Nodal peripheral T-cell lymphomas are not well understood, and most of them are classified in the “not otherwise specified group” (PTCL-NOS). Data on… [301813]

Nodal peripheral T-[anonimizat] “not otherwise specified group” (PTCL-NOS). Data on their normal cellular derivation are ambiguous. Most peripheral T-cell lymphomas are composed of tumor cells and a (sometimes dominant) [anonimizat] T-lymphocytes.

Peripheral T-cell lymphomas (PTCLs) represent a [anonimizat]; [anonimizat]. There have been significant advances in our understanding of the molecular and signaling alterations seen in these malignancies. These observations have led to novel therapeutic strategies that have had a meaningful impact on outcomes.

T-Nodal peripheral T-cell lymphomas are a [anonimizat] T lymphocytes. [anonimizat] :

peripheral T-cell lymphoma not otherwise specified (PTCL-NOS),

angio-immunoblastic T-cell lymphoma (AITL),

[anonimizat] (ALCL-ALK+),

and a [anonimizat] (ALCL-ALK−)

Peripheral T-cell lymphomas (PTCLs) constitute approximately 10% to 20% [anonimizat]. [anonimizat] 20 subtypes, including T-[anonimizat].[1-4]

PTCLs have a [anonimizat], and adults aged 50 to 60 years.[5-9] [anonimizat], which could be partially explained by diagnostic advances and the aging of the population.[10] Several studies have demonstrated the epidemiologic variability found across different geographic populations (Figure 1).

[anonimizat], and ethnicity.[3,5,8] Additional risk factors are a [anonimizat] (autoimmune etiology or inflammatory response), alcoholism, and smoking.[8,9,11]

Based on clinical presentation, a PTCL may be characterized as one of four subtypes:

nodal,

extranodal,

leukemic

cutaneous.

[anonimizat], [anonimizat].[4,12] Part of the current World Health Organization (WHO) classification for PTCLs is described in Table 1.[4]

The complexity of the histologic classification and the low incidence explain why diagnosing PTCL is challenging.[3,13] [anonimizat], as is combining morphologic evaluation with immunohistochemical analysis.[1,5,14-16] Molecular and genetic studies are important tools for distinguishing subtypes.[13]

Once diagnosed, a patient’s [anonimizat], and imaging findings.[13] It is crucial to consider the patient’s age, [anonimizat], because these will have an impact on treatment decisions.

The International Prognostic Index (IPI), specifically devised for assessing the prognosis of aggressive B-[anonimizat] (OS).[7,17] The Prognostic Index for T-cell lymphoma (PIT), developed by Gallamini et al[18] in 2004, is based on these investigators’ study of Italian patients with PTCL not otherwise specified (PTCL-NOS; Table 2). Although the PIT has already been modified, both these indexes have significant shortcomings. They were developed with small cohorts and before PTCL treatment improved, and they did not differentiate between subgroups.[10,15,18]

In general, patients with PTCL have a poor prognosis. Complete responses are expected in only half of patients, and relapses are common.[9,17] For this reason, autologous stem cell transplant (autoSCT) is often indicated in first remission.[13]

Because the treatment and prognoses of these neoplasms involve different principles,it is essential to distinguish each one by its clinical, immunophenotypic, genetic, and molecular features. Except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, which has no adverse international prognostic index, the prognosis of nodal peripheral T-cell lymphomas is worse than that of aggressive B-cell lymphomas. Chemotherapy based on anthracyclines provides poor outcomes because these neoplasms frequently have multidrug-resistant phenotypes. Based on this, the current tendency is to use intensified cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) regimens with the addition of new drugs, and autologous hematopoietic stem cell transplantation. This paper describes the clinical features and diagnostic methods, and proposes a therapeutic algorithm for nodal peripheral T-cell lymphoma patients.

Introduction

Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of malignancies of the immune system, encompassing more than 40 entities with specific clinical, morphologic,immunophenotypic, and molecular characteristics. In the Western World, NHLs originate from B lymphocytes in 85–90%of cases and from lymphoid T cells and natural killer cells (NK)in 10–15% of cases, while T-cell lymphomas represent a higher proportion of NHL cases in Asian countries, accounting for up to 25% of these neoplasms.1 T-cell malignancies derived from precursor or immature T cells originate from leukemia-lymphoblastic T-cell lymphoma. Otherwise, the NHLs that originate from mature T lymphocytes or NK cells are recognized as peripheral T-cell lymphomas (PTCL). The latter represent 12–15% of all NHL sand, according to the World Health Organization (WHO) Classification of Tumors, comprise 22 different entities categorized according to clinical presentation as primary nodal, primary extranodal, primary cutaneous, and disseminated or leukemic forms as summarized in Table 1.1–3This review discusses the main clinical and therapeutic aspects of primary nodal PTCLs such as peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angio-immunoblastic T-cell lymphoma (AITL), anaplastic large-cell lymphoma-anaplastic lymphoma kinase (ALK) positive (ALCL-ALK+), and anaplastic large-cell lymphoma-ALK negative (ALCL-ALK−).

