Jaffe PTL ALCL Afula - hematology.org.il … · JCO 2008;26:4124-4130 ©2008 by American Society of...

Peripheral T-cell Lymphomas

Anaplastic Large Cell Lymphoma

Elaine S Jaffe, M.D.

.

JCO 2008;26:4124-4130

©2008 by American Society of Clinical Oncology

International T-cell Lymphoma Study: Frequency of SubtypesStudy limited to adults

Vose et al. JCO 2008

Peripheral T-cell Lymphoma, NOS

• A diagnosis of exclusion, by definition a heterogeneous category

• Characterized by a broad morphologic spectrum– New approaches include segregation of tumors of TFH

origin (follicular variant) – Gene expression profiling recognizes tumors of TH1

and TH2 origin

• The “diffuse large B-cell lymphoma” of the PTLs

Lymphoepithelioid variant

Peripheral T-cell lymphomas, not otherwise specified

CD 3

Subclassification of PTCL, NOS by gene expression

TBX21 / TBET (Th1) Unclassifiable GATA3 (Th2)

Subclassification of PTCL, NOS: GATA3 & TBX21

GATA3Unclassifiable

TBX21 /TBET

0.91.412.08

Median OS (yrs)

TBX21/TBET (Th1 cells) - GATA3 (Th2 cells)

Angioimmunoblastic T-cell Lymphoma

• Initially thought to be an abnormal reactive process, a disorder of immune regulation

– Later defined as a form of peripheral T-cell lymphoma

• The clinical syndrome is a nearly universal part of the disease definition

• One would be hesitant to make the diagnosis in the absence of the characteristic clinical picture

Angioimmunoblastic T-Cell Lymphoma

Clinical Features:

• Older adults, generalized lymphadenopathy

• Hepatosplenomegaly

• Skin rash, effusions, fever,

• Polyclonal hypergammaglobulinemia, hemolytic anemia

• Diverse constitutional signs & symptoms

• Aggressive clinical course, high risk of infectious complications with treatment

Angioimmunoblastic T-Cell Lymphoma

Pathologic Features:

• Arborizing vasculature

• Atypical T-lymphocytes with clear cytoplasm

• Scattered B-immunoblasts

• Plasmacytosis, eosinophils

• Regressed or absent follicles in most cases

• Some cases have follicular hyperplasia

B-cell areas compressed at periphery of the lymph node – far cortex

CD20

Clear cells

BasophilicImmunoblasts

Angioimmunoblastic T-cell Lymphoma

is a disease of germinal center derived T-cells (TFH cell)

PD-1/CD279Normal tonsil

Angioimmunoblastic T-Cell LymphomaImmunophenotypic & Genotypic features

• CD4+, CD10+, PD-1+, BCL-6- T-cells (TFH)

• Expression of CXCL 13

• Extensive FDC CD21+ meshwork surrounding high endothelial venules (HEV)

• Scattered large B-cell blasts, often EBV+

• Polyclonal/ rarely monoclonal plasma cells

• > 90% TCR clonally rearranged

• 10-30% IG clonally rearranged

CXCL13 and Germinal Center TFH cells

• CXCL 13 causes induction and proliferation of

follicular dendritic cells

• CXCL 13 is involved in B-cell recruitment to

LN’s and activation of B-cells

• CXCL13 is required for the adhesion and arrest

of B-cells on HEV’s

CD21 CD21

CD10 CD3

Angioimmunoblastic T-cells Express CD10 CD10

Perifollicular Localization of AITL T-cells

PD1-CD279

What is the utility of PD-1 immunostaining in differential diagnosis of AITL vs Reactive

Hyperplasia ?

Exercise caution – Intensity is key !

