I. General Aspects [301819]

I. General Aspects

T-[anonimizat] “not otherwise specified ” (PTCL-NOS). The majority of the PTCLs include resting and activated T-lymphocytes and also tumoral cells.

The PTCLs develop as an unique epidemiology and it has been proved that has a low incidence. Being a [anonimizat]. [anonimizat] a lot and there are new understandings of the molecular and signaling alterations of these malignancies.[anonimizat] a very important impact on the prognosis of the patients.

It is known that PTCL lymphomas come from T [anonimizat]. [anonimizat]:

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

angio-immunoblastic T-cell lymphoma (AITL),

[anonimizat] (ALCL-ALK+),

a [anonimizat] (ALCL-ALK−)

Peripheral T-cell lymphomas (PTCLs) represent a non-homogeneous category of diseases (and their main attributes are presented in Table I) [anonimizat], almost 10% [anonimizat].

Because they are very rare and because they have a [anonimizat] ,compared to their B-Cell counterparts.

[anonimizat] B-cell lymphomas.The cytogenetic abnormalities are few compared to B-cell lymphomas. [anonimizat],known as anaplastic large cell lymphoma.

From 10% to 20% [anonimizat] . There are > 20 subtypes, [anonimizat] a favourable prognosis.[1-4]. For peripheral T [anonimizat], and people with age from 50 to 60 years.[5-9]

The incidence of peripheral T cell lymphomas has increased in the last years and this is because there are a lot of diagnostic advantages evolved and the population that is met nowadays is an aged population with multiple comorbidities.[10] There were a lot of studies that explained the differences between the populations across the globe. (Figure 1).

[anonimizat],the ethnicity and the gender.[3,5,8] A [anonimizat] (inflammatory response or autoimmune etiology), [anonimizat].[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]

The World Health Organization (WHO) classification for PTCLs is described in Table II.[4]

Having a [anonimizat]CL is challenging because this condition has a complex histologic classification.[3,13] In order to distinguish the subtypes, molecular and genetic studies can be used.[13] It is an important need of an experienced hemato-pathologist for an accurate diagnosis and subclassification, combined with the immunohistochemical analysis and morphologic evaluation.[1,5,14-16] The patient’s risk should be then stratified using laboratory, imaging findings and clinical aspects, after the disease is diagnosed.[13] Important factors are the, performance status the patient’s age and comorbidities because these can always influence the treatment and also the prognosis.

The International Prognostic Index (IPI), specifically used for assessing the prognosis of aggressive B-cell lymphomas, is also used and applied for PTCL and it correlates with overall survival (OS) of the patients.[7,17]

The Prognostic Index used for T-cell lymphomas (PIT), was created after a study conducted with patients with PTCL-NOS; (Table III). Both IPI and PIT were created before the improval of the treatment for the peripheral T cell lymphomas .There were no differences in the conducted study based on the indexes.[10,15,18]

As is known that PTCL is having a poor prognosis, only half of the patients are expecting a complete response.[9,17] Because of this ,there is an indication in first remission for the use of autoSCT.[13]

It is essential to distinguish each condition by its clinic, genetic, immunophenotypic, and molecular patterns ,because the prognoses and treatment involve different ways of solving them.The outcome of PTCLs is worse than that of aggressive B-cell lymphomas(exception: ALKL-ALK + , because it has no adverse international prognostic index).

These diseases present multidrug-resistant phenotypes most of the times and chemotherapy based on anthracyclines brings poor outcomes in most of the cases. Current tendency is to use intensified cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) regimens with the addition of new drugs, and autoSCT .

Non-Hodgkin lymphomas are malignancies of the immune system, with > 40 entities with specific morphologic, immunophenotypic, molecular and clinical attributes.

Non-Hodgkin lymphomas (in western countries) come from lymphoid T cells and natural killer cells in 10–15% of cases and from B lymphocytes in 85–90%of cases. T-cell lymphomas have a higher proportion of non-Hodgkin lymphomas cases in Asian countries, accounting for up to 25% of these neoplasms. T-cell malignancies come from precursor or immature T cells originate from leukemia-lymphoblastic T-cell lymphoma. The Non-Hodgkin lymphomas that originate from mature T lymphocytes or NK cells are recognized as PTCLs. The latter represent 12–15% of all Non-Hodgkin lymphomas , according to the WHO.It comprise 22 different entities usually divided based on the clinical description as primary nodal, primary cutaneous, primary extranodal, and disseminated or leukemic forms as summarized in Table IV. [19-21]