Clinical and epidemiological aspects

PTCL-NOS

The nodal subtypes of PTCL occur predominantly in patients from Europe and North America, and of these, PTCL-NOS is the most common histology.[8,10] The median age at presentation is approximately 60 years, with a male predominance. Clinically, most patients present with advanced disease.[13]

PTCL-NOS is not a distinct entity.[13] It can be described as an assortment of histologies with cytologic and phenotypic heterogeneity that cannot be subclassified as other PTCLs.[4,8]

Clinical

Most common T cell lymphoma category in non-EBV-endemic populations (North America/Europe)

Predominantly nodal presentation

Extranodal involvement common

skin, gastrointestinal tract, liver, bone marrow

Generally aggressive lymphomas with poor response to therapy

Category likely comprises heterogeneous clinical entities which cannot be reliably distinguished

Morphologic categories not prognostically useful

Cytotoxic marker (granzyme and/or TIA-1) positivity has been proposed as a poor prognostic factor in a Japanese study; however the poor outcome could also have been due to concomitant EBV positivity, and it is not clear whether this is true in non-EBV endemic populations

Diagnostic Criteria

Morphologic features are highly variable

Cell size usually medium to large, but can be small

Pattern of infiltration usually diffuse

T-zone variant

Malignant infiltrate spares follicles

Cytologic atypia is subtle

Vascular/mixed inflammatory background

Cytologically malignant features usually present

Nuclear pleomorphism and irregular nuclear contour

Vesicular or hyperchromatic chromatin pattern

Prominent nucleoli

Background often vascular with admixed plasma cells, eosinophils, histiocytes, immunoblasts

Lymphoepithelioid cell variant (“Lennert lymphoma”)

Clusters of epithelioid histiocytes

Malignant infiltrate with subtle cytologic atypia

Accompanying B cell proliferation in ~20%

Diagnosis of diffuse large B cell lymphoma requires sheets of monoclonal large B cells

Diagnosis of plasmacytoma requires sheets of monoclonal plasma cells

Molecular evidence of B cell clonality is NOT sufficient for diagnosis of B cell lymphoma/plasmacytoma

Grading / Staging / Report

Stage I

I if involvement of a single lymph node region

IE if involvement of a single extralymphatic organ or site

Stage II

II if two or more lymph node regions on same side of diaphragm

IIE if localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm

Stage III

III if Involvement of lymph node regions on both sides of the diphragm

IIIS if spleen involved

IIIE if extralymphatic site involved

Stage IV

Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement

Systemic Symptoms in 6 months preceding admission

Fever, night sweats, 10% weight loss

A = absent

B = present

Extranodal sites are also designated

M+ = marrow

L+ = lung

H+ = liver

P+ = pleura

O+ = bone

D+ = skin and subcutaneous tissue

Although originally designed for Hodgkin lymphoma, the Ann Arbor System is also used for non-Hodgkin lymphomas.

The pathology report should contain the following information:

Diagnosis in the World Health Organization (WHO) classification

Equivalent diagnosis in other classifications used by relevant clinicians

Results of supplementary studies if performed

Relationship to other specimens from the same patient

Information relevant to staging if available

Immunohistology

Non-lineage specific markers

CD30+ 30-60%

Cytotoxic marker ~10%

TIA-1 and/or granzyme

CD56+ ~10%

T lineage markers:

Loss of T cell markers is common and is helpful in diagnosis

CD3+ 80-90%

CD5+ 50-60%

CD4+ 50%

CD8+ 20%

CD4/CD8 double negative ~30%

Genetic analysis

Most cases show T cell gene rearrangement

~1/3 show clonal immunoglobulin gene rearrangement

NOT sufficient for diagnosis of B cell lymphoma/plasmacytoma (see Diagnostic Criteria)

Complex cytogenetic abnormalities often present and are highly variable

Help establish clonality but are not prognostically significant

In situ hybridization for EBV early region RNA (EBER):

~60% of cases positive; EBV+ cells correspond to CD20+ B immunoblasts

Gene expression profiling has identified three subtypes of PTCL-NOS: TBX21-overexpressing, GATA3-overexpressing (associated with the worst prognosis), and PTCLs expressing other cytotoxic genes (Table 3).[3,4,19]

Conventional cytogenetic tests suggest limited recurrent karyotype abnormalities, which in most cases lack disease specificity.[6] MicroRNA profiling is being explored as another alternative for characterization and as an aid in improving our understanding of tumor biology.[16,20]

The treatment regimens developed for PTCL were derived from those designed for B-cell lymphomas.[21-24] In particular, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), with or without consolidation radiotherapy, is the regimen most often employed. The addition of etoposide to CHOP (CHOEP or dose-adjusted EPOCH) potentially benefits a subset of younger patients. Although adding etoposide to CHOP does not affect OS, it is associated with improved treatment-free intervals.[22-24]

Other CHOP-based combinations for first-line therapy feature the addition of alemtuzumab, denileukin diftitox, or bortezomib. Other intensive regimens include hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with methotrexate and cytarabine) and ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone), but to date, none of these regimens has been shown to be superior to the others.[13]

Due to the heterogeneity of PTCL-NOS and its poor outcomes, there is no standard of care for treatment.[13,25-27] However, most centers will consider consolidation with high-dose chemotherapy and autoSCT.[24]

In cases of relapsed/refractory disease, there are several options for second-line therapy (Table 4).[24] It is important to note that not all are approved by the US Food and Drug Administration for use in PTCL-NOS, and even fewer have been approved for this indication by the European Medicines Agency.