PD-1+ T-cells are invariably present in reactive paracortical hyperplasia

Reactive paracortical hyperplasia – 18 yo drug hypersensitivity

Strong PD-1 + cells in germinal centerWeak PD-1 in reactive paracortical T-cells

Nodal Peripheral T-cell Lymphomas of TFH Origin

NODALPTCL,NOS

Follicular

Variant

AITL

TFH

• Gene expression profiling and mutation analysis has helped to clarify the interrelationship among nodal T-cell lymphomas of TFH origin

Relative Level of Expression (x median value)

AITL ALK- NKALK+ TATL PTCL-NOS

Gene expression profiling allowed reclassification of 14% of PTCL, NOS as AITL

Gene expression signatures of PTCL; Iqbal et al. Blood 2014

Genomic Findings in AITL and TFH derived lymphomas

• 20-45% in IDH2, DNMT3A and TET2 in AITL

– Genes involved in pathogenesis of gliomas, AML

• TET2 mutations also seen in other PTCL of TFH origin (up to 60%)

• RHOA mutations in 60% of AITL and some PTCL, NOS, all with TET2

• IDH2 most specific for AITL

Lemonnier 2012, Cairns 2012; Couronne 2012, Sakata-Yanagimoto 2014, Palomero 2014

Nodal Peripheral T-cell Lymphomas (2008)

PTCL, NOS

T-zone variant

Lymphoepithelioid cell variant

Follicular variant

Angioimmunoblastic T-cell lymphoma

Nodal Peripheral T-cell Lymphomas (2016)

PTCL, NOS

T-zone variant

Lymphoepithelioid cell variant

Follicular T-cell lymphoma

AngioimmunblasticT-cell lymphoma

Nodal peripheral T-cell lymphoma with TFH

phenotype

Follicular Variant of PTCLde Leval AJSP 2001

• Intrafollicular T-cell lymphomas derived from TFHcells

• Usually CD4+, BCL-6+, CD10+/-

• PD-1/CD279+

• Clusters of clear cells within GCs

• May simulate follicular lymphoma

• Lack typical clinical findings of AITL

• Will be grouped with AITL in revised WHO classsification

CD3BCL6

Peripheral T-cell lymphoma, T-zone variant

Perifollicular growth pattern

Plasmacytosis, Capsular fibrosis

CD4 phenotype

May have a better prognosis than other PTCL

More often localized LN presentation

REF: Rudiger et al., Am J Surg Pathol, 2000Warnke et al., Am J Clin Pathol, 2007

Peripheral T-cell lymphoma, T-zone variant

CD4 CD8 CD5

CD3

Biphasic pattern for CD5

CD5

B-cell proliferations in AITL & PTCL

• EBV-positive– Variable numbers of EBV+ blasts, may be dominant

picture

– Hodgkin/Reed-Sternberg like cells

• EBV-negative– B-immunoblasts

– Polyclonal plasma cells

– Monotypic/ Monoclonal plasma calls

– Hodgkin/Reed-Sternberg like cells

EBER

CD20

CD20 + B-immunoblasts

EBV neg B-cell proliferations in Angioimmunoblastic T-cell lymphoma

Plasma cells

Often Abundant

May be monoclonal &atypical

Balague et al. Am J Surg Path 2007

Huppmann et al JCO 2012

T

T

T

CD3

CD279/ PD-1

CD138

κ λ

TCR

IGH FR2

IGH FR3

Huppmann et al JCO 2012

Peripheral T-cell lymphoma with EBV+ HRS cellsQuintanilla-Martinez et al. Am J Surg Pathol 1999

CD30EBER

CD15

T-cell population clonal, Cytologically atypical Usually has a TFH phenotype“HRS-cells” are “B-lineage”

PTCL with HRS-like cells – An Update (57 cases)Nicolae et al AJSP 2013

• PTCL classified as AITL, PTCL, often with TFH markers

• Intimate relationship between the HRS-like cells & neoplastic T-cells

• HRS-like cells

–EBV-positive (52 cases)

–EBV-negative (5 cases)

• Progression to classical Hodgkin’s lymphoma not observed

CD15 CD30

CD3 CD10

CD15 PAX5 EBER

CD10PD1

EBV-negative HRS like cells are also rosetted by neoplastic TFH cells

Angioimmunoblastic T-cell LymphomaTake Home Points & Remaining Questions

• AITL is characterized by proliferation and sometimes clonal expansion of B-cells, as well as neoplastic TFH-cells

• If B-cells are passively expanded secondary to function of TFH cells, why do they appear so atypical, or evolve to a clonal proliferation in some cases?

