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Lymphoreticular 109

MUM1 = IRF4: melanoma and most lymphomas (B-cell, T-cell, ALCL, classical RS cells, plasma

cells / myeloma, activated B subtype of DLBCL), −ve in Burkitt’s, mast cell and histiocytic

lesions

NP57 = Neutrophil Elastase: myeloid lineage / PMN

NSEst = non-speciﬁc esterase: diffuse cytoplasmic +vity in monoblasts (spotty/Golgi in

lymphoblasts)

p24 = an HIV nucleocapsid protein: stains HIV-infected FDC

p53 nuclear stain ‘progression marker’ in lymphomas

p63 = vs38c: endoplasmic reticulum protein, stains the cytoplasm / membrane of plasma cells,

naevocytes and some melanoma cells. ! Do not confuse with the p53-related protein (also

called p63) which stains nuclei of basal cells of various epithelia

PAX5 nuclear +vity in pre-B to mature B-cells (incl. lymphomas −ve for CD45, CD20 & CD79a)

but may be −ve in plasma cells and CD20 −ve myelomas; −ve in most non-lymphoid

neoplasia (except a minority of Merkel and TCC)

perforin marker of cytotoxic function (see also granzyme B, TIA-1, CD57)

S100 Langerhans cells, IDC, mast cells (for a longer list, see Chapter 2: Histological Techniques)

Tdt a nuclear stain (cytoplasmic staining should be discounted) for pre-T or pre-B cells

TIA-1 T-cell Intracellular Ag 1: marker of cytotoxic function (see also granzyme B, perforin, CD57)

TRAP HCL and some mast cells

vs38c see p63 above (plasma cells, naevocytes, melanoma cells)

Zap-70 +ve in CLL with un-mutated Ig genes (more aggressive than mutated CLL)

Interdigitating Reticulum Cells (= Interdigitating Dendritic Cells, IDC )

Paracortical histiocytoid cells related to Langerhans cells

Immuno: +ve for S100, CD24, HLA-DR; −ve for CD1a,3,20,21,30,35,79a

EM: no desmosomes (unlike FDC) or Birbeck granules

Lymphomas Positive for the Triad–CD30, EMA, CD138

◦

ALCL,

◦

anaplastic myeloma,

◦

primary effusion lymphoma (PEL)

B-Cell Reactions

Follicular Hyperplasia

d/dg FCL see under ‘Follicular Lymphoma’

d/dg Hodgkin lymphoma (vide infra)

d/dg progressive transformation of the germinal centres (vide infra)

d/dg RhA (also Felty syndrome) which may show:

 ﬂorid follicular hyperplasia – may seem to be present throughout the LN – d/dg FCL

 ↑ plasma cells in medulla and paracortex

 assoc

with splenic B-cell hyperplasia

d/dg adult Still’s disease (also shows a paracortical T-cell reaction)

d/dg SLE or other CTD

d/dg HIV (vide infra)

d/dg toxoplasmosis (for a full list of features, see Chapter 23: Infection and Immunity)

d/dg leishmaniasis (Leishman-Donovan bodies in epithelioid M – see pp.348–349)

d/dg drainage of inﬂammatory sites (CIBD, peptic ulcer, etc.)

d/dg 1

◦

and 2

◦

syphilis, but these also show:

 1

◦

shows capsulitis with ↑ vascularity and plasma cells

 2

◦

shows ﬁbrotic thickening of capsule and septa

 1

◦

and 2

◦

show ↑ plasma cells and paracortical epithelioid M aggregates

 perivascular spirochaetes demonstrable in tissue (!serology may be −ve if HIV co-infection)

Sinus Lymphocytosis (Sinus B-Cell Reaction)

B-cells (often monocytoid) predominate in sinuses

Occurs in: prolonged reactive states, toxoplasmosis, HIV, EBV, early stages of some lymphomas

d/dg CLL or nodal MZL

d/dg sinus histiocytosis (esp. if monocytoid B-cells)

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Lymphoreticular 110

B-Cell Lymphomas

Small Cell B-cell Lymphomas – Immuno and General Points

TABLE 10.1 Small cell B-cell lymphomas

CD5 CD10 CD23 Other positive findings

FCL −+ −Bcl-2, Bcl-6, CD21 & CD23 [FDC network], t(14;18)