II.Clinical and epidemiological aspects

PTCL-NOS

The category of PTCL has a lot of nodal subtypes and most of them are met in North America and in Europe.From them,PTCL-NOS is the most common.[8,10] The patients that had presentations at the hospital were having usually 60 years and most of the them were males. The stage of the disease is usually advanced when the patients present to the hospital.[13]

PTCL-NOS is known to have a heterogeneous combination of histologies and most of the time, it is presented a diversity of cells that differ from one another having different phenotypes .As a result,this condition cannot be subclassified as other PTCLs.[4,8]

Clinical

This condition is from the T cell lymphoma category and is found in non-EBV-endemic populations (North America/Europe)

They have usually a nodal presentation

For the extranodal involvement,there can be found in gastrointestinal tract, skin, bone marrow, liver

This disease usually has poor response at the therapy

It is an aggressive lymphoma

As a poor prognostic factor ,it was found the presence of cytotoxic marker (granzyme and/or TIA-1) positivity; the poor outcome can be related to concomitant EBV positivity

Diagnostic Criteria

There is a high variability for morphologic features

The cells are usually medium to large, but they can also be small

Pattern of infiltration usually diffuse

T-zone variant

Spares follicles are malignant infiltrated

The cytologic atypia is subtle

Vascular/mixed inflammatory background

There is the presentation of cytologically malignant features

irregular nuclear contour and nuclear pleomorphism

hyperchromatic or vesicular chromatin pattern

There are presented vascular with admixed plasma cells, immunoblasts ,eosinophils, histiocytes,

Lymphoepithelioid cell variant (“Lennert lymphoma”)

Clusters of epithelioid histiocytes

A subtle cytologic atypia with malignant infiltrate

This disease is accompanying B cell proliferation in ~20%

sheets of monoclonal large B cells are needed in order to diagnose diffuse large B cell lymphoma.

sheets of monoclonal plasma cells are needed to diagnose plasmacytoma

the diagnosis of B cell lymphoma/plasmacytoma need molecular evidence of B cell clonality ,but this aspect is not sufficient.

Grading / Staging / Report

Stage I

I there is a single lymph node region involved

IE a single site or extra lymphatic organ is involved

Stage II

II there is an involvement of two or more lymph node regions that are presented in the same side of diaphragm

IIE there is an involvement of a site or extra lymphatic organ and one or more lymph node regions that are present in the same side of the diaphragm

Stage III

III the lymph node regions are involved and they are presented on both sides of the diphragm

IIIS the involvement of the spleen

IIIE extra-lymphatic site involved

Stage IV

There is a disseminated involvement of one or more extralymphatic organs or tissues, that are usually with or without associated lymph node involvement

Systemic Symptoms in 6 months preceding admission

Fever, 10% weight loss night sweats,

A = absent

B = present

Extranodal sites are also designated :

M+ = marrow

L+ = lung

H+ = liver

P+ = pleura

O+ = bone

D+ = skin and subcutaneous tissue

The Ann Arbor System is used for non-Hodgkin lymphomas although it was initially created for Hodgkin lymphomas

The pathology report should contain the following information:

Information relevant to staging if available

If there were supplementary studies done,the results should be presented

Diagnosis that is in the World Health Organization (WHO) classification

Relationship to other specimens from the same patient

Immunohistology

Non-lineage specific markers

CD30 + in 30-60%cases

Cytotoxic marker in 10% cases

TIA-1 and/or granzyme

CD56 + in 10% cases

T lineage markers:

The loss of T cell markers is helpful in diagnosis

CD3 + in 80-90% cases

CD4 + in 50% cases

CD4/CD8 double negative in 30% cases

CD5 + in 50-60% cases

CD8 + in 20% cases

Genetic analysis

Gene rearrangement of the T cells are presented in most of the cases

clonal immunoglobulin gene rearrangement is shown in 1/3 of the cases

this aspect is NOT sufficient for diagnosis of plasmacytoma/ B cell lymphoma

There is a high variability of cytogenic abnormalities

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

there are 60% positive cases;EBV+ cells correspond to CD20+ B immunoblasts

There has been found three subtypes of PTCL-NOS using the gene expression (Table V)[3,4,22]:

TBX21-overexpressing,

GATA3-overexpressing (it is usually associated with the worst prognosis),

other cytotoxic genes

Limited recurrent karyotype abnormalities, which in most cases lack the disease specificity are suggested by conventional cytologic tests.[6] An alternative for characterization is done with the use of microRNA , for understanding the tumor biology.[16,23]