– Might they harbor some of the same mutations as the

neoplastic T-cells?

– Are PD-1 positive cells providing immunoprotection?

Adult T-Cell Leukemia/Lymphoma

• Endemic in Japan, Caribbean, associated with HTLV-I in endemic and ‘sporadic’ cases

• Medium-sized to large cells with pronounced nuclear pleomorphism, often polylobated cells in PB

• Reed-Sternberg-like cells may be present

• CD3+, CD4+, CD7-, CD25++, FoxP3 +/-

• Clonally integrated HTLV-I, rearranged TCR genes

Prevalence of HTLV-1 Worldwide

Hodgkin’s-like picture in early ATLL - RS-like cells are EBV+ B-cells

Clinical Features ATLL

• Leukemia (more common in Japan)– Often without bone marrow infiltration

• Skin lesions > 60%• Hypercalcemia• Lytic bone lesions, 30%

• Lymphadenopathy

• Hepatosplenomegaly

• Stage IV, nearly 100%

ATLL Sezary

ATLL Skin LesionsCutaneous Involvement ATLL

CD3

Immunophenotype of ATLL

• CD3+, CD4+, CD25++, FOXP3 +\-

• Negative for CD7

• CD30 variable

Cells phenotypically and functionally are Treg cells, function as suppressors of immune function

Correlates with immunodeficiency characteristic of ATLL

ATLL:Opportunistic infections in the absence of therapy or granulocytopenia

• Pneumocystis carinii pneumonia

• Cryptococcal meningitis

• Cytomegalovirus infections

• Candida

• Strongyloides

• Mycobacterial infections

Adult T-cell Lymphoma/Leukemiafrom Yamaguchi et al., Kawano et al.

Smoldering ATLL Chronic ATLLNormal WBC Increased WBCATL cells <3% ATL cells >10%No lymphadenopathy Mild lymphadenopathyNo hepatosplenomegaly Slight hepatosplenomegalySkin rash Skin rash variable

erythema, papulesNormal LDH, Ca++ LDH slightly inc, Ca++ nl.Survival > 2 yrs. Survival usually > 2 yrs.

CD 3 CD25

Smoldering ATLL - Skin Biopsy

OS according to the clinical subtypes.

Hiroo Katsuya et al. Blood 2015;126:2570-2577©2015 by American Society of Hematology

Lymphomas of the Innate Immune System

T-cells, NK-like T-cells, NK-cells

• Often cutaneous, mucosal, spleen & BM

• Cytotoxic • Activated cells show

frequent apoptosis, necrosis

• Includes most pediatric T/NK neoplasms

Hepatosplenic T-cell lymphoma• Most common in young males

• May be seen with chronic immune suppression– Crohn’s disease, late occuring PTLD

• Hepatosplenomegaly, cytopenias, systemic symptoms; lack LN and PB involvement

• Aggressive behavior and dismal prognosis (<2y survival)

• Differential Dx: T-LGL in bone marrow, spleen

CD3+, CD4-/CD8-, CD5-, CD56+, TCRγδ+

Nonactivated cytotoxic profile: TIA-1+, GZB-, Perforin-

Rare cases αβ, similar clinicopathologic and molecular features

Cytogenetics Isochromosome 7q, +8, -Y

Derive from functionally immature cytotoxic γδ T-cells with Vδ1 usage

Immunophenotype

CD5

TCRγ

CD56

TIA-1

Liver TCRγ

TCRγ CD56

BM

Recurrent Mutations in HSTCL

• HSTCL STAT5B (33%); STAT3 (10%)

SETD2 (71%)

• T-LGL STAT3 (40%); STAT5B (2%)

• T-ALL JAK1, JAK3, STAT5B (subset)

• T-PLL STAT5B (36%)