CLL +− +±proliferation centres, CD43 +ve

MCL +− −Bcl-1, t(11;14), crinkly cells, epithelioid M

LPL

−− −cytoplasmic IgM (not D), epithelioid M , elderly, high stage

MZL −− −translocations ± Bcl-10, MALT1 & IgM, Bcl-2 ±ve, Bcl-6 −ve

Splenic MZL −− −IgD may be +ve (unlike other MZL variants)

IPSID −− −IgA ( heavy chain only – no  or  light chains)

HCL −− −+ve for CD25, DBA44, TRAP (& Bcl-1 in 50–85%)

rare cases ... ++depends ...of otherwise typical FCL, MCL, CLL, B-ALL, DLBCL

Lymphoplasmacytic lymphoma is a diagnosis of exclusion: exclude CLL, FCL, MZL

MCL are CD43 +ve and upto 20% of MCL are Bcl-1 −ve

Some MCL are CD5 −ve, Bcl-1 +ve; these have typical morphology and most have a t(11;14)

FCL are CD43 −ve and upto 40% of FCL are CD10 −ve. Bcl-2 may be −ve in cases without t(14;18)

MCL vs. CLL:  CLL can be CD38 +ve (upto 40% – represent a good prognosis subgroup)

 MCL are CD38 −ve and do not have paraimmunoblasts / proliferation centres

 MCL have a ‘two-tone’ positivity for CD5 (T-cells stain strongly, MCL cells

weakly)

 CLL have strong diffuse staining for CD5

 Ki-67 +vity may be clustered on CLL but is diffuse in MCL

MCL has classical, blastic, pleomorphic, small cell and other morphological variants

CLL transformations: Richter’s, paraimmunoblastic and prolymphocytoid – see p.105

LPL vs. CLL:

◦

lack of CD5 in LPL

◦

strong cytoplasmic Ig (heavy chains) in LPL

Nodal MZL = ‘monocytoid B-cell lymphoma’

Cutaneous B-cell Lymphomas

Diagnosis requires CPC, best left to a specialist pathologist as these break many of the rules of nodal

lymphomas. See Cerroni (2006), Slater (2003) and Goodlad and Hollowood (2001) in the Bibliography

for details.

◦

MZL:  follicles with germinal centres and expanded mantle zone

 sheets of small B-cells in between the follicles (may be vaguely nodular / perivascular)

 LEL may be absent and the neoplastic B-cells may be CD43 +ve

 combination of cell types: monocytoid, plasma cells / plasmacytoid, centrocyte-like

 colonisation of germinal centres: shown as CD10 and Bcl-6 −ve cells in follicle centres

with surrounding condensation of FDC (+ve for CD21 and CD23). (Also, the germinal

centre looses its ‘starry sky’ appearance on H&E as the tingible body M are replaced)

 locally recurrent but tends not to spread to other organs / systems

◦

FCL:  follicles with attenuated / absent mantles

 CD10 and Bcl-6 +ve cells outside follicles as well as inside

 CD21 +ve FDC network visible

 Bcl-2 and t(14;18) often negative: if +ve, you should consider skin involvement by

systemic spread of nodal FCL

◦

DLBCL incl. intravascular lymphoma (see p.113) – may not require toxic systemic chemoRx if it is

a solitary lesion conﬁned to the skin

MCL: this is rarely a 1

◦

skin tumour – look for nodal / GI disease, etc.

CLL:  diffuse pattern superﬁcially

 ± heavy perivascular pattern deeper

Lymphomatoid granulomatosis: see p.91

d/dg B-cell cutaneous lymphoid hyperplasia: if follicular, there are well-formed mantles with a mixed

interfollicular inﬁltrate (B:T-cell ratio <3:1); no sheets of plasma cells; B-cells are CD43 −ve; adnexa

are not destroyed; inﬁltrate is top-heavy (a weak feature); a stimulus is seen (e.g. tattoo pigment) or

discovered from the history (for a list, see p.302 under ‘B-Cell and Other Lymphomas’)

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Lymphoreticular 111

Signet Ring Lymphomas

FCL or myeloma variant (due to immunoglobulin cytoplasmic globules)

Some T-cell lymphomas may also show this pattern

d/dg signet ring carcinoma

Follicular Lymphoma (FCL)