Patients with PTCL-NOS have a poor prognosis, with a 5-year OS rate of approximately 30%.[8] Those with a higher IPI score usually have an even worse OS.[13]

PTCL-NOS are represented by nodal or extranodal T-cell lymphomas not otherwise categorized as any specific entity in the current WHO classification. These tumors represent 60–70% of all PTCLs, and 5–7% of all NHLs. They occur more commonly in adults with a median age of 60 years and have a slight male predominance.4–6 Although lymph node involvement predominates in the majority of cases, these lymphomas often disseminate to the bone marrow, liver, spleen, and other extranodal sites such as the skin and lung. They rarely have a leukemic presentation.5,6 Patients often present with unfavorable clinical characteristics including B symptoms, elevated lactate dehydrogenase (LDH) levels, high tumor burden, advanced disease (Stage III or IV), and poor performancestatus.5,6

Differential Diagnosis

Other lymphomas

Angioimmunoblastic T cell lymphoma

Systemic anaplastic large cell lymphoma

Extranodal NK/T cell lymphoma, nasal type

T cell rich diffuse large B cell lymphoma

Nodular lymphocyte predominance Hodgkin lymphoma

Classical Hodgkin lymphoma

Non-neoplastic lymphadenopathies

Paracortical (T zone) lymphoid hyperplasaia

Viral lymphadenitis, especially infectious mononucleosis

Anticonvulsant associated lymphadenopathy

Dermatopathic lymphadenopathy

Toxoplasmosis lymphpadenitis

Granulomatous disease

Autoimmune lymphoproliferative syndrome (ALPS)

Kikuchi-Fujimoto disease, proliferative phase

AITL

AITL is the second most prevalent PTCL. It occurs most often in Europe and North America in persons who are between 60 and 70 years of age.[8] Most patients are symptomatic, with lymphadenopathy, constitutional and associated B symptoms, and often with advanced-stage disease and bone marrow infiltration (more than 70% of cases).[1,2,6,7,18,29,30] AITL has a particular signature, which is associated with hepatosplenomegaly, dysgammaglobulinemia, immune compromise, and cutaneous manifestations (eg, rash).[31,32] The diagnosis often follows an immune event, such as exposure to a medication, an infection, or an allergic reaction.[33] The autoimmune phenomena typical of AITL are likely related to the similarity between neoplastic and follicular helper T cells.[34]

Pathologic diagnosis is often difficult due to the presence of atypical B cells that are often EBV-positive and simulate Reed-Sternberg cells.[34] As in Hodgkin lymphoma, neoplastic cells are in the minority and the microenvironment of AITL is composed of an infiltration of reactive small lymphocytes, eosinophils, plasma cells, epithelioid cells, immunoblasts, histiocytes, and follicular dendritic cells.[34,35] The hyperplasia of follicular dendritic cells and the high concentration of endothelial venules are also typical histologic changes of AITL; patients with FTCL usually do not have these characteristics, helping us to differentiate between the two groups.[4,8,28] However, the immunohistochemical and genetic abnormalities are similar in both, demonstrating a concordant cellular origin.[28,34] RHOA, TET2, and DNMT3A mutations are seen in the majority of patients.[36]

First-line therapy for patients with AITL remains an anthracycline-based regimen, similar to the regimen used for the majority of patients with T-cell lymphomas.[23,24] Complete responses are expected in only half of patients, and relapses are common.[9,17] For this reason, and similar to PTCL-NOS and anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALCL), high-dose chemotherapy followed by autoSCT has been utilized to consolidate treatment in chemosensitive patients. Those who achieve a complete response have better outcomes. Timing of high-dose chemotherapy and autoSCT remains controversial.[7,12,21,22,30,37,38]

Older or unfit patients should not receive intensive treatment. Although cyclosporine with or without prednisone has provided some short-term benefit, results are not optimal.[13]

Patients with chemotherapy-refractory AITL, similar to those with refractory PTCL-NOS, may respond to a variety of new drugs, available as mono- or combination therapy (Table 4).[25,29,37,39]

The AITL subtype is characterized by a specific clinical syndrome and polymorphic infiltrate involving lymph nodes, with proliferation of high endothelial venules in a tree-like pattern and irregular proliferation of follicular dendritic cells(FDC) with predominantly perivascular distribution.

AITL represents the second most common subtype of PTCL (15–20% of cases) with its prevalence only being exceeded by PTCL-NOS. It occurs most commonly in elderly patients (aged 60–65 years),with a slight male predominance.7 Typical cases of AITL show acute or subacute systemic features that may mimic drug reactions or systemic infections. Clinically, AITL presents as small and generalized lymphadenopathy, hepatosplenomegaly, and constitutional symptoms. Maculo-papular rash occurs in 50% of cases and paraneoplastic manifestations such as arthritis, vasculitis,serous effusions, and neurological manifestations are not uncommon. Laboratory features include eosinophilia, poly-clonal hyper gamma globulinemia, elevated serum LDH and erythrocyte sedimentation rate (ESR), as well as circulating autoantibodies (cryo agglutinins, cryoglobulins, immune complexes, positive direct Coombs test) and para neoplastic phenomena of an immune nature (hemolytic anemia, leukocytoclastic vasculitis, rheumatoid arthritis, and auto immune thyroid disease).1,4,7ALCL is a PTCL characterized by large polymorphic lymphoid CD30+cells with abundant cytoplasm and horseshoe-or kidney-shaped nuclei. The three recognized subtypes are ALCL-ALK+, ALCL-ALK−, and primary cutaneous anaplasticlymphoma.8ALCL-ALK+predominates in younger patients, with a median age of 30 years, and represents 3–5% of NHLsin adults and 30% of NHLs in children, with a male pre dominance. Extra nodal involvement is frequent, and 50% of cases are diagnosed at an advanced stage (III or IV) and inpatients with B symptoms. The most commonly involved sites include the skin, subcutaneous tissue, bone, lung, and liver.Bone marrow involvement occurs in 10–30% of cases, but the leukemic phase is unusual and occurs more frequently in the small-cell morphological variant. It rarely presents with gastrointestinal and central nervous system involvement. Despite the advanced stage involving multiple extra nodal sites, most patients present with low-risk or low-intermediate risk disease according to the International Prognostic Index(IPI), since performance status is frequently preserved and most patients are younger, with normal LDH levels atdiagnosis.4,9ALCL-ALK−is morphologically indistinct from ALCL-ALK+, but does not show chromosomal translocations involving the ALK gene or expression of the ALK protein. The disease pre-dominates in the elderly; extra nodal involvement occurs in up to half of cases and is usually diagnosed in patients with advanced stage disease who have B symptoms and aggressive disease. Recently, an unusual variant associated with prosthetic breast implants that has an indolent behavior has beendescribed.8