Clinical Spectrum of Cutaneous T-cell lymphomas

Activated Cytotoxic Immunophenotype

Primarily Dermal T-cell lymphoma Cutaneous TCL - “panniculitis-like”

Cutaneous Gamma Delta T-cell lymphoma – may involve mucosal sitesStomach Subcutaneous

Non-hepatosplenic T-cell lymphomasMainly cutaneous, but also involving other extranodal

sites Garcia-Herrera et al. AJSP 2011

• Skin / subcutaneous tissue 31%

• Skin + other (GI, LN) 19%

• Small bowel 19%

• Tongue 6%

• Orbit 6%

• Lung 6%

• LN 12%

50%

Subcutaneous Panniculitis-Like T-cell Lymphoma

CLINICAL FEATURES:

Broad age range (1 yr to 57 yrs) Median age - 30

Males = Females

Deep subcutaneous nodules

primarily affecting extremities, trunk

Overall survival > 80% 5 years

Low risk of nodal involvement

Subcutaneous Panniculitis-Like T-cell Lymphoma

MORPHOLOGY:

Usually confined to subcutis

Absence of dermal, epidermal involvement

Necrosis and karyorrhexis prominent

May show vascular invasion

Primarily lobular distribution

CCD8 TIA-1

Subcutaneous Panniculitis-like T-cell Lymphoma

Immunophenotype & Genotype

Activated T-cytotoxic phenotype

• CD3+, CD8+

• TIA-1+, Granzyme B+, Perforin +

• CD56 negative - in contrast to • EBV-negative

• TCR genes rearranged

Differential Diagnosis of SPTCLLupus erythematosus profundus

• Mixture of T-cells, B-cells, plasma cells

• Lobular pattern with preserved septa

• Fibrinoid change in connective tissue

• Interstitial infiltration, but infrequent rimming of fat spaces

• Mixture of CD4+/CD8+ cells

• Scattered gamma-delta T-cells

• Increased PDC’s (CD123+)

CD3 CD4 CD8

TCR gamma CD123 Subcutaneous Panniculitis-like TCL & Lupus

Willemze et al. Blood 2008

• 19% of patients with SPTCL (αβ) had history of autoimmune disorder

– SLE, RA, ITP

Pincus et al. Am J Derm 2009

• 5 patients with established SLE and “SPTCL”– 3/5 had clonal TCR genes

– Variable numbers of B-cells in all cases

– 1 patient had progressive disease (HPS)

– 3 in CR (prednisone, Vorinostat)

Subcutaneous Panniculitis-like TCLvs. Lupus profundus – Not always easy

• Oligoclonal T-cell populations can be seen in some

patients with lupus, inclusive of the cutaneous

lesions

• Correlate clinical, histological, and genetic features

• One should be cautious about making the diagnosis

of SPTCL in a patient with lupus

Primary cutaneous CD8 positive aggressive epidermotropic cytotoxic T-cell lymphoma (Provisional)

Primary cutaneous CD4 positive small/medium T-cell LPD (revised term 2016)

Primary cutaneous CD4 positive small/medium T-cell LPD

Primary cutaneous CD4+ small/ medium“T-cell LPD” (2016)

• Usually localized, often involving head and scalp

• Distinction with atypical hyperplasia often difficult

• Lesions sometimes contain numerous B-cells

• Good prognosis if single lesion, most < 3 cm – Infrequent recurrences, no deaths

– Patients with bulky or advanced disease (very few) had aggressive course

CD3 CD4

PD-1

TFH phenotypePD-1+ but usually CD10-Clonal by PCR

Enteropathy Associated T-cell Lymphoma (EATL)

• Broad morphological spectrum Adjacent mucosa shows villous atrophy

• CD3+, CD103+, Cytotoxic markers, TCR often double negative for CD4/CD8

Often presents with intestinal perforationaggressive clinical course with poor prognosis

Enteropathy-associated T-Cell Lymphoma[Classical form or Type I]

