Week 6 - Non-Hodgkin's Lymphoma Overview

8/6/2019 Week 6 - Non-Hodgkin's Lymphoma Overview

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NON-HODGKINS LYMPHOMA

General Most common lymphoid maliganacy Heterogenous group resulting from distinct lymphocyte subsets and neoplastic processes >10 subtypes with variable response to treatment Common clonal expansion of lymphoid cells

Epidemiology

Prevalence increases with age Incidence rising 3-5% over past 20 years

Risk factorscongenital disorders (ataxia-telangiectasia, Wiskott-Aldrich syndrome, celiac disease), prior

chemo/radiotherapy, immunosuppressive therapy, Epstein-Barr infection, HIV infection, human T-

cell lymphoma virus [HTLV]-1 infection, Helicobacter pylori gastritis, Hashimoto thyroiditis and

Sjogren syndrome

Aetiology Originates from B cells, T cells or histiocytes (tissue macrophage) Mutations, c-some translocations, altered genes eg. BCL2, c-mYC, FAS, BCL6 88% of NHLs derived from B cells

Presentation

Non-tender enlarged lymph nodes 1/3 casses originate outside lymph nodes (eg. Mucosal surfaces, bone marrow, skin)


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Table 104-1 WHO Classification of Lymphoid Malignancies

B CELL T CELL HODGKIN'S DISEASE

Precursor B cell neoplasm Precursor T cell neoplasm Nodular lymphocyte-predominant

Hodgkin's disease

Precursor B lymphoblastic leukemia/lymphoma

(precursor B cell acute lymphoblastic leukemia)

Precursor T cell lymphoblastic

lymphoma/leukemia (precursor T cell acute

lymphoblastic leukemia)

Mature (peripheral) B cell neoplasms Mature (peripheral) T cell neoplasms Classic Hodgkin's disease

B cell chronic lymphocytic leukemia/small

lymphocytic lymphoma

T cell prolymphocytic leukemia Nodular sclerosis Hodgkin's disease

B cell prolymphocytic leukemia T cell granular lymphocytic leukemia Lymphocyte-rich classic

Hodgkin's disease

Lymphoplasmacytic lymphoma Aggressive NK cell leukemia Mixed-cellularity Hodgkin's disease

Splenic marginal zone B cell lymphoma ( villous

lymphocytes)

Adult T cell lymphoma/leukemia (HTLV-I

+)

Lymphocyte-depletion Hodgkin's

disease

Hairy cell leukemia Extranodal NK/T cell lymphoma, nasal type

Plasma cell myeloma/plasmacytoma Enteropathy-type T cell lymphoma

Extranodal marginal zone Hepatosplenic T cell lymphoma

B cell lymphoma of MALT type

Mantle cell lymphoma Subcutaneous panniculitis-like T cell

lymphoma

Follicular lymphoma Mycosis fungoides/Szary syndrome

Nodal marginal zone B cell lymphoma ( monocytoid

B cells)

Anaplastic large cell lymphoma, primary

cutaneous type

Diffuse large B cell lymphoma Peripheral T cell lymphoma, not

otherwise specified (NOS)

Burkitt's lymphoma/Burkitt cell leukemia Angioimmunoblastic T cell lymphoma


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Prognosis and Treatment

Generally: empiric and usually uses cytotoxic chemo with monoclonal antibody directed at CD20

Aggressive (diffuse large B-cell lymphoma)~40 to 45% in US

Indolent (follicular lymphoma) ~30% in US

F

eatures

Constitutional symptoms and more often at

earlier stagesSpread more diffusely throughout lymph nodesLarger, less differentiated cell types

Rapid growth rateIncreased rate of early mortality

Often more curableExtranodal lymphomas usu in (oropharynx,paranasal sinuses, thyroid, GIT, liver, testicles,skin and bone marrow)

Few Sx but widespread disease

Generally incurable

M

anagement/Treatment

Guided by IPI

Low risk lymphoma: CHOP (cyclophosphamide,doxorubicin, vincristine and prednisone) chemoplus rituximab

Radiotherapy after chemo for bulky tumours

High-risk lymphoma: intensive chemo regimensand rituximab, potentially high dose XRT toowith autologous stem cell transplantation (alsoconsider for relapsing/failure to enter remissionafter induction chemo)

Tositumomab: anti-CD20 mab bound to 131 I(Bexxar) kills via antibody-mediated cellularcytotoxicity, activation of complement-mediated

tumour cell lysis, tumour specific radiation, treats

CD20 antigen expressing relapsed or refractory

Localised disease treated with XRT only

Most have disseminated chronic relapsing andremitting diseaseRarely curative therapy, more palliative

Watch and wait recommended for asymptomatic

patientsFollow up patients until more aggressive disease,major symptoms or organ dysfunctionWithholding chemotherapy does not reduce survivalbut improves quality of life