Angioimmunoblastic T Cell Lymphoma

Definition

T cell lymphoma of probable germinal center T cell origin, characterized by a polymorphous infiltrate with a prominent proliferation of high endothelial venules and follicular dendritic cells, frequently with marked constitutional symptoms

Alternate/Historical Names

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD)-type T cell lymphoma

Angioimmunoblastic-type T cell lymphoma

Immunoblastic lymphadenopathy

Lymphogranulomatosis X

Historical note

Angioimmunoblastic lymphadenopathy was originally felt to be a precursor lesion that in some cases evolved into T cell lymphoma

Presence in most cases of clonal T cell receptor gene rearrangements has led to re-classification as T cell lymphoma, even when the malignant T cell population is not histologically evident

Diagnostic Criteria

Loss of normal lymph node architecture

Atretic or absent germinal centers

Prominent arborizing high endothelial venules with PAS positive amorphous perivascular material

Patent subcapsular sinus, even in the presence of extracapsular extension

Diffuse polymorphous paracortical infiltrate including lymphocytes, immunoblasts,plasma cells, histiocytes, and eosinophils

Follicular dendritic cell proliferation outside germinal centers/around high endothelial venules (usually requires immunohistochemistry)

Neoplastic T cell population often obscured by reactive infiltrate

Small to medium-sized but occasionally large cells

Abundant clear cytoplasm and irregular nuclear contour

Often appear in clusters around high endothelial venules

Often requires immunohistochemistry

An early form shows hyperplastic germinal centers

Germinal centers lack mantle zones, have irregular borders

Subtle sprouts of follicular dendritic cells extend from germinal centers (usually requires immunohistochemistry)

Many cases show accompanying B cell proliferation

About 70% are EBV related

May be polymorphic or monmorphic, immunoblastic or plasmacytic

Diagnosis of diffuse large B cell lymphoma requires sheets of monoclonal large B cells

Diagnosis of plasmacytoma requires sheets of monoclonal plasma cells

Molecular evidence of B cell clonality is not sufficient for diagnosis of B cell lymphoma or plasmacytoma

May produce a Hodgkin-like proliferation with Reed-Sternberg-like cells

Constitutional symptoms and laboratory abnormalities common

Clinical

Aggressive T cell lymphoma of middle-aged/older adults

~20% of peripheral T cell lymphomas

Usually presents at advanced stage with constitutional symptoms, systemic lymphadenopathy+/- hepatosplenomegaly, and bone marrow involvement

Occasionally involves extranodal sites, such as skin

Constitutional symptoms and findings may include fever, pruritic skin rash, edema

Polyclonal hypergammaglobulinemia

Inflammatory disorders (arthritis, vasculitis, pleuritis)

Autoimmune disorders (hemolytic anemia)

Laboratory abnormalities common

Results in immunocompromised with susceptibility to infection

Secondary lymphomas may develop

usually diffuse large B cell lymphoma, often EBV+

Prognosis poor

Death frequently due to infection

Immunohistology and Flow Cytometry

Neoplastic T cell population:

T lineage markers

CD2+

CD3+

CD4 ~90% +

CD5+

CD7 often lost (~1/3+)

Germinal center T cell markers

CD10 60-90%+

Native germinal center B cells are larger and weakly CD10+

Granulocytes are strongly CD10+

CXCL13+

Bcl6 70-80%+

Proliferation of follicular dendritic cells outside follicle centers/around high endothelial venules is characteristic

CD21+ (more sensitive marker)

CD23+

Genetic analysis

Molecular clonality studies

80-90% of cases show clonal T cell receptor gene rearrangement

~1/4 of T cell gene rearrangements are oligoclonal

~ 1/3 show immunoglobulin gene rearrangement

rare cases show immunoglobulin gene rearrangement in the absence of a T cell receptor gene rearrangement

Cytogenetic abnormalities often present

help establish clonality

not specific for this diagnosis

In situ hybridization for EBV early region RNA (EBER):

~50% of cases positive, including 70% of cases with accompanying B cell proliferation