Commonest adult lymphoma in UK, rare in people <30 years old

FDC are present – their presence, esp. in a nodular conﬁguration, is supportive evidence for FCL vs.

other lymphomas and is a useful feature for core Bx diagnosis of FCL

‘Early’ FCL is conﬁned to the follicles with normal small lymphocytes in interfollicular areas

Progression to higher grades is accompanied by inﬁltration of interfollicular areas by FCL cells with

consequent blurring of follicular deﬁnition, merging of follicles and ↑ mitotic rate

‘Follicles’ throughout the node (! but this may also be seen in ﬂorid reactive nodes e.g. RhA)

Extension into perinodal (not hilar) fat as nodules or mindless sheets

Reticulin:  ‘early’: reticulin-free

follicles with condensation of interfollicular areas

 ‘later’: destruction of interfollicular reticulin as follicles merge

 generally: loss of sinus architecture

‘Signet ring’ FCL contains cells with large cytoplasmic globules of immunoglobulin

Grading FCL depends on the centroblast (Cb) count as follows:

1. 0–5 / 10 hpf a hpf is 0.45 mm diameter (0.159 mm

area) and the count

2. 6–15 / 10 hpf

⎫

⎬

⎭

should be adjusted for other ﬁeld diameters (e.g. by counting

3. >15/10hpf <10 ﬁelds for microscopes with larger diameter hpf)

3a. centrocytes (Cc) still present

3b. sheets of Cb without Cc (d/dg DLBCL – FCL 3b is still nodular but it often lacks t(14;18)

and is Bcl-2 −ve)

 must count in 10 representative neoplastic follicles (not those with most Cb) – 10hpf in each

 must distinguish Cb from large centrocytes and FDC nuclei

 variation in grade between regions of the LN should be noted (e.g. ‘predom. G1 with focal

G3a’)

If <75% follicular architecture state proportion of diffuse (DLBCL) component

If <25% follicular this is considered a focally follicular DLBCL

Diffuse variant of FCL: see ‘Diffuse Large B-Cell Lymphoma’, p.113, for deﬁnition and d/dg

d/dg follicular hyperplasia (see Table 10.2)

Progressive Transformation of Germinal Centres

The follicles are larger, more centrally placed within the node and ill-deﬁned

Residual tingible body M may be seen

More reactive T-cells and ↑ marginal zone cf. ordinary follicles

Peripheral ‘collections’ of epithelioid M

May be an isolated reactive feature or assoc

with lymphoma e.g. LPHL (d/dg FCL)

Regressed Follicle

Smaller

Absence of transformed lymphocytes

No mantle

M and PAS +ve hyalinised vessels prominent (≈ Castleman’s disease)

MALT Lymphoma (MALToma, Extranodal MZL)

In the GIT these are usu. localised and amenable to surgery (but can be disseminated e.g. IPSID)

Lymphoepithelial lesions (LEL) show epithelial damage / destruction (swelling, eosinophilia and

loss – use CAM5.2 to demonstrate LEL if not obvious) by clusters of ≥3 B-lymphocytes per

cluster – not just interposition of lymphocytes in between epithelial cells

Cytol. of neoplastic lymphocytes: small non-descript / centrocyte-like / monocytoid (abundant clear

cytoplasm) / plasma cell / scattered blasts (≤10%). Reactive plasma and T-cells admixed

except immediately around blood vessels

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Lymphoreticular 112

TABLE 10.2 Follicular lymphoma or follicular hyperplasia? Table reprinted (with modiﬁcations and additions)

from Lymph Node Biopsy Interpretation, Stansfeld AG, d’Ardenne AJ (Eds.), Ch. 9 ‘Low grade B-cell lymphomas’,

p.253, Copyright (1992), with permission from Elsevier Ltd.