Symptomscombination of rituximab and alkylatorchemotherapy has high response rates and canalleviate symptoms

Rituximab: binds to B-cell surface Ag CD 20 (found

on vast majority of B cell lymphomas) well


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Type of NHL Epidemiologyand Survival

Features Pathology Images

B-Cell Lymphomas

Small lymphocyticlymphoma Patientsusually >60years old

Nonleukaemic form,generalised lymphadenopathy

B cells express CD5 and CD23,

some CD20 and restricted lightchain

More favourable prognosis if

cells express mutated IGH

genesZAP-70 expressed by leukemia

cells that express unmutated

IGH genes

Diffuse infiltrate of small mature lymphocytes mixed with prolymphocytesand paraimmunoblasts in ill-defined

nodules (proliferation/growth

centres)

Vague nodular appearance,

proliferation centres

Small lymphocytes, mature chromatin pattern

Lymphoplasmacyticlymphoma

Typically dont express CD5,

not usu blood involvementAssoc with Ig M serum protein

causing hyperviscosity or

cryoglobulinemia

(Waldenstrommacrogolbulinema)

Controversial assoc with

t(9;14)(p13;q32)

small lymphocytes and cells withplasmacytoid features (eccentric

nuclei and bluish cytoplasm)

Mantle celllymphoma

Median

survival of ~3

years, can

differ by >5years

Most commonly involves LN,

can involve extranodal sites:

GIT (lymphomatous polyposis)

Diffuse growth pattern usu butcan see nodular or mantle zone

pattern

A) Large bowel with mantle cell lymphoma (multiple lymphomatous

polyposis)

B) Monomorphous small lymphocytes surrounding benign germinal centre

C) Mantle-zone pattern stained with antibody to cyclin D1D) Diffuse pattern with monomorphous infiltrate of small irregular

lymphocytes with many mitotic figures


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Uniform population of small to

medium lymphocytes, irregularnuclei and virtual absence of

large transformed cells

Cells express CD5, CD23 and

Cyclin D1Cyclin D1 expression results

from the chromosomal

translocation t(11;14)(q13;q32)Also have chromosomal

translocations involving

expression of cyclin D2

Burkitts

Lymphoma

30% of

children withNHL

American type: GIT, para-

aortic nodesAfrican type: jaw

Bone marrow involvementLeukemic phase common

EBV relationship with t(8;14)

MYC gene on c-some 8 tranl to

IGH gene on c-some 14t(8;14)(q24;q32)

Can involve light-chain genes

on c-somes 2p12 ( ) and 22q11( )

Dx on morphology, support by

being + CD20, CD10, BCL6; -/focally weakly + BCL2;

growth fraction near 100% as

determined by Ki-67 stain;

MYC transl

A)Starry sky appearance with neoplastic B cells (dark) and tangible body

macrophages (lighter stars)B)Diffuse infiltrate of medium-sized cells with small nucleoli and high mitotic

activity

Diffuse large B-cell 25-30% of all Localised disease with Diffuse large B cells resembling centroblasts or immunoblasts


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lymphoma

=>Mediastinal large

B-cell lymphoma

NHL; 50% of

adults withNHL; elderly

and childhood

populations

Younger

extranodal involvement: GIT,

brain (EBV assoc with AIDS)Derives from germinal centre B

cells (GCBs), activated B cells

(ABCs) and unclassified (not

GCB or ABCs)GCB-type better prognosis

ABC-type: NF- B activation

=> proliferation and survival ofcells

Presents in mediastinum

WHO recog can be

intermediate btw DLBL andclassical HL

CD20 Ab stain

Mediastinal large B-cell lymphoma

large cells w. abundant cytoplasm and diffuse

fibrosis

Follicularlymphoma

40% of adultswith NHL;

elderly patients

Generalized lymphadenopathyBone marrow involvement

~90% derives from germinal

centre t(14;18) causing

overexpression of BCL2antiapoptosis gene

Germinal centre markers

BCL6, CD10; folliculararchitecture with nodular

aggregates of CD21-positive

follicular dendritic cells

Variable mixture of centrocytes

(small cleaved) andcentroblasts (large noncleaved)

Grade 1 (15 centroblasts

A) Grade 2crowded follicles

B) Grade 1small centrocytesC) Grade 3A


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per)

Can have diffuse area (DLBL)transforming to more

aggressive disease

D)Positive BCL2 immunostain

Marginal zone

lymphomas:-Extranodalmarginal zonelymphoma of MALT-Splenic-Nodal

50% of adults

with NHL;elderly and

childhood

populations

Association with Helicobacter

pylori gastritisDerived from MALT

Low-grade malignant

lymphoma of the stomach

Early responds to antibioticsLater include c-somal transl

=>NF- B signalling=>antigen-

independent growthA) benign germinal centres and mantle zones surrounded by expanded pale

marginal zonesB) Salivary gland w. MALT lymphoma, diffuse infiltrate of small

lymphocytes, pale cytoplasm in enlarged salivary gland duct

(lymphoepithelial lesion)