The regimens for treating PTCL came from the treatments used for treating B cell lymphomas.[21-24] The most used type of therapy is CHOP.This therapy consist of: doxorubicin, vincristine,cyclophosphamide, and prednisone), with or without radiotherapy.The most beneficial for younger patients considered to be the use of etoposide to CHOP(CHOEP or dose-adjusted EPOCH) and it is associated with improved treatment-free intervals.[22-24]

Other CHOP-based combinations used for first-line therapy feature the addition of alemtuzumab, denileukin diftitox, or bortezomib. Usually,the regimens that work intensively against the disease consist of:

ACVBP (bleomycin, doxorubicin ,cyclophosphamide, vindesine, and prednisone)

hyper-CVAD (doxorubicin,vincristine, cyclophosphamide, and dexamethasone)

None of these regimens is superior to the others and there is no standard of care for treatment.[13,25-27] There are centers that use the consolidation with high-dose chemotherapy and auto-SCT.[24]

In cases of relapsed/refractory disease, there are also therapy options for second-line therapy . [24] A poor prognosis is for the patients with PTCL-NOS, with a 5-year OS rate of approximately 30%.[8] Those with a higher IPI score usually have an even worse OS.[13]

Patients often present with unfavorable clinical characteristics including advanced disease (Stage III or IV), high tumor burden, elevated lactate dehydrogenase (LDH) levels, and poor performance status.[26,27]

Differential Diagnosis

Other lymphomas

Extranodal NK/T cell lymphoma, nasal type

Angioimmunoblastic T cell lymphoma

Classical Hodgkin lymphoma

T cell rich diffuse large B cell lymphoma

Systemic anaplastic large cell lymphoma

Nodular lymphocyte predominance Hodgkin lymphoma

Non-neoplastic lymphadenopathies

Granulomatous disease

Autoimmune lymphoproliferative syndrome (ALPS)

Paracortical (T zone) lymphoid hyperplasaia

Viral lymphadenitis, especially infectious mononucleosis

Anticonvulsant associated lymphadenopathy

Dermatopathic lymphadenopathy

Toxoplasmosis lymphpadenitis

Kikuchi-Fujimoto disease, proliferative phase

AITL

AITL is a T cell lymphoma that is thought to have germinal center T cell origin. It presents a heterogeneous infiltrate that has a prominent proliferation of both endothelial venules and follicular dendritic cells.

From the PTCL category,AITL is the second most prevalent form. Its prevalence is in Europe and North America in persons who have 60 to 70 years of age.[8]

Usually ,patient are symptomatic and present [1,2,6,7,18,28,29,30] :

advanced-stage disease(most of the times)

lymphadenopathy,

constitutional and associated B symptoms,

bone marrow infiltration (more than 70% of cases).

AITL is associated with :

hepatosplenomegaly,

dysgammaglobulinemia,

immune compromise,

cutaneous manifestations (eg, rash).[31,32]

The diagnosis is usually done after an immune event, like an exposure to a medication, or an allergic reaction, or an infection.[33]

The diagnosis for this condition can brig difficulty in order to be made because there are situations when atypical B-cells , most of the times with EBV positivity, simulate Reed-Sternberg cells. [34]

The microenvironment of AITL is composed of an infiltration of

:

plasma cells,

immunoblasts,

eosinophils,

reactive small lymphocytes,

epithelioid cells,

histiocytes,

follicular dendritic cells. [34,35]

Like in Hodgkin lymphoma, there are neoplastic cells that are in the minority .The high concentration of endothelial venules and the hyperplasia of FDC are also typical histologic changes met in AITL; patients presenting FTCL(follicular T cell lymphoma) usually do not have such characteristics, and this is really helpful because it can be made differences between the two groups.[4,8,28] The similarities between them are the immunohistochemical and genetic abnormalities .[28,34] TET2, DNMT3A and RHOA are mutations that are usually seen in most of the patients.[36]

Anthracycline-based regimens are the first-line therapy that is used for patients with AITL.[23,24] Only half of patients are expecting complete response. The relapses are also common.[9,17] Because of this , anaplastic large-cell lymphoma (ALCL) and PTCL-NOS (similar to anaplastic lymphoma kinase (ALK)-negative) high-dose chemotherapy followed by auto-SCT can be utilized to consolidate treatment for the patients having chemo-sensitivity. The timing of high-dose chemotherapy and also of auto-SCT remains controversial and there are studies that are debating these.[7,12,21,22,30,37,38]

Patients that do not have a healthy status or patients that are not in a stable condition,should not receive intensive treatment. Some short-term benefit, was provided by the use of cyclosporine with or without prednisone,but the results are not optimal.[13]