Feature Follicular Hyperplasia Follicular Lymphoma

Architecture preserved lost (unless partial LN involvement)

Distribution of follicles predom. cortical spread throughout the node

Extracapsular spread absent / limited present as nodules & ‘mindless sheets’

Size of follicles variable with large ones uniform in any given case

†

Shape of follicles may be irregular usu. regular and rounded

Deﬁnition of follicles usu. sharp, no cracks sharp (± cracks

‡

) / poorly deﬁned

Mantle zone present (unless the germinal usu. absent or narrow

centre is very large)

Reticulin (see text) (see text)

Bcl-2 positivty in B-cells



absent present (except cutaneous FCL)

Polarity/Ki-67 zonation present absent

Acetyl cholinesterase activity present absent

AED

in follicles often present occ. present

Mitoses in follicles numerous, typical fewer, ± atypical forms

Tingible body M frequent occ. present but usu. absent

centrocytes conﬁned to follicles not conﬁned unless ‘early’ FCL

maturing plasma cells and other

inﬂam

cells in interfollicular areas often numerous scant / absent

†

Cases with large (‘giant’) follicles correspond to the original Brill-Symmers disease;

‡

these are artefactual cracks

between the follicle edge and surrounding lymphoid tissue;



it is usu. the centrocytes that stain best with Bcl-2 (cf.

centroblasts):

AED = acidophilic extracellular deposits.

Dense diffuse inﬁltrates of B-cells between reactive follicles and interstitially between mucosal glands

Colonisation of germinal centres (→ loss of ‘starry sky’ admixture of tingible body M):

 invasion of the germinal centre by CD10 and Bcl-6 −ve neoplastic cells (! but may be Bcl-2

+ve)

 displacement and peripheral condensation of FDC (CD21 and CD23 +ve)

Immuno: CD20 +ve, CD43 +vity in B-cells is helpful if present (but T-cells are also +ve), light chain

restricted and heavy chain +ve (usu. IgM) but IgD −ve; −ve for CD5, CD10, Bcl-1 and Bcl-6

Transformation to DLBCL (do not use ‘high grade MALT lymphoma’) is diagnosed when there are

solid sheets of transformed blasts; some accept clusters (of usu. >20) blasts but ! d/dg germinal centres

Some translocations are seen in the various MALTomas, the following three are mutually exclusive:

 t(11;18)  rare in nodal or splenic MZL; usu. does not have any other chromosomal

anomaly

 indicates:

◦

resistance to response to anti-helicobacter Rx



in gastric

◦

resistance to (i.e. protection against) MALToma

transformat

 immuno: moderate nuclear +vity for Bcl-10, weak cytoplasmic +vity for

MALT1

 t(1;14)  occurs in a small proportion of gastric and pulmonary MALTomas

 immuno: strong nuclear +vity for Bcl-10, weak cytoplasmic +vity for MALT1

 t(14;18)  found in extraintestinal MALToma (salivary gland, eye, liver, etc.)

 it is different to the t(14;18) seen in FCL

 immuno: strong cytoplasmic +vity for both Bcl-10 and MALT1

Other MALTomas have none of the above translocations and these usu. show weak cytoplasmic +vity

for both Bcl-10 and MALT1

Nuclear Bcl-10 +vity in ocular MALTomas may confer a worse prognosis

Intestinal Lymphomas (other than MALToma)

FCL

Usu. 2

◦

so diagnose 1

◦

only if limited to gut wall and local draining LN

Well-deﬁned nodules based on an FDC network

Frequently produce IgA (not IgG as in 1

◦

nodal FCL)

t(14;18) frequent (unlike intestinal MALToma)

Do not show plasma cell differentiation (MALTomas often do)

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Lymphoreticular 113

MCL

CD43 +ve unlike FCC (but CLL and some MALTomas are CD43 +ve)

Plasma cell differentiation is not seen

LEL are sparse or absent

d/dg DLBCL vs. blastoid variant of MCL

Lymphomas in chronic inﬂammatory bowel disease

Related to immunosuppression

Usu. EBV +ve

Includes extranodal HL with

◦

polyclonal H/RS cells

◦

possible regression upon stopping immunosuppression

EATL/ETTL (see p.115)

Extra-Intestinal MALT Lymphoma of Salivary Gland

Arises on a background of LESA (also known as MESA) – see pp.132–133

The earliest lymphomatous change is the presence of a pale zone of clear monocytoid centrocyte-like

(Cc-like) cells around a duct or epimyoepithelial island

These Cc-like cells loose their mantle B-cell phenotype (IgD +ve, IgM +ve) to display a marginal

zone phenotype (IgD −ve, IgM +ve) and show light chain restriction

Later Cc-like cell zones coalesce to form sheets that destroy the epimyoepithelial islands and displace/

colonise and replace the follicles

± Sclerosis

± Granulomas

Transformation to DLBCL may occur (deﬁned as the presence of solid sheets of blasts)