EBV+ cells correspond to CD20+ B immunoblasts

Clinical laboratory

A variety of abnormalities may be found

Cold agglutinins

Positive Coombs test

Circulating immune complexes

Anti-smooth muscle antibodies

Rheumatoid factor

Anti-nuclear antibodies

Paraproteins

Cryoglobulins

Differential Diagnosis

Other lymphomas

Peripheral T cell lymphoma, unspecified

Nodal marginal zone lymphoma

T cell / histiocyte rich diffuse large B cell lymphoma

Nodular lymphocyte predominance Hodgkin lymphoma

Classical Hodgkin lymphoma

Non-neoplastic lymphadenopathies

Paracortical (T zone) lymphoid hyperplasia

Viral lymphadenitis, especially infectious mononucleosis

Anticonvulsant-associated lymphadenopathy

Dermatopathic lymphadenopathy

Toxoplasmosis lymphadenitis

Angiofollicular lymphoid hyperplasia (Castleman disease), plasma cell type

Staging

70% present in stage III or IV

Ann Arbor Staging System

Stage I

I if involvement of a single lymph node region

IE if involvement of a single extralymphatic organ or site

Stage II

II if two or more lymph node regions on same side of diaphragm

IIE if localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm

Stage III

III if Involvement of lymph node regions on both sides of the diphragm

IIIS if spleen involved

IIIE if extralymphatic site involved

Stage IV

Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement

Systemic Symptoms in 6 months preceding admission

Fever, night sweats, 10% weight loss

A = absent

B = present

Extranodal sites are also designated

M+ = marrow

L+ = lung

H+ = liver

P+ = pleura

O+ = bone

D+ = skin and subcutaneous tissue

Although originally designed for Hodgkin lymphoma, the Ann Arbor System is also used for non-Hodgkin lymphomas.

The pathology report should contain the following information:

Diagnosis in the World Health Organization (WHO) classification

Equivalent diagnosis in other classifications used by relevant clinicians

Results of supplementary studies if performed

Relationship to other specimens from the same patient

Information relevant to staging if available

ALCL

ALCL, in particular the ALK-positive subtype, affects a younger population (median age, 35 years).[5,8] Clinically, ALCL can be divided into three subtypes: cutaneous, systemic, and breast implant–associated (BIA).[4,8] Patients with systemic disease usually have generalized lymphadenopathy, characteristic of stage IV disease, and extranodal involvement. Bone marrow, bone, and lung are the sites most often affected.[13] Although ALCL has variable morphologic features, the presence of large, highly irregular cells with wreath-like or horseshoe-shaped nuclei is a hallmark.[40]

CD30 and ALK protein expression are the signature markers of this distinctive entity; these give ALCL unique clinical features and a distinctive prognosis. The rearrangement of the ALK gene is a classic biomarker, present in > 50% of ALCLs and with prognostic significance. The most common rearrangement—t(2;5)(p23;q35)—creates a fusion gene composed of nucleophosmin and ALK.[13] Patients with ALK-positive ALCL have a higher OS rate than ALK-negative patients (OS at 5 years: 70% vs 49%).[8,20,41] However, this survival difference is not seen in patients younger than 40 years.[13]

Other prognostic markers, seen in ALK-negative ALCL, are rearrangements of DUSP22 and T63; these are associated with a better and worse prognosis, respectively.[20]

The CHOP-like regimens are also used for ALCL, as first-line treatment in both ALK-positive and ALK-negative patients.[23,37] Patients with ALK-positive ALCL typically have a good outcome.[23,24] For this reason, autoSCT is only indicated for relapse.[37,42] AutoSCT can be considered in ALK-negative patients without rearrangement of DUSP22 (Table 2). To achieve more consistent and durable responses in the first line, studies have explored combining new drugs, such as brentuximab vedotin (an anti-CD30 immunoconjugate) and crizotinib (oral ALK inhibitor), with CHOP. Targeted agents are also used for salvage treatment.[12,29,30,39]

Definition

Systemic CD30+ T cell lymphoma usually composed of cohesive large cells witih abundant cytoplasm and pleomorphic nuclei; half or more express anaplastic lymphoma kinase (ALK1)

Alternate/Historical Names

Anaplastic large cell lymphoma (T/null cell type)

Ki-1 lymphoma (included some cases of diffuse large B cell lymphoma)

Diagnostic Criteria

Cohesive large cells with abundant cytoplasm and pleomorphic nuclei

Hallmark cells (“horseshoe cells”)

Characteristic large cells with U-shaped or C-shaped nuclei surrounding a brightly eosinophilic Golgi area

Most frequent in the common variant

Scattered hallmark cells usually also found in small cell, lymphohistiocytic and other variants

Cohesive growth pattern

Intrasinusoidal growth in lymph nodes (if lymph node is not effaced)

Numerous histological variants have been described, and may coexist

Common variant

large anaplastic cells with abundant eosinophilic cytoplasm and pleomorphic nuclei

Small cell variant

Smaller cells with less irregular nuclei than common variant

Hallmark cells in perivascular location

Lymphohistiocytic variant

Predominance of histiocytes

Hallmark cells in perivascular location

Less common subtypes: neutrophil-rich, giant cell rich, signet ring, sarcomatoid, Hodgkin-like with nodular sclerosis

T cell or “null cell” immunophenotype

Lack of B cell or classical Hodgkin immunophenotype

ALK1 immunopositivity/ALK1 translocation is definitional in this setting, but is absent in up to 40% of cases

It is debated by some experts that ALK1-negative cases should be classified as peripheral T-cell lymphoma, NOS

A rare set of large B cell lymphomas express ALK1

May involve multiple lymph node and soft tissue sites, including skin, but must not be limited to the skin

See primary cutaneous anaplastic large cell lymphoma

Primary Systemic Anaplastic Large Cell Lymphoma

Immunohistochemistry and flow cytometry

Non-lineage specific markers

ALK1

60-85% of cases overall

91% of pediatric cases positive

CD30 >95%

In small cell and lymphohistiocytic variants, strongest CD30 staining is present in larger cells in perivascular location

EMA >95%

Keratin reported in some older studies

clusterin > 90%

CD45 >90%

CD56 (NCAM) 15%

T lineage-associated markers

T cell antigen loss is common, but most cases express at least one

Rare cases with “null-cell” phenotype by immunohistochemistry

CD43, CD45RO commonly positive (~2/3 positive)