• Associated with celiac disease

–95% of patients have HLA-DQ2 and HLA-DQ8

–Autoantibodies against tissue transglutaminase

–Antibodies against gliadin

–Gluten-free diet may reduce risk of lymphoma

Ireland Italy Netherlands Sweden USA

Overall

Diagnosed

Celiac Disease IcebergsF.A. Hamilton, NIDDK

1% of White population in the U.S. has “laboratory celiac disease”

CD30

Enteropathy Associated T-cell Lymphoma, Types I & II are distinct

EATL IUsually αβ

Celiac diseaseN European

EATL IUsually αβ


EATL IUsually αβ


EATL IIUsually γδ

EpitheliotropicAsian, Hispanic

γδ

Monomorphic epitheliotropic intestinal T-cell lymphoma

(EATL II)

• Medium sized cells with

clear cytoplasm

• CD56 +, CD8+, CD4-

• Usually gamma delta +

• MAT kinase +

Recurrent Mutations in Intestinal T-cell Lymphomas

Authors

Nairismagi 2016

• EATL II αβ and γδ

Roberti 2016

• EATL II

Nicolae 2016

•EATL Type II > I

– αβ and γδ and TCR silent

Mutations

• 63% STAT5B

• 35% JAK3, 24% GNAI2

• 93% SETD2

• 60% STAT5B, 46% JAK3

• 67 % JAK/STAT pathway

STAT5B/ JAK3/ STAT3

• 24% RAS pathway

KRAS/ NRAS/ BRAF

JAK/STAT Pathway is an attractive target for therapyof Cytotoxic T-cell Lymphomas and Leukemias

T-cell & NK cell Lymphomas of Gastrointestinal Tract

Extranodal NK/TEBV+ NK or T Mainly Asian

MEITL

γδ > αβ

EATL“Classical”

αβ > γδ

All clinically aggressiveAll cytotoxic

EBV+ T/NK cell lesions – WHO update (2016) Y-H Ko, L Quintanilla Martinez, H Kimura, ES Jaffe

• EBV-associated HLH (non-neoplastic)

• Cutaneous CAEBV

– Hydroa Vacciniforme LPD (T/NK)

– Severe Mosquito Bite Allergy (NK)

• Systemic CAEBV, T-cell or NK-cell

• Systemic EBV+ T-cell lymphoma of childhood

• Aggressive NK-cell leukemia

• Extranodal NK/T-cell lymphoma, nasal type

Marked variation in clinical behavior from indolent to highly aggressive

• Hydroa-vacciniforme-like LPD• Asian or Hispanic children• Lesions in sun exposed areas• Chronic course but may progress to

acute phase with systemic disease

EBER

Cells of T-cell or less often NK cellorigin

Systemic CAEBV

Most often Asian or Hispanic children

T-cell or NK-cell origin

Symptoms for > 3mos. after acute EBV infection

Involves BM, liver, spleen

May be accompanied by HLH

Asian or Hispanic children

Acute systemic illness with hemophagocytic syndrome

Usually an acute presentation

EBV+ T-cells are clonal

May follow chronic active EBV infection (CAEBV)

Overlaps with what has been termed severe CAEBV

Systemic EBV+ T-cell Lymphoma 2 yo Hispanic M

Double Label CD8/ EBER

Let’s switch gears …….


• Paradigm for process used to define disease entities (REAL)

• First recognized based on

–Morphology - sinusoidal growth

–Antigenic phenotype - CD30+• Studies of molecular pathogenesis led to new

diagnostic tools

–RT-PCR and ALK-1 monoclonal antibody• New diagnostic tools define the borderlands of

the disease


• The ultimate histologic spectrum of ALCL is both broader and narrower than the original concept

• Small cell and lymphohistiocytic variants included

• Most Hodgkin’s-like and highly pleomorphic CD30+ lymphomas excluded

• New diagnostic tools enhance our diagnostic acumen on routine H&E (e.g. “Hallmark cells”)

• Importantly, what we recognize as ALCL has clinical and prognostic significance

CD30

ALK CD30Anaplastic Large Cell Lymphoma

Clinical Features

• Presents most commonly in lymph nodes

• Cutaneous & extranodal involvement may be seen

• Most common in children, young adults

• Frequent presence of systemic symptoms

• Aggressive natural history but good response to chemotherapy

Anaplastic Large Cell LymphomaExtranodal Sites of Involvement (Falini, Blood 1999)