Diffuse Large B-Cell Lymphoma (DLBCL)

‘Large’ is deﬁned as ≥ twice the size of a normal lymphocyte

Centroblastic, immunoblastic

, plasmablastic (oral, HIV, EBV), anaplastic (unrelated to ALCL)

Need >90% immunoblasts to classify as immunoblastic DLBCL

LN involvement may be partial, interfollicular or sinusoidal

Variants:  T-cell-rich



a ‘rich’ variant is deﬁned as a tumour where

 histiocyte-rich <10% of the cells are neoplastic

 sclerosing 1

◦

mediastinal / thymic: CD45 +ve (unlike d/dg classical HL), CD30 +ve

and CD10 −ve. Also CD23 +ve unlike most other DLBCL

 PEL (1

◦

effusion lymphoma – see p.362)

 PAL (pyothorax-assoc

lymphoma – see p.362)

 1

◦

CNS

 intravascular (cyclin D1 and CD23 −ve)

 DLBCL with full length ALK (see under d/dg of ALCL on p116)

Immuno: pan-B +ve, CD5 ±ve, CD10 (+ve in 50%), CD30 +ve (esp. in anaplastic)

Adverse prognostic variant: ‘Activated’ B-cell phenotype: high Ki-67 LI, p53 +ve in >50% of the

cells, Bcl-2 strongly +ve, FOX-P1 +ve, Bcl-6 −ve, CD10 −ve, often immunoblastic morphology

Good prognostic variant: ‘Germinal Centre’ B-cell phenotype: centroblastic, Bcl-6 +ve, CD10 +ve

d/dg blastoid MCL: DLBCL is Bcl-1 −ve

d/dg mediastinal grey zone lymphoma = clinical, morphological and immuno features in between

NSHL and 1

◦

mediastinal DLBCL; M>F; some treat as for DLBCL not HL but more data needed.

d/dg diffuse FCL:  diffuse FCL must

◦

have centroblasts as the minority of the neoplastic cells

◦

be grade 1 or 2 at most (if grade 3 then = DLBCL)

◦

have no follicular areas

 presence / absence of a CD21 +ve FDC network is not useful

Burkitt’s Lymphoma

Children, extra-nodal (jaws, gonads, breast, intestines), EBV-assoc

Medium-sized B-cells with squared-off cytoplasm

Round nuclei with multiple small central nucleoli

Monotonous population

an immunoblastoid variant expressing cytoplasmic IgA is ALK +ve, t(2;5) −ve and highly aggressive

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Lymphoreticular 114

++ Mitoses, apoptoses and tingible body M (‘starry sky’)

Immuno: +ve for: lipid, surface IgM, CD10, Bcl-6, pan-B; −ve for: CD5, Tdt, Bcl-2, CD23

Immuno: Ki-67 LI ≈ 100%

Atypical Burkitt’s Lymphoma (Burkitt-like Lymphoma)

Adults, nodal

CD10 −ve Burkittoid lymphocytes

Less monotonous – half way between classical Burkitt and DLBCL

Cells have more prominent (but fewer) nucleoli cf. classical Burkitt

Ki-67 LI of ≈ 100% is required for diagnosis

Microlymphoma (HHV8-Associated)

Usu. occurs in the context of multicentric Castleman’s disease in LN or spleen

Deﬁned by small conﬂuent aggregates of HHV8 +ve plasmablasts, often impinging on germinal centres

There is light chain restriction by immuno but may be polyclonal or monoclonal (by genetics)

Post Transplant Lymphoproliferative Disorders (PTLD)

Plasmacytic hyperplasia: nodal, normal architecture, ! may be adjacent to a worse grade PTLD

PTLD IM-Like: nodal and Waldeyer’s ring, normal architecture, blasts prominent

PTLD Plasma Cell Rich: nodal and extranodal; equivalent to plasmacytoma

PTLD Polymorphic: invasive and destructive, oligoclonal

PTLD Monomorphic: immunoblasts or follicle centre cells, monoclonal, less likely to respond to a

reduction in immunosuppression, N-ras / p53 mutations common

PTLD Multiple Myeloma-like: monoclonal, N-ras, not likely to respond to ↓immunosuppression