The patients presenting with chemotherapy-refractory AITL, and patients presenting refractory PTCL-NOS, may respond to a large variety of mono- or combination therapy ,all the drugs being new (Table VI). [25,29,37,39]

The typical cases of AITL can show subacute or also acute systemic features that can mimic systemic infections or even drug reactions . Maculo-papular rash from AITL occurs in 50% of cases and there are also manifestations that are not uncommon : the paraneoplastic manifestations like vasculitis, serous effusions, arthritis, and neurological manifestations. Laboratory features include :

elevated serum LDH

polyclonal hyper gamma globulinemia,

erythrocyte sedimentation rate (ESR)

eosinophilia,

circulating auto-antibodies

cryo agglutinins,

cryoglobulins,

immune complexes,

positive direct Coombs test)

para neoplastic phenomena of an immune nature

hemolytic anemia,

leukocytoclastic vasculitis,

rheumatoid arthritis,

auto immune thyroid disease).[41]

ALCL is presented as large polymorphic lymphoid CD30+ cells with a lot of cytoplasm that has horseshoe-or kidney-shaped nuclei. The three recognized subtypes are :

1.ALCL-ALK+,

2.ALCL-ALK−,

3.Primary cutaneous anaplastic lymphoma.[42]

ALCL-ALK+ has the highest prevalence in younger persons, with the age of 30 years, and represents 30% of NHLs in children and 3–5% of NHLs in adults, males are predominant in this category. There are almost 50% of the cases that are diagnosed at an advanced stage (III or IV).

The most commonly involved sites include

subcutaneous tissue,

bone,

the skin,

liver

lung

The leukemic phase is not very usual to happen and it occurs more frequently in the small-cell morphological variant, bone marrow being involved in 10% to 30% of the cases. There are really few situations with central nervous system and gastrointestinal involvement.

Patients present low-intermediate or low-risk risk disease according to the International Prognostic Index, despite the advanced stage involving multiple extra nodal sites, since performance status is most of the times preserved and usually the patients are young, with normal LDH levels when they are diagnosed.[43]

ALCL-ALK−is morphologically indistinct from ALCL-ALK+, the difference is that it does not show chromosomal translocations involving the ALK gene or any presence of the ALK protein. Extra nodal happens in 50% of the situations and is usually diagnosed in patients with an advanced stage of the disease who have aggressive disease and B symptoms, the disease being also predominant in the elderly.[41]

Alternate/Historical Names

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

Immunoblastic lymphadenopathy

Lymphogranulomatosis X

Angioimmunoblastic-type T cell lymphoma

Diagnostic Criteria

Neoplastic T cell population discovered because of the reactive infiltrate

Small to medium-sized but sometimes large cells

Abundance of clear cytoplasm

irregular nuclear contour

Sometimes it appears in clusters surrounding high endothelial venules

Most of the times requires immunohistochemistry

There is a loss of the architecture of the normal lymph node

absent or atretic germinal centers

PAS positive perivascular material present in the high endothelial venules

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

the FDC proliferation is outside germinal centers/around high endothelial venules

An early form shows hyperplastic germinal centers

Germinal centers lack mantle zones,

Germinal centers have irregular borders

follicular dendritic cells can extend from germinal centers

There are a lot of cases that accompany B cell proliferation

Some of them are EBV related 70%

May be monomorphic or polymorphic, plasmacytic or immunoblastic

sheets of monoclonal large B cells are required for the diagnosis of diffused large B cell lymphoma

sheets of monoclonal plasma cells are required for plasmacytoma diagnosis

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

Clinical

Aggressive T cell lymphoma of middle-aged/older adults

~20% of peripheral T cell lymphomas

Results in immune-compromised patients that will have a high susceptibility to infection

There are presentations at a very advanced stage with systemic lymphadenopathy+/- hepatosplenomegaly, bone marrow involvement and constitutional symptoms

Sometimes involves extranodal sites, for example skin

The constitutional symptoms and findings may include:

Polyclonal hypergammaglobulinemia

Fever

pruritic skin rash

Inflammatory disorders (arthritis, vasculitis, pleuritis)

Edema

Autoimmune disorders (hemolytic anemia)

Secondary lymphomas may develop

diffuse large B cell lymphoma, most of them being EBV+

Prognosis poor

Death frequently because of infection

Immunohistology and Flow Cytometry

Neoplastic T cell population:

T lineage markers

CD4 ~90% +

CD3+

CD5+

CD2+

CD7

Germinal center T cell markers

CD10 in 60-90% cases +

B cells native germinal center are larger and weakly CD10+

Granulocytes are CD10+

CXCL13+

Bcl6 70-80%+

The main characteristic is the proliferation of follicular dendritic cells around high endothelial venules /outside follicle centers

CD21+ (usually being a more sensitive marker)

CD23+

Genetic analysis

Cytogenetic abnormalities often present

Can help for establishing clonality

it is usually not specific for the diagnosis

Molecular clonality studies

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

~ 1/3 show immunoglobulin gene rearrangement

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

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

EBV+ cells correspond to CD20+ B immunoblasts

Clinical laboratory

A variety of abnormalities may be found

Positive Coombs test

Circulating immune complexes(CIC)

Cryoglobulins

Cold agglutinins

Anti-nuclear antibodies

Paraproteins

Rheumatoid factor

Anti-smooth muscle antibodies

Differential Diagnosis

Other lymphomas

Nodal marginal zone lymphoma

Peripheral T cell lymphoma, not specific

T cell / histiocyte rich diffuse large B cell lymphoma

Classical Hodgkin lymphoma

Nodular lymphocyte predominance Hodgkin lymphoma

Non-neoplastic lymphadenopathies

Paracortical (T zone) lymphoid hyperplasia

Viral lymphadenitis, most of the cases with infectious mononucleosis

Dermatopathic lymphadenopathy

Toxoplasmosis lymphadenitis

Anticonvulsant-associated lymphadenopathy

Angiofollicular lymphoid hyperplasia (Castleman disease), plasma cell type

Staging

70% of the cases are presenting 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 extra-lymphatic organ or site

Stage II

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

IIE if localized involvement of an extra-lymphatic 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 diaphragm

IIIS if spleen involved

IIIE if extralymphatic site involved

Stage IV

Diffuse or disseminated involvement of one or more extra-lymphatic 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

Source: https://www.cancer.org/cancer/non-hodgkin-lymphoma/detection-diagnosis-staging/staging.html

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

ALCL

Definition

This condition presents as a systemic CD30+ T cell lymphoma ,being a composition of cohesive large cells ,abundant cytoplasm and pleomorphic nuclei;

50% or more of them present anaplastic lymphoma kinase (ALK1)

A subtype of the ALCL, ALK-positive is usually affecting young people (below 40 years old).[5,8]

ALCL has three subtypes:

cutaneous

breast implant–associated (BIA)[4,8]

systemic

Systemic disease is found in persons that present in an advanced stage of the disease,having generalized lymphadenopathy,when admitting to the hospital. The bones, bone marrow and lungs are usually involved. [13]

ALCL is usually described by cells that have an increase in size,with irregularities and with wreath-like or horseshoe-shaped nuclei. [40]

When there is ALK protein expression and CD30 ,these both can bring another entity;ALCL with unique clinical features and a different prognosis. A biomarker, present in > 50% of ALCLs is the rearrangement of the ALK gene .The common rearrangement is —t(2;5)(p23;q35)—. [13] A higher OS rate is presented for the persons with ALK-positive than for the persons that are ALK-negative-the OS at 5 years is 70% vs 49% .[8,20,41] In people younger than 40 years, this difference in the survival is not seen.[13]

Rearrangements of DUSP22 and T63 are other prognostic markers that are seen in ALK-negative ALCL.[20]

For both ALK-negative and ALK-positive patients,the first line therapy is the use the CHOP-like regimens.[23,37] Autologous stem-cell transplantation has one indication: for relapse for the patients that have ALK-positive ALCL because they usually have a good outcome.[23,24,37,42] The indication for autologous stem-cell transplantation can be taken into account when there are ALK-negative patients that do not have a rearrangement of DUSP22 . Combining new drugs was studied in order to achieve durable responses in the first line therapy, These drugs are: crizotinib (oral ALK inhibitor) and brentuximab vedotin (an anti-CD30 immunoconjugate) with CHOP.[12,29,30,39]

Alternate/Historical Names

Ki-1 lymphoma

Anaplastic large cell lymphoma (T/null cell type)

Clinical

There is a presentation of widespread systemic involvement

lymph nodes

bone marrow

IHC for CD30, EMA or ALK1

extranodal locations

especially bone,skin, soft tissues

central nervous system and rarely gastrointestinal tract

ALK1 + cases:

Predominance of children and young people,

male > female

Better outcome than ALK1 negative cases

ALK1 – cases:

Older adults

poorer outcome in comparison to ALK1 + cases (this outcome is similar to other peripheral T-cell lymphoma, NOS)