Site %Skin 22%Soft tissue 22%Bone 22%Bone marrow 15%Lung 15%Liver 10%Other sites <10%

PB, pleura, muscle, CNS, gut, testicle, parotid gland

May be the sole manifestation of diseaseOschlies et al. Haematologica 2013

ALCL

Bone marrowInvolvement

Scatteredsingle cells inbiopsy & smear

Anaplastic Large Cell LymphomaImmunophenotype

• CD30+, EMA+, ALK+, clusterin +, CD 15-, LCA +

• T-cell antigen expression variable:

CD 2+, CD5+, CD4+/-, CD 8-/+, CD3 often negative

• Activated cytotoxic ag expression:

TIA-1 +, perforin +, granzyme B+, CD25+

ALK

CD30 EMA

Granzyme B

ALK

Nucleophosmin Anaplastic Lymphoma Kinase

t(2;5) cytoplasmic/nuclear/

nucleolar

ALKNPM

t(1;2)

Tropomyosin 3

cytoplasmicALKTPM3

t(2;17)

Clathrin heavy chain cytoplasmic

granularALKCLTC

Inv2 ALKATICATIC (Pur H gene)

cytoplasmic

t(2;3) ALKTFGTrk Fusion Gene

cytoplasmic

Translocations and fusion proteins involving ALK

Frequency

70-80%

10-20%

2-5%

2-5%

2-5%

1-2%t(2;19) /others ?ALK?

Staining Histological Spectrum of ALCL, ALK+

• Anaplastic large cell lymphoma– Common– Lymphohistiocytic – Small cell

• Other common histological patterns– Sarcomatoid appearance with myxoid stroma– Hypocellular with edematous background

Histologic Variants of ALCLLymphohistiocytic or Histiocyte-Rich

(Pileri et al., Histopathology, 1990)

• Common in children and young adults

• Abundant histiocytes with pink cytoplasm mask minor population of tumor cells

• May be mistaken for infectious or reactive process - delay in diagnosis is common

• Recurrent biopsies contain fewer histiocytes, more tumor cells

Lymphohistiocytic variant of ALCL CD30

CD30

Histologic Variants of ALCLSmall Cell Variant (Kinney et al., AJSP, 1993)

• Common in children and young adults

• Usually presents in lymph nodes

• Most tumor cells are small, with clear cytoplasm, irregular nuclei

• Minor population of classical ALCL cells, often around blood vessels

• May be mistaken for PTL, NOS, but neoplastic cells are often CD 3 negative

• ALK +, but small cells may show variable staining

PC

ALCL

Small Cell Variant of ALCL CD 30

Time to treatment failure curve according to the presence of a small-cell (SC) and/or lymphohistiocytic (LH) component (n = 361 patients).

Lamant L et al. JCO 2011;29:4669-4676

©2011 by American Society of Clinical Oncology

Other Histological Patterns in ALCLSarcomatoid or Hypocellular

• Myxoid stroma with prominent fibroblasts

• Edematous, often hypocellular infiltrate

• Differential diagnosis includes ALK+

myofibroblastic tumors - also children

• ALCL may present as soft tissue or bone lesion,

differential diagnosis with sarcoma

Sarcomatoid variant of ALCL

ALCL resembling NS CHL Vassalo et al AJSP 2006 CD30 ALK

Hodgkin’s Like ALCL is NOT ALCL “Hodgkins Like ALCL”

• Originally proposed as a variant of ALCL, but most cases are aggressive variants of CHL or “grey zone” lymphomas

• Common in young males with med masses

• Capsular thickening, nodular fibrosis

• Sheeting out of Reed-Sternberg-like cells– May contain eosinophils, neutrophils

• ALK- negative

but usually CD30+, CD15 -/+, CD20 -/+, PAX5+

OCT-2, Bob.1 usually +

ALK-negative ALCL Should have very similar morphology and phenotype as ALK + ALCL

