proportion of “hallmark” cells showing typical horseshoe-shaped nuclei. In ALK+ ALCL, morphological patterns that have been recognized are: (1) Common pattern (60%); (2) lymphohistiocytic pattern (10%); (3) small cell pattern (5–10%); (4) Hodgkin-like pattern (3%); and (5) composite pattern (15%).[1],[4] One case of ALK+ ALCL in our series showed nodular sclerosis Hodgkin-like pattern. The rest showed “common pattern.” The histology of ALK− ALCL shows a similar morphologic spectrum.[2],[4] PC-ALCL shows nonepidermotropic infiltrates of anaplastic cells with a variable number of inflammatory cells in the background which are especially prominent in ulcerated lesions. To differentiate such cases from LyP features like lesions limited to an anatomical region and infiltration into subcutaneous tissue favor a diagnosis of PC-ALCL.[7]

The defining feature of all types of ALCL is strong and diffuses CD30 staining in more than 75% of tumor cells. All eight cases in our series had a uniform and intense CD30 staining. Positivity for CD30 is not specific for ALCL and can be expressed by HRS cells and a subset of B- and T-cell lymphomas.[4] However, the CD30 immunostain is generally less intense in CD30+ PTCL-NOS and DLBCL and is often seen only in a fraction of tumor cells. ALCL usually demonstrate an aberrant T phenotype, with frequent loss of T-cell markers. Null cell ALCL by IHC can usually be proven to be lymphoma of T-cell origin with clonal T-cell receptor rearrangements.[4] In our series, aberrant T-cell antigen loss was a frequent finding. A diagnostic pitfall is negative or weak staining for LCA in some cases of ALCL.[8] One case of PC-ALCL was LCA negative with loss of T-cell antigens and initially misdiagnosed as melanoma at another institute. Hence in suspected cases, CD30 should always be included in the initial IHC panel. In certain situations, like Case number 4 in our study, which was a treated case of carcinoma esophagus, metastatic carcinoma may enter the histological differential diagnosis. It is preferable to use cytokeratin immunostain than EMA for this purpose as ALCL can be EMA positive.[4] EMA expression is more frequent in ALK+ than ALK− ALCL (83% vs. 43%).[5]

In histologically suspected cases which are a CD30 positive, further evaluation with markers for T-cells (CD2, CD3, CD5), B-cells (CD20, PAX5), Hodgkin lymphoma (CD15, PAX5) and ALCL (ALK-1) is required. To distinguish PC-ALCL from systemic ALCL with secondary skin involvement, EMA can be helpful, which is usually negative in the former.[7] Feature which differentiates ALK− ALCL from PTCL-NOS is weak and heterogeneous staining of CD30, consistent expression of T-cell markers and EMA negativity in the latter.[5]

Systemic ALK+ ALCL show t(2;5)(p23;q35) in 84% cases. Variant translocations also occur, albeit with a much lower frequency.[9] Translocation t(2;5) results in a nuclear and diffuse cytoplasmic staining for ALK-1 on IHC. All the four ALK+ ALCL cases in our series showed nuclear and diffuse cytoplasmic staining and two of these who were tested for t(2;5) by FISH were positive. Variant translocations can produce cytoplasmic, membranous or nuclear staining patterns.[1]

CHOP chemotherapy regimen remains the standard of care in primary systemic ALCL. The addition of etoposide to the standard CHOP regimen is an important consideration for young patients with ALK+ ALCL.[10] Immunologic strategies with anti-CD30 agent brentuximab vedotin and ALK inhibitor crizotinib have also been used. Solitary or localized PC-ALCL is best treated with radiation therapy or surgical excision.

Five year overall survival (OS) rates for ALK+ ALCL have ranged from 70% to 93% and that of ALK− ALCL from 15% to 49%.[5] PC-ALCL has a very high OS of 90% at 10 years.[3] Two patients of ALK+ ALCL and one of PC-ALCL who were given CHOP therapy showed good response to treatment and were in clinical remission at their last follow-up.


  Conclusions Top


The clinical and histopathological findings of our study are commensurate with that recorded in literature. LCA negativity and aberrant T-cell antigen loss are potential diagnostic pitfalls. However, a diligent search for hallmark cells with the inclusion of CD30 and at least two T-cell markers in the initial IHC panel will clinch the diagnosis in most cases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Delsol G, Falini B, Muller-Hermelink HK, Campo E, Jaffe ES, Gascoyne RD, et al. Anaplastic large cell lymphoma (ALCL), ALK-positive. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO Classification of Tumours of Haemopoietic and Lymphoid Tissue. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2008. p. 312-6.  Back to cited text no. 1
    
2.
Mason DY, Harris NL, Delsol G, Stein H, Campo E, Kinney MC, et al. Anaplastic large cell lymphoma, ALK-negative. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO Classification of Tumours of Haemopoietic and Lymphoid Tissue. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2008. p. 317-9.  Back to cited text no. 2
    
3.
Ralfkiaer E, Willemze R, Paulli M, Kadin ME. Primary cutaneous CD30-positive T-cell lymphoproliferative disorders. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO Classification of Tumours of Haemopoietic and Lymphoid Tissue. 4th ed. Lyon: International Agency for Research on Cancer (IARC); 2008. p. 300-1.  Back to cited text no. 3
    
4.
Inghirami G, Pileri SA; European T-Cell Lymphoma Study Group. Anaplastic large-cell lymphoma. Semin Diagn Pathol 2011;28:190-201.  Back to cited text no. 4
    
5.
Savage KJ, Harris NL, Vose JM, Ullrich F, Jaffe ES, Connors JM, et al. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ALCL and peripheral T-cell lymphoma, not otherwise specified: Report from the International Peripheral T-Cell Lymphoma Project. Blood 2008;111:5496-504.  Back to cited text no. 5
    
6.
Burg G, Kempf W, Cozzio A, Feit J, Willemze R, Jaffe ES, et al. WHO/EORTC classification of cutaneous lymphomas 2005: Histological and molecular aspects. J Cutan Pathol 2005;32:647-74.  Back to cited text no. 6
    
7.
Calzado-Villarreal L, Polo-Rodríguez I, Ortiz-Romero PL. Primary cutaneous CD30+ lymphoproliferative disorders. Actas Dermosifiliogr 2010;101:119-28.  Back to cited text no. 7
    
8.
Gustafson S, Medeiros LJ, Kalhor N, Bueso-Ramos CE. Anaplastic large cell lymphoma: Another entity in the differential diagnosis of small round blue cell tumors. Ann Diagn Pathol 2009;13:413-27.  Back to cited text no. 8
    
9.
Amin HM, Lai R. Pathobiology of ALK+ anaplastic large-cell lymphoma. Blood 2007;110:2259-67.  Back to cited text no. 9
    
10.
Schmitz N, Trümper L, Ziepert M, Nickelsen M, Ho AD, Metzner B, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: An analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood 2010;116:3418-25.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

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