Primary Systemic Anaplastic Large Cell Lymphoma Grading / Staging / Report

Originally considered a high grade lymphoma,

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

Source:https://www.cancer.org/cancer/non-hodgkin-lymphoma/detection-diagnosis-staging/staging.html

The pathology report should contain:

Diagnosis in the World Health Organization classification

Results of supplementary studies if performed

Results of ALK1 staining are clinically important

Relationship to other specimens from the same patient

If available,information relevant to staging

Diagnostic Criteria

The presence of cells increased in size with pleomorphic nuclei and huge amount of cytoplasm

The presence of a cohesive growth pattern

The presence of intrasinusoidal growth in lymph nodes if the lymph node is not effaced

Hallmark cells (“horseshoe cells”)

These are characteristic large cells that have C-shaped or U-shaped nuclei and that surround a brightly eosinophilic Golgi area

Other places where the scattered hallmark cells can be found : small cell, lymphohistiocytic and other variants

Numerous histological variants have been described, and may coexist

Small cell variant

In comparison to the common variant,it has smaller cells with less irregular nuclei

Presence of Hallmark cells located in the perivascular zone

Common variant

large anaplastic cells with pleomorphic nuclei and abundant eosinophilic cytoplasm

Lymphohistiocytic variant

histiocytes are predominant

Hallmark cells are located in the perivascular zone

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

The immunophenotype of T cell or “null cell”

There is a lack of classical Hodgkin or B cell immunophenotype

ALK1 translocation / ALK1 immunopositivity is mandatory, but there is sometimes absent in almost 40% of the cases

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

ALK1 is expressed by a rare set of large B cell lymphomas

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

Immunohistochemistry and flow cytometry

Non-lineage specific markers

clusterin > 90%

CD45 >90%

EMA >95%

CD30 >95%

CD56 (NCAM) 15%

ALK1

There is a presence of 91% of the pediatric cases that are positive

There is a presence of 60-85% overall

Strongest CD30 staining is present in larger cells in perivascular location

T lineage-associated markers

Even if the loss of the T cell antigen is common, most cases express at least one

CD45RO , CD43 that are commonly + (~2/3 positive)

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

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

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

Cytotoxic proteins

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

> 90%  + for one or more

Genetic analysis

The gene translocation involving ALK is mandatory if will correlate with ALK1 expression pattern at the IHC :

t(1;2) translocation (tropomyosin3-ALK) is present in 10-20% of the situations and it has cytoplasmic ALK1 at immunohistochemistry

t(2;5) translocation (ALK-nucleophosmin) – usually the most common (70-80 %) and it has nuclear and cytoplasmic ALK1 by immunohistochemistry

there are also less common translocations that are involving ALK and these show cytoplasmic ALK1 by immunohistochemistry

T cell receptor gene rearrangements are shown in most of the cases (but are negative for immunoglobulin gene rearrangements) and this aspect can be helpful in case there is a “null-cell” phenotype presented ad IHC

Differential Diagnosis

Classical Hodgkin lymphoma

Anaplastic variant large B cell lymphoma

ALK+ diffuse large B cell lymphoma

Carcinoma

Primary cutaneous anaplastic large cell lymphoma

BIA-ALCL

WHO classification included BIA-ALCL because it has connetion with ALCL.[4] BIA-ALCL does not damage the parenchyma in comparison to primary breast lymphoma; it presents with pain and is usually described as a localized seroma involving the implant.[4,11] This disease is creating more problems when the people admit to the hospital presenting a mass.[41-44] Systemic simptoms appear very rare.[44]

The response of the immune system to the implant is presented as a lymphomatous expression.[43] A higher susceptibility to germs proliferation are having the implants with a more textured surface.This activates lymphocytes and can causes a chronic inflammatory process because of the implant can be surrounded by a bacterial biofilm infection.[45,46] There are germs ,especially from the implant-related infection and these are:Ralstonia species, gram-negative bacilli found in soil and water.[11,46] The etiology and pathogenesis of this entity are still in debate.

Similar to ALK-negative ALCL, BIA-ALCL includes the absence of ALK expression and the.presence of :

CD30,

CD4,

CD43,

CD45,

CD2, [11,44]

The presence of SOCS3 (suppressor of cytokine signaling 3) is also identified in BIA-ALCL cases, as in systemic ALCL.[47]

Results in an excellent outcome is when a complete surgical excision is done with the removal of the implant and also capsulectomy.[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]

III. Histopathological and molecular diagnostic criteria

For a good diagnosis,a tumoral biopsy must be done. There is no recommendation for a biopsy using a needle and being guided by imaging.A hemato-pathologist needs a considerable amount of tissue in order to vizualise a large pattern of lymph node infiltration.He also needs to apply an immune histo-chemical panel in order to get the diagnosis accurate.