Note Hallmark Cells

Required: Cohesive growth pattern with hallmark-like cellsStrong and uniform CD30 expressionDesirable but not essential: EMA+, Cytotoxic +, Sinusoidal growth, Loss of “T-cell ag”

Vose et al. JCO 2008

ALK+

ALK-

Activating mutations of JAK1 or STAT3 or both (20%)Crescenzo Cancer Cell 2015

Constitutive Activation of the JAK/STAT pathway in

Systemic and Cutaneous ALK-negative ALCL

0

10

20

30

40

50

60

70

80

90

100

0 24 48 72 96 120 144 168 192 216 240

Per

cent

Sur

viva

l

Months After ALCL Diagnosis

p<0.0001

Genetic correlates with survival in ALCL, ALK+/ ALK-Feldman et al. Blood 2014

DUSP22 (# 22)ALK+ (# 32) P63 (# 6)

ALK neg, no aberrations (#45)

Subset with DUSP22 RComparable to ALK+

DUSP22 translocations also seen in primary cutaneous CD30+ T LPD

• LYP with 6p25.3 (<5%) 11 pts with localized skin lesions (Karai 2013)

– Same translocation (DUSP 22 locus), as in systemic ALCL, ALK-

• Primary cutaneous ALCL with 6p25.3 – 3 patients, pagetoid reticulosis-like pattern (Onaindia

2015

– C-ALCL, intralymphatic localization, skin limited (Samols2014)

• Evidence for close relationship between some cases of systemic and cutaneous ALCL

Implant-associated anaplastic large cell lymphoma, ALK-negative

• Seen with a variety of breast implants, both saline and silicone

• Usually years after implant

• Symptoms related to accumulation of seroma fluid in cavity surrounding the implant

• Diagnosis best made by cytology

• Cells grow within cavity and on surface of cavity lining, usually without invasion

Location of ALCL Adjacent to Breast Implant

Breast

Implant

(Seroma)

Modified from Thompson PA et al Haematologica 2010

CD30

Biological Features

• Clonal TCR reported in most but not all cases

• JAK1 & STAT3 mutations – Similar to ALK+/ALK- ALCL (Blombery 2016)

• Surprisingly indolent course, despite very atypical cytological features

• Therapy varies in literature

–Chemo, Radiation, Observation following removal

• Removal of implant is probably adequate therapy in most cases – if no invasion of capsule

CD30 CD3 Ax LN

Breast implant–associated anaplastic large-cell lymphomaLong Term Follow up in 60 Patients

Miranda R N et al. JCO 2014;32:114-120

93% CR in patients with disease confined to the capsule72% CR in patients with a mass No difference in OS or PFS in patients who had chemorx

Recommended rx: Implant removal with capsulectomy

Histological Spectrum of ALCL

• Marked variation in cell size from case to case

–Hallmark cells are always present

• Distinctive architectural features

–Sinusoidal infiltration

–Perivascular rosetting

• Cellular density varies markedly

–Hypercellular to hypocellular

–Hypocellular cases may simulate an inflammatory process

Pitfalls in the Diagnosis of ALCL

• CD30 is not specific for ALCL

+ in CHL, +/- in EBV+ B-cell lymphomas, other T-cell

lymphomas, embryonal carcinoma

• ALCL is not a wastebasket for pleomorphic or “anaplastic”

tumors. The term “ALCL” was based in part on the

sinusoidal growth and unusual cytologic features, not

resembling normal lymphs.

Many ALCL are not pleomorphic, but monomorphic

• Reed-Sternberg-like cells are uncommon in ALCL

HD PTCL

CD30+EMA+LCA+CD15-CD3 -/+

t(2;5)NPM;ALK

ImmunophenotypicStudies

Ki-1+Sinusoidallymphoma

MolecularPathogenesis

Definitionof Entity

Hallmark cellsALK+

MH

Initial Description

EVOLUTION OF ANAPLASTIC LARGE CELL LYMPHOMA

Fully integrated with the revised WHOClassification

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