PTLD T-cell Type: Not EBV-related (unlike most of the others), aggressive, poor prognosis

PTLD Hodgkin’s-Like: Few cases, must fulﬁl criteria for HL (because RS-like cells occur in other

PTLD)

PTLD Composite: two distinct types must be present – not a gradation

PTLD NOS

EBV-unrelated PTLD:  may be related to HHV8

 occur later

 may respond to ↓immunosuppression

 most are conventional lymphomas

T-Cell/NK Lymphomas and Reactions

Abbreviated List of T-Cell / NK Lymphomas

T-ALL/CLL

Hepatosplenic (type) – see p.124 and p.105

ETTL

(= EATL)

PTCL-U (peripheral TCL – unspeciﬁed)

Subcutaneous panniculitis-like TCL ( type) and mucocutaneous lymphoma

Angiocentric/Angioimmunoblastic/Adult TCL (HTLV-1)/Anaplastic

Large granular lymphocyte lymphoma

Mycosis Fungoides and variants (e.g. Pagetoid Reticulosis)

Subcutaneous Panniculitis-like TCL (+ve for CD8 and ; −ve for CD56 and EBV)

Restricted to the adipose (unlike ); is one cause of cytophagic histiocytic panniculitis (CHP)

Rimming of adipocytes by variably-sized Ki-67 +ve lymphocytes, clear cytoplasm, ±necrosis ++

In CHP cytophagocytotic histiocytes from ‘bean bag’ cells full of RBC ±WBC ±debris

d/dg: other causes of CHP (EBV, nasal-type NK/TCL), subcutaneous MF, TCL

T-CLL

Like B-CLL but no proliferation centres

LN inﬁltrate accompanied by high endothelial venules

Immuno: pan-T +ve (incl. CD4 and CD7), Tdt −ve

WHO terminology = Enteropathy Type TCL (cf. Associated – because there may not be enteropathy)

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Lymphoreticular 115

Enteropathy Type / Associated TCL (EATL / ETTL)

In un-complicated coeliac disease the IELs are CD8 +ve

In refractory coeliac disease (± ulcerative jejunitis) the IELs loose CD8 and become monoclonal

(= intraepithelial EATL)

The subsequent invasive EATL (inﬁltration of mucosa and submucosa) may be dominated by medium

to large lymphocytes of the same clone as for refractory coeliac

An ulcerated mass next to atrophic small intestinal mucosa is the typical macro

! The stromal inﬂammatory component (incl. eosinophils and histiocytes) may obscure the lymphoma

Immuno: CD8 ±ve, CD4 −ve (an unusual phenotype for a T-cell lymphoma)

Angioimmunoblastic TCL (AITCL)

Elderly, generalised LNp, systemic Sx, d/dg drug reaction (antibiotic / phenytoin, etc.)

Effacement of architecture but preserved subcapsular sinus and regressed follicles

Arborising proliferation of high endothelial venules

Proliferation of CD21 +ve FDC-like cells outside follicles around vessels → fascicles / whorls of

plump spindle cells

Small–medium T-cells incl. clear cell clusters and sheets → ‘mottled’ look at medium power

Immunoblast clusters (may be intravascular)

Background: rich in plasma cells ± eosinophils ± epithelioid M clusters

± RS-like cells (CD15 +ve, CD30 +ve, EBV ±ve, CD20 ±ve)

Grading: no numerical score but disease progression ∝ amount of immunoblasts

Immuno: mainly T4 cells, CD10 +ve (most periph. TCL are −ve), interspersed B-cells also present

d/dg:  T-cell-rich DLBCL: but atypical cells are T and B-cells are polytypic ( and )

 PTCL-U, but AITCL has: distinctive clinical

 AILD (vide infra) arborising high endothelial venules

 Classical HL plasma cell-rich background

extrafollicular FDC proliferation

Angioimmunoblastic Lymphadenopathy with Dysproteinaemia (AILD)

Similar clinical features to AITCL with polyclonal hypergammaglobulinaemia

Similar arch., arborising high endothelial venules and extrafollicular FDC prolif

to AITCL

Overall hypocellular

Lack clear cells or immunoblasts in clusters / islands / sheets

No cytological atypia

Angioimmunoblastic Lymph Node Reaction / Immunoblastic Reaction

Preservation of architecture and follicles

Otherwise like AILD

Speciﬁc causes include:  drugs

 infections: EBV / other viral infection, brucellosis

 adult Still’s disease

Angiocentric TCL (WHO: Extranodal NK/TCL, Nasal Type)