T-cell Lymphomas Note: Mature T cells and NK cell NHLs make up 10-15% of NHLs in West, higher incidence in Asia

Precursor T-celllymphoblasticlymphoma

40% ofchildhood

lymphomasChildren and

young

adolescence

Male pred

Primarily involves the anteriormediastinum and cervical

nodesBone marrow and CNS

involvement common

W/o Rx=>rapid dissemination,

ALL, early death

lymphoblasts

have highnucleus:cytoplas

m, many

mitoses, finely

stippledchromatin,

inconspicuous

nucleoli,round/convolute

d nuclear

contours


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Mycosis fungoidesand Sezarysyndrome

Adults 40-60

yrs

Involve neoplastic peripheral

CD4 TH cellsMycosis fungoides

Begins in skin (rash to plaque

to nodular masses) progressing

to LN, lung, liver and spleenGroups of neoplastic cells in

epidermis are called Pautriers

microabscessesSezary syndrome

Mycosis fungoides with a

leukaemic phase

Circulating cells called Sezarycells (prominent nuclear cleft)

Pautrier microabscess epidermotropism of neoplastic

lymphoid cells (MF)Three Szary cells in blood smear. The nucleus in the larger cell in the upperfield has delicate folds imparting a cerebriform appearance. The two smaller

cells in the lower field have a more condensed chromatin and markedly

lobulated nuclei.marked nuclear

irregularities,

mycosisfungoides

Peripheral T-celllymphoma

One of most

common

mature T-celllymphomas in

adults

Diffuse pattern, effaces normal

nodal architecture, diverse sizes

(large-intermediate,occasionally pred small)

Cell type=no prognostic

relevance

Large cells CD3 Ab stain


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AngioimmunoblasticT-cell lymphoma

Adults

middle agedand elderly

Uncommon

Type of PTCL

Mature T-cell lymphomaSystemic Sx and polyclonal

hypergammaglobulinemia,

rash, anaemia

Monoclonal T-cell R generearrangement

Increased risk for secondary

lymphomas, prognosis poor

small lymphocytes,

plasma cells,immunoblasts,

abundant eosinophils,

burnt out germinal

centres, proliferationof post-capillary

venules

Anaplastic large celllymphoma

Particularly

common in

children

Significant morphologic

variability, large pleomorphic

cells w. horseshoe/kidney-

shaped nuclei and perinucleareosinophilic region

Early: sinuses

Later: obliterate nodalarchitecture

Uniform strong CD30

expression=/>1 T-cell Ag and clonal T-

cell R gene rearrangement

ALK-+ in 1st

30yrs, favourable

prognosisFrom c-somal transl of ALK

gene on c-some 2p23, mostcommon is t(2;5)(p23;q35)nucleophosmin is on c-some 5

Wreath-shaped nuclei CD30 Ab stain

Eosinophilic perinuclear region

ALK Ab stain

Uncommon mature T/NK cell lymphomas

Enteropathy-associated T-cell lymphoma Arises in SI from celiac diseaseExtranodal NK/T-cell lymphoma Nasal type- aggressive EBV-associated neoplasm


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References

http://www.webpathology.com/

http://www.pathconsultddx.com

Sabel Michael S, "Chapter 44. Oncology" (Chapter). Doherty GM: CURRENT Diagnosis & Treatment: Surgery, 13e:

http://www.accessmedicine.com/content.aspx?aID=5316764.

Linker Charles A, Damon Lloyd E, "Chapter 13. Blood Disorders" (Chapter). McPhee SJ, Papadakis MA: CURRENT Medical Diagnosis & Treatment 2011:

http://www.accessmedicine.com/content.aspx?aID=5476.

Gascoyne Randy D, Skinnider Brian F, "Chapter 98. Pathology of Malignant Lymphomas" (Chapter). Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K,

Prchal, JT: Williams Hematology, 8e: http://www.accessmedicine.com/content.aspx?aID=6237265.
http://www.webpathology.com/http://www.webpathology.com/http://www.pathconsultddx.com/http://www.pathconsultddx.com/http://www.accessmedicine.com/content.aspx?aID=5316764http://www.accessmedicine.com/content.aspx?aID=5316764http://www.accessmedicine.com/content.aspx?aID=5476http://www.accessmedicine.com/content.aspx?aID=5476http://www.accessmedicine.com/content.aspx?aID=5476http://www.accessmedicine.com/content.aspx?aID=5316764http://www.pathconsultddx.com/http://www.webpathology.com/

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Week 6 - Non-Hodgkin's Lymphoma Overview