The lymph node that is compromised presents diffuse or para-cortical infiltration (PTCL-NOS), loosing the normal lymph node pattern. Even though most of the times there is a high predominance of large tumor cells, there also exist some cases that have presented small neoplastic cells. There is a presentation of morphology that goes from monotonous to pleomorphic cells having an excess of mitotic cells

The WHO classification presents also histological patterns such as follicular, lympho-epitheliod lymphoma (Lennert lymphoma) and T-like zone. Most cases express the CD4 antigen, although some others (the lympho-epitheliod variant) may be CD8+. The presence of some immune-histologic markers of common T-cell neoplasms are presented in Table VII

The phenotypic profile and morphologic aspect allow PTCL-NOS to be differentiated from ALCL-ALK−since the latter contains cytotoxic granules and it also expresses membrane antigens (EMA) from epithelial stuctures. PTCL-NOS present with a strong and homogeneous expression of CD3 and a high proliferative rate, having Ki67 higher than 70%.

The PTCL-NOS category can include cases of PTCL CD30+/ALK−that are not similar to the classic ALCL based on their histologic aspect. In PTCL-NOS a mono clonal rearrangement of the T-cell receptor (TCR) can be seen using polymerase chain reaction (PCR). The presence of a diffuse pattern made by the infiltration with polymorphic cells and atypical neoplastic T-cells together with small immunoblasts,lymphocytes, histiocytes, eosinophils, and plasma cells with peri-lymph node infiltration in the subcortical sinuses are the morphologic aspects of the classical AITL. (Figure 3).

Neoplastic cells express a pattern of follicular T helper cells such as

CD3+,

CD4+,

CD10+,

BCL-6+,

CXCL13+,

PD1+,

ICOS+

Vascular expansion can be demonstrated by immuno-histo chemistry for CD34 and CD31.

The irregular proliferation of follicular dendritic cell can be defined by :

CD21,

CD23

CD35

A monoclonal population of T cells if found in the majority of AITL cases. EBV genome is detected in nearly 100%of the situations and the presence of B lymphocyte clones can be detected in 30% of cases .Karyotypic aberrations occur in 70–80% of the situations, mainly trisomy of chromosome 3 and 5, and an additional X chromosome [.48-51]

A broad morphological spectrum is found in the ALCL-ALK+ cases and all of them contain a variable proportion of cells with eccentric nuclei (kidney-like or horseshoe-shaped) with abundant cytoplasm and an eosinophilic perinuclear area ; these cells are named ‘hallmark cells’. The morphological findings of this disease vary from small to very large malignant cells (Figure 4).

Five distinct morphological patterns are recognized including

lymphohistiocytic,

small-cell,

classical,

‘Hodgkin-like’ variant,

mixed pattern.

60–70% of the cases are represented by variants where the malignant cells are sometimes Reed-Sternberg-like cells.The cells may simulate metastatic tumors and can grow within sinusoids when the lymph node architecture is partially compromised. Expression of the CD2 antigen is common, and CD5, CD7 and CD45RO are usually negative. The majority of patients present aCD4+/CD8−phenotype and show co-expression of cytotoxic antigens :

granzyme B,

TIA-1

perforin

EMA antigen

The morphological and phenotypic aspects of ALCL-ALK−cases are identical to those observed in ALCL-ALK+ cases [52].Table VIII presents the differential diagnosis between the types of T-cell Lymphomas.

IV. Prognostic factors and therapeutic considerations

There were studies that explained that the phenotype of T-cell lymphomas can be divided using IPI index .[53,54] PIT was also developed in order to have more accurate prognostic indicators. The four risk factors that were identified were :

age,

serum LDH,

performance status,

histopathological involvement of the bone marrow.