Nose (‘lethal midline granuloma’), pharynx, skin, testis

Diffuse angiocentric and angiodestructive inﬁltrate

Coagulative necrosis, apoptoses (and ulceration at mucosal sites ± PEH)

Cell size varies from case to case (small to anaplastic)

Nucleoli inconspicuous or small, even in large cell types

Mitoses ++, even in small cell types

± Heavy mixed inﬂammatory cell inﬁltrate (hence old name: polymorphic reticulosis)

Immuno: +ve for CD2, EBV, CD56, TIA-1 and granzyme B; −ve for CD3

HTLV-1 Adult T-cell Leukaemia / Lymphoma

Hypercalcaemia and lytic bone lesions (d/dg myeloma), multi-organ involvement

CD25 +ve CD3 +ve cells inﬁltrating skin esp. at dermoepidermal junction

Cerebriform atypical cells (medium-sized)

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Lymphoreticular 116

Assoc

with hyperinfection with Strongyloides stercoralis (see p.350)

d/dg MF

Immuno:  positive for CD3,CD25,CD30(±ve)

 negative for ALK, CD7, TIA-1, granzyme B

Anaplastic Large Cell Lymphoma (T/Null/NK Type) – Nodal ( for Cutaneous, see p.302)

◦

(nodal/cutaneous/soft tissues/bone/lung) or 2

◦

(transformation of nodal TCL / MF / LyP / HL)

Sinusoidal, diffuse or interfollicular growth pattern (d/dg HL)

Anaplastic cells, horseshoe / wreath nuclei surrounding central eosinophilic blob, multiple nucleoli

Variants:  lymphohistiocytic



more typical ALCL large neoplastic cells tend

 small cell to cluster around vessels in these variants

Immuno:  ±ve for CD30 (Golgi blob), EMA, CD25, CD45, LMW CK

 ALK

◦

nucleus and cytoplasm (nucleophosmin-ALK translocation)

◦

granular cytoplasmic (clathrin-ALK translocation)

◦

diffuse cytoplasmic (other ALK translocations)

Criteria for assigning T-cell differentiation:

 any of CD2,3,4,8 +ve (CD3 and CD8 are often −ve)

Criteria for null-cell differentiation:

 CD2,3,4,8 all negative

 B-cell markers all negative

Criteria for NK-cell differentiation (whether T or Null):

 CD56, TIA-1, granzyme B, perforin

Prognostics:  ALK–vity is a bad prognostic unless 1

◦

cutaneous form

 many NK-type T-cells are a bad prognostic

d/dg systemic vs. 1

◦

cutaneous ALCL:

 1

◦

cutaneous is usu. −ve for EMA, −ve for ALK t(2;5) translocation and is rare in children

 systemic/1

◦

LN ALCL are assoc

with aberrant clusterin expression

d/dg other ALK +ve tumours:

 RMS and neuroblastoma

 inﬂammatory myoﬁbroblastic tumour

 the rare immunoblastic ‘DLBCL with full length ALK’ (are t(2;5) −ve, CD30 −ve, IgA +ve)

d/dg classical HL:  CD15 rarely expressed in ALCL and then only focal sparse cells

 ALCL are EBV −ve

Hodgkin Lymphoma (HL, older term = Hodgkin’s Disease)

Classical Reed-Sternberg (at least two nuclear lobes / nuclei) and Hodgkin (mononuclear) cells

Rounded nuclei

Accentuated nuclear membrane

Large eosinophilic nucleoli (cf. smaller bluer nucleoli of ﬂorid reactive immunoblasts)

Pale chromatin

Abundant amphophil cytoplasm

± Mummiﬁed forms: pyknosing nuclei and condensed eosinophilic cytoplasm

Variants:

◦

L&H: has a multilobated nucleus with small nucleoli (nucleus looks like a popcorn)

◦

lacunar: see ‘Nodular Sclerosis HL (NSHL)’, below

◦

pleomorphic

◦

small cell

Immuno: there are two immunophenotypes

◦

the L&H cell phenotype seen only in NLPHL (q.v.)