CD43 is also expressed in monocytes, acute myeloid leukemia, and some B cell lymphomas

CD2, CD4, LAT sometimes positive (40-50%)

LAT is also expressed in megakaryocytes, mast cells

CD3, CD5, CD7, CD8 commonly negative (<25% positive)

Cytotoxic proteins

TIA-1, granzyme B, or perforin (80-90% positive)

> 90%  positive for one or more

Genetic analysis

Gene translocation involving ALK is definitional if present and correlates with ALK1 expression pattern by immunohistochemistry

t(2;5) translocation (ALK-nucleophosmin)

most common (70-80 %)

cytoplasmic and nuclear ALK1 by immunohistochemistry

t(1;2) translocation (tropomyosin3-ALK)

10-20%

cytoplasmic ALK1 by immunohistochemistry

a variety of other less common translocations involving ALK predominantly show cytoplasmic ALK1 by immunohistochemistry

Most cases show T cell receptor gene rearrangements (but are negative for immunoglobulin gene rearrangements)

May be useful in cases with a “null-cell” phenotype by immunohistochemistry

Differential Diagnosis

Carcinoma

ALK+ diffuse large B cell lymphoma

Anaplastic variant large B cell lymphoma

Classical Hodgkin lymphoma

Primary cutaneous anaplastic large cell lymphoma

Clinical

Commonly presents with widespread systemic involvement

lymph nodes

extranodal sites

especially skin, bone, soft tissues

rarely gastrointestinal tract, CNS

bone marrow

immunohistochemistry for CD30, EMA or ALK1 may be required to recognize minimal involvement

ALK1 positive cases:

Predominance of children and young adults, male > female

Better prognosis than ALK1 negative cases

ALK1 negative cases:

Older adults

Poorer prognosis than ALK1 positive cases (similar to other peripheral T-cell lymphoma, NOS)

Primary Systemic Anaplastic Large Cell Lymphoma

Grading / Staging / Report

Originally considered a high grade lymphoma, but responds well to therapy

Ann Arbor Staging System

Stage I

I if involvement of a single lymph node region

IE if involvement of a single extralymphatic organ or site

Stage II

II if two or more lymph node regions on same side of diaphragm

IIE if localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm

Stage III

III if Involvement of lymph node regions on both sides of the diphragm

IIIS if spleen involved

IIIE if extralymphatic site involved

Stage IV

Diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement

Systemic Symptoms in 6 months preceding admission

Fever, night sweats, 10% weight loss

A = absent

B = present

Extranodal sites are also designated

M+ = marrow

L+ = lung

H+ = liver

P+ = pleura

O+ = bone

D+ = skin and subcutaneous tissue

Although originally designed for Hodgkin lymphoma, the Ann Arbor System is also used for non-Hodgkin lymphomas.

The pathology report should contain the following information:

Diagnosis in the World Health Organization (WHO) classification

Equivalent diagnosis in other classifications used by relevant clinicians

Results of supplementary studies if performed

Results of ALK1 staining are clinically important

Relationship to other specimens from the same patient

Information relevant to staging if available

BIA-ALCL

The correlation between breast implants and ALCL has recently been recognized, and BIA-ALCL has been incorporated into the WHO classification as a new provisional entity (Table 1).[4] Different from primary breast lymphoma, BIA-ALCL does not compromise the parenchyma; it presents clinically as a localized seroma involving the implant and is associated with pain and swelling.[4,11] A minority of patients may present with a mass, and in these cases the disease is much more aggressive.[40,43] Irrespective of presentation, systemic symptoms are rare.[44]

There are several theories regarding the etiology and pathogenesis of this rare entity. An inadequate response of the immune system to the implant could explain the lymphomatous proliferation.[43] Implants with a more textured surface are more susceptible to bacterial proliferation, which activates lymphocytes and causes a chronic inflammatory process secondary to a bacterial biofilm infection around the implant. Currently, this is the most compelling theory that has been put forth to explain the development of BIA-ALCL.[43,44] Ralstonia species, gram-negative bacilli found in soil and water, have been associated with nosocomial infections, especially implant-related infection.[11,43]

Similar to ALK-negative ALCL, BIA-ALCL has an anaplastic morphology, with an immunophenotype that includes expression of CD30, CD4, CD43, CD45, and CD2, and the absence of ALK.[11,44] The expression of SOCS3 (suppressor of cytokine signaling 3) is also identified in BIA-ALCL cases, as in systemic ALCL.[44]

Most often, complete surgical excision, including removal of the implant and capsulectomy, results in an excellent outcome.[40] In contrast, when the lymphoma invades the capsule or is systemic, primary treatment should be complemented with chemotherapy. In these cases, relapse is not uncommon and the prognosis is worse.[11]

10Histopathological and molecular diagnostic criteria

An excisional tumor biopsy is essential for correct diagnosis. Needle biopsy guided by imaging is not recommended.1Itshould be highlighted that for the correct diagnosis and classification of PTCL, histo-pathological analysis by an experienced hemato-pathologist using a large sample with a considerable amount of tissue that allows visualization of the broad pattern of lymph node infiltration is necessary, as well as applying a wide immune histochemical panel. In PTCL-NOS, the compromised lymph node shows para-cortical or diffuse infiltration with loss of the normal lymph node architectural pattern. Although large tumor cells pre-dominate, a few cases exhibit small neoplastic cells. The morphologic spectrum varies from monotonous to pleomorphic cells with an excess of mitotic cells (Figure 1). The WHO classification recognizes histological variants such as lympho-epitheliod lymphoma (Lennert lymphoma), follicular, and T-like zone. Phenotypically, it exhibits aberrant antigen expression characterized by a lack of T-cell markers such as CD5 and CD7. Most cases express the CD4 antigen, although some others may be CD8+, particularly the lympho-epitheliod variant.