There were risk groups made for the persons, from 1 to 4, with 0, 1, 2, or more than 2 risk factors that have overall survival (OS) of 62%; 53%, 33%, and 18% .[55] Another used index was the modified Prognostic Index for T-cell Lymphoma (mPIT), that comprise the biological variable(Ki67 expression) and clinical aspects,like: performance status ,age, and LDH. The mPIT distinguishes three different risk groups:

good risk prognosis,

intermediate risk,

and poor risk.[56]

A project based on these kind of conditions was developed and it was named International Peripheral T-cell Lymphoma Project(IPTCLP) .This study brought another prognostic score that involves: performance status,platelet count and age. 55-57]

Therapeutic considerations

CHOP(a multidrug regiment used for aggressive B cell NHL) is routinely given for PTCL treatment. The anthracycline-based regimens bring a lot of unwished outcomes with ALCL-ALK+ with low risk met at the IPI. The highest expression of P-glycoprotein , associated with anthrax-cycline resistance phenotype (MDR phenotype) is an adverse result of PTCL. The response rate is low for the patients having this condition and they also have an increased rate of early death during first-line treatment. For the first two years after the treatment is made,there are some relapses. CHOP regimen remains the usual first-line therapy because there are not too many other choices.There were some studies that brought the demonstration of a complete response (CR) rates of 50% and OS at 5 years of 30% with the CHOP regimen for this disease. With these results,there was an intensified search for new therapeutic strategies like intensified chemotherapy and other protocols like high-dose therapy. After them a rescue with autologous hematopoietic stem cell transplantation (a HSCT) can be made.

A CHOP regimen that has etoposide added, has shown a progression-free survival(PFS) that is better for the people that had under 60-year.There were also described spontaneous remissions .The AITL one of the types presenting almost everytime with aggressive clinical manifestations. If there are asymptomatic patients ,they can also be treated,having the use of corticosteroids or immunomodulators and antiangiogenic drugs such as thalidomide, cyclosporine, and bevacizumab.

Because of the aggressive course,the patients with AITL that need therapy,should be included in clinical studies. CHOP or fludarabine and cyclophosphamide (FC) regimens have been used the most often.[58-59]

Patients that are presenting with ALCL-ALK+ without adverse IPI risk factors have an advantage that they have a chemosensitive disease that responds when treated with anthracycline-based therapy . Several studies have demonstrated overall response rate (ORR) of 90% with CHOP and 5-year OS of 70–80%.

There are high risk groups like ALCL-ALK−and ALCL-ALK+ that have an intermediate prognosis between ALCL-ALK+ without adverse risk factors and PTCL-NOS. The management of these patients is the same approach used for PTCL-NOS with intensification of CHOP by adding etoposide or allocating patients to clinical trials or consolidation with a HSCT.[56-59]

Most of the times, the therapeutic approach to PTCL does not involve irradiation, that is usually reserved for tumor greater than 10 cm or a residual mass after chemotherapy.There is insufficient evidence of the clinical benefits using this approach .The role of aHSCT in PTCL that is not ALK positive for first CR or partial response(PR) has been studied a lot. It is considered that 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.[58,59,61-64]

Patients with refractory or relapsed PTCL, that have an acceptable performance status, and no other comorbidities are thought to be treated with platinum-based rescue chemotherapy followed by aHSCT. There is little information regarding allogeneic bone marrow transplantation for these patients, with mortality rates as high as 30–50% when using myeloablative conditioning regimens. Because of this,reduced intensity conditioning regimens are now used in some cases.[65,66]

The nowadays treatment strategies are ineffective for the patients with PTCL and new therapies should be explored. The overcome of the p-glycoprotein system is made using Gemcitabine( a nucleosid analog). Antifolate agents (pralatrexate) and Bendamustine are being tested in these lymphomas.[64-65] Therapy with monoclonal antibodies like alemtuzumab (anti CD52), brentuximab vedotin (anti CD30), and zanolimumab (anti CD4) have also been evaluated. The patients that have PTCL and whose tumors express the CD30 antigen, particularly systemic ALCL and CD30+ PTCL-NOS,the therapy used consist of brentuximab vedotin. This therapy combines a monoclonal antibody against CD30 with an agent named monomethylauristatin E(MMAE) that is a potent anti-microtubule drug. Because of its uniform and strong expression in anaplastic lymphoma CD30,this therapy is an ideal therapeutic target. Brentuximab vedotin is internalized after binding to its target molecule and MMAE,then is cleaved from the antibody molecule, and it exerts its action with the inhibition of microtubule formation.Significant adverse events of brentuximab vedotin met in some trials were neutropenia, peripheral neuropathy, lung toxicity, and thrombocytopenia.[67,68] Alisertib (MLN8237)is another new treatment of these neoplasms. It is a selective inhibitor of Aurora A kinase (AAK), and its results are seen in the PTCL cell lines and patient samples.

Modulators of epigenetic phenomenon drugs that are able to restore the transcriptional status of tumor suppressor genes (histone deacetylase inhibitors),targeted therapies(ALK inhibitor crizotinib), and immunomodulating agents that have greater anti-tumoral activity in AITL are used for this tumors.[69-73]