About 30% of PTCL-NOS express the CD30 marker, but the phenotypic profile and morphologic aspect allow it to be distinguished from ALCL-ALK−since the latter expresses epithelial membrane antigens (EMA) and contains cytotoxic granules. Distinguishing it from classical Hodgkin’s lymphoma (HL) can be achieved by observing the expression of CD15, PAX-5, and Epstein–Barr virus (EBV). Also, PTCL-NOS present with a high proliferative rate, with Ki67higher than 70%, and strong and homogeneous expression ofCD3.1,4,11Cases of PTCL CD30+/ALK−with no histologic similarity to classic ALCL should be categorized as PTCL-NOS.1A mono clonal rearrangement of the T-cell receptor (TCR) gene is usually seen in PTCL-NOS by polymerase chain reaction (PCR);a cytogenetic abnormality with complex karyotype is the rule. In the subtype with a follicular growth pattern, it is common to observe the recurrent aberration t(5;9)(q33;q22) that produces the oncogenic protein ITK-SYK.11The morphological aspects of classical AITL include a diffuse pattern of infiltration by polymorphic cells and variable proportions of atypical neoplastic T-cells together with small lymphocytes, histiocytes, immunoblasts, eosinophils, and plasma cells with peri-lymph node infiltration into subcortical sinuses. Likewise, there is prominent vascular proliferation

with a tree-like pattern of endothelial venules and irregular proliferation of FDC. B immune blasts are usually present in the para-cortical region and may mimic HL (Figure 2). Neoplastic cells express a pattern of follicular T helper cells such asCD3+, CD4+, CD10+, BCL-6+, CXCL13+, PD1+, and ICOS+ cells. Indeed, vascular expansion can be demonstrated by immuno-histo chemistry for CD31 and CD34. Irregular proliferation of FDC can be defined by CD21, CD23, and CD35 staining that are often found with vessels. The B-cell-associated antigen markers, such as CD20 and CD79a, may show immune blasts in the inter-follicular areas. These cells are infected by EBV and are Reed-Sternberg-like cells mimicking classical HL.7,11–14Most of the AITL cases contain a monoclonal population of T cells. The presence of B lymphocyte clones can be detected in up to 30% of cases and the EBV genome is detected in nearly 100%. Karyotypic aberrations occur in 70–80% of cases, mainly trisomy of chromosome 3 and 5, and an additional Xchromosome.11,15Although ALCL-ALK+ presents with a broad morphological spectrum, all cases contain a variable proportion of cells with eccentric nuclei (kidney-like or horseshoe-shaped) with an eosinophilic perinuclear area corresponding to the Golgi, and abundant cytoplasm; these cells are called ‘hallmark cells’. The morphological findings of this disease vary from small to very large malignant cells (Figure 3). In addition, five distinct morphological patterns are recognized including classical, lymphohistiocytic, small-cell, ‘Hodgkin-like’ variant, and mixed pattern.9,11The classical variants represent 60–70%of all cases and their malignant cells are almost exclusively large and sometimes Reed-Sternberg-like. When the lymph node architecture is partially compromised, the cells grow within sinusoids and may simulate metastatic tumors. The cell phenotype exhibits diffuse positivity for CD30 and some-times presents as a ‘perinuclear dot’ that corresponds to Golgi. Expression of the CD2 antigen is common, but CD45RO, CD5, and CD7 are usually negative. Most patients present with aCD4+/CD8−phenotype and show co-expression of cytotoxic antigens such as granzyme B, TIA-1, perforin and the EMAantigen.4,9,11Most cases of ALCL-ALK+ have t(2;5)(p23;q35),resulting in the hybrid product NPM1-ALK. In these cases, the ALK protein can be found in both the cytoplasm and nucleus .About 90% of these lymphomas have a clonal rearrangement of the TCR gene. In addition to the classic t(2;5), a variant chromosome translocation involving the ALK gene and other genes located on chromosomes 1, 2, 3, 17, 19, 22, and X may occur. The morphological and phenotypic aspects of ALCL-ALK−cases are identical to those observed in ALCL-ALK+cases.4,11,16

Prognostic factors

Different studies have shown that the phenotype of T-cell lymphomas can be effectively stratified using the IPI.17,18However,a Prognostic Index for T-cell Lymphomas (PIT) was developed in an attempt to produce more accurate prognostic indicators.This prognostic index identified four risk factors; age, serum LDH, performance status, and histopathological involvement of the bone marrow. Patients were stratified into four risk groups with 0, 1, 2, or more than 2 risk factors with overall survival (OS) of 62%; 53%, 33%, and 18% for each risk group,respectively.19Another index is the modified Prognostic Index for T-cell Lymphoma (mPIT), which incorporates a biological variable(Ki67 expression) and clinical aspects such as age, LDH, and performance status. The mPIT distinguishes three different risk groups:

good risk prognosis,

intermediate risk,

and poor risk.20

The International Peripheral T-cell Lymphoma Project(IPTCLP) proposed another prognostic score that includes age, performance status, and platelet count.18,21

Therapeutic considerations

Conventional multidrug regimens used for aggressive B cell NHL such as CHOP are routinely considered for PTCL treatment. However, the outcomes with anthracycline-based regimens have been disappointing in patients with ALCL-ALK+ with low risk IPI.21–23 The worse outcome of PTCL is the result of many adverse factors such as high expression of P-glycoprotein, which is associated with the anthrax-cycline resistance phenotype (MDR phenotype).3Usually, the overall response rate is low and there is a high rate of early death during first-line treatment. Relapses are common and often occur in the first two years after treatment. Because of the lack of more effective treatment for PTCL that is not ALK positive, the CHOP regimen remains the most commonly used first-line therapy for these malignancies. Several studies demonstrated complete response (CR)rates of 50% and OS at 5 years of 30% with the CHOPregimen.23These disappointing results led to the investigation of new therapeutic strategies such as intensified chemotherapy and alternative protocols such as high-dose therapy followed by rescue with autologous hematopoietic stem cell transplantation (a HSCT). Although the results between different studies were discordant, an intensified CHOP regimen with the addition of etoposide has shown better progression-free survival(PFS), especially in under 60-year-old patients with favorable risk factors.23–25Although spontaneous remissions have been described, AITL often presents with an aggressive clinical course. Occasionally, asymptomatic patients may be observed or treated with corticosteroids or immunomodulators and antiangiogenic drugs such as cyclosporine, thalidomide, and bevacizumab. In general, patients with AITL requiring therapy should be allocated to clinical studies. Of those, CHOP or

Or fludarabine and cyclophosphamide (FC) regimens have been used the most often.7,22,23 On the other hand, patients with ALCL-ALK+ without adverse IPI risk factors have very chemosensitive disease that responds with comparable or superior outcomes to diffuse large B cell lymphoma (DLBCL) when treated with anthracycline-based therapy. Several studies have demonstrated overall response rate (ORR) of 90% with CHOP and5-year OS of 70–80%. ALCL-ALK−and ALCL-ALK+ high risk groups have an intermediate prognosis between ALCL-ALK+ without adverse risk factors and PTCL-NOS, with a 5-year OS of 49% for ALCL-ALK−and 19% for PTCL-NOS. Currently, the management of these patients is similar to those positive for the variant ALK with low IPI, but because the outcome is worse, the same approach used for PTCL-NOS is recommended, with intensification of CHOP by adding etoposide or allocating patients to clinical trials or consolidation withaHSCT.6,16,22,23Usually, the therapeutic approach to PTCL does not involve irradiation, which is reserved for bulky disease (tumor greater than 10 cm) or a residual mass after chemotherapy. However, there is insufficient evidence of clinical benefits using this approach . Many groups have evaluated the role of aHSCT in PTCL that is not ALK positive for first CR or partial response(PR). Although controversial, outside of the clinical trial set-ting patients with AITL, ALCL-ALK−and PTCL-NOS should be treated with CHOP-like therapy and consolidated with aHSCT after the first CR or PR.22,23,26–29 Patients with relapsed or refractory PTCL, acceptable performance status, and no comorbidities should be treated with platinum-based rescue chemotherapy followed by aHSCT. There is still no consensus regarding allogeneic bone mar-row transplantation in these patients, with mortality rates as high as 30–50% when using myeloablative conditioning regimens. This fact has promoted the use of reduced intensity conditioning regimens in some cases.23,30,31

For many patients with PTCL, the available treatment strategies are ineffective and new therapies should be explored. Gemcitabine is a nucleoside analog that overcomes the p-glycoprotein system. Bendamustine and antifolate agents such as pralatrexate are being tested in these lymphomas.32,33Therapy with monoclonal antibodies such as brentuximab vedotin (anti CD30), alemtuzumab (anti CD52),and zanolimumab (anti CD4) have also been evaluated. For the subgroup of PTCL patients whose tumors express the CD30 antigen, particularly systemic ALCL and CD30+PTCL-NOS, brentuximab vedotin has emerged as an interesting therapy. The antibody-drug conjugate combines a monoclonal antibody directed against CD30 with a potent anti-microtubule agent named monomethylauristatin E (MMAE). CD30 is an ideal therapeutic target because of its strong and uniform expression in anaplastic lymphoma. After binding to its tar-get molecule, brentuximab vedotin is internalized and MMAEis cleaved from the antibody molecule, exerting its action through inhibition of microtubule formation. In a phase II multicenter trial of brentuximab vedotin in relapsed and refractory ALCL, the overall response rate was 86%, with a CR rate of 53%. Significant adverse events were peripheral neuropathy, lung toxicity, neutropenia, and thrombocytopenia.34 34 Another new interesting drug for the treatment of these neoplasms is alisertib (MLN8237). This drug is a selective inhibitor of Aurora A kinase (AAK), and shows preclinical activity in PTCL cell lines and patient samples. Recently, Friedberg et al. reported the interim results of a phase II clinical trial of alisertib in patients with aggressive B and T-cell NHL. ORR for the whole study population was 32%, but when divided by subtype, patients with PTCL had an ORR of57%.35 A better understanding of the pathophysiology of these tumors is allowing the use of targeted therapies, such as the ALK inhibitor crizotinib, modulators of epigenetic phenomenon drugs able to restore the transcriptional status of tumor suppressor genes (histone deacetylase inhibitors),and immunomodulating agents that have greater anti-tumoral-activity in AITL. Disease progression is associated with more dysregulation of the immune system than tumor growth phenomena.31,36–40Table 2 shows a comparative analysis of the major epidemiological and clinical characteristics, pathological and therapeutic approaches, prognosis, and new therapeutic agents that can be employed in patients with each of the four main entities discussed in this article.

Coor atlas of clinical hemato

http://surgpathcriteria.stanford.edu/tcell/primary_systemic_anaplastic_large_cell_lymphoma/classificationlists.html