◦

the phenotype of all other H/RS cells in all other variants of HL (see ‘Lymphocyte-rich classical

HL (LRCHL)’, below)

 CD15, CD30 (and EMA in NLPHL) typically show membranous accentuation with a Golgi

dot

d/dg RS-like cells in AITCL have variable intensity CD30 staining (uniform in HL)

d/dg reactive blasts show diffuse cytoplasmic (or membrane + dot) CD30, are −ve for CD15 and +ve

for T/B markers

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Lymphoreticular 117

Diagnosing HL Recurrence or Occurrence Outside LN (e.g. Bone Marrow, Effusions, etc.)

Must have either Hodgkin or RS cells (CD15 +ve and/or CD30 +ve) in an appropriate background

Seeing an appropriate (e.g. mixed cellularity) background without H/RS cells is not sufﬁcient to conﬁrm

HL but may suggest it

Plasma cell nodules or broad areas of ﬁbrosis in a bone marrow trephine should suggest the possibility

of HL and search for H/RS cells instigated if clinically consistent

Epithelioid granulomas may be found together with HL or in LN without HL draining sites affected by

Mixed Cellularity

Diffuse, vaguely nodular or interfollicular growth pattern

LN capsule not thickened and no bands of ﬁbrosis / sclerosis (else = NSHL)

Classical H/RS cells

Background of lymphocytes, plasma cells, eosinophils, neutrophils, M± granulomas

Nodular Lymphocyte Predominant HL (NLPHL, Nodular Paragranuloma)

Adult, MF, low stage, good prog., assoc

with progressive transformation of the germinal centres

L&H popcorn cells rosetted by CD57 +ve T-cells in a background of mantle B-cells (but may resemble

more classical Hodgkin cells morphologically)

L&H cells lie predominantly centrally in the nodule of mantle B-cells

the nodules contain an expanded FDC network (seen with CD21) but not tight rounded clusters of FDC

representing remnants of ordinary follicles overrun by lymphoma as seen in LRCHL

Eosinophils and neutrophils are absent in both nodular and diffuse regions

Immuno of L&H cells: BOB-1, OCT2, J-chain, Bcl-6, EMA, CD20, CD45 +ve; CD30 ±ve; CD15

−ve; EBV −ve (this is important, if EBV is +ve reconsider diagnosis – e.g. LRCHL)

d/dg: T-cell-rich DLBCL:

 just one nodule typical of NLPHL in an otherwise diffuse pattern is sufﬁcient to diagnose

NLPHL

 the background small lymphocytes are predominantly B-cell (in the nodular areas) of NLPHL

cf. T-cell in DLBCL

d/dg Lymphocyte-rich classical HL: vide infra

Lymphocyte-Rich Classical HL (LRCHL)

Usu. nodular with attenuated T-zone (but rarely it is diffuse with a mainly T-cell background)

Classical H/RS cells (although some may resemble L&H cells)

CD57 +ve T-cells are present but not rosetting H/RS cells

Eosinophils and neutrophils are sparse / absent

H/RS cells appear to lie eccentrically within the follicles with germinal centre to one side. They lie in

the expanded mantle of the follicle and not in the germinal centre

Immuno: CD15 +ve, CD30 +ve, EBV ±ve, EMA −ve

, −ve for J-chain, CD45, BOB-1 and OCT2,

CD20 is usu. −ve but not in all cases

d/dg NLPHD (q.v.): ! this is a common mis-diagnosis amongst general pathologists

Nodular Sclerosis HL (NSHL)

Nodular growth, ﬁbrous bands and thickened capsule

RS cells have multiple small lobes with multiple small nucleoli and retraction artefact (‘lacunar cells’)

– this artefact is not seen on frozen section.

Lacunar cells may form aggregates (= syncytial variant if this is pronounced)

Necrosis may be present

Variable background: mixed cellularity to hypocellular

Grading (BNLI method):

I ≥75% of the nodules have scattered RS cells with a non-neoplastic cell-rich background

(lymphocytes, mixed cellularity or ﬁbrohistiocytic)

II ≥25% have at least 1 ×40 ﬁeld ﬁlled with RS cells. (These are also usu. associated with

lymphocyte depletion but it is the abundance of RS cells that make it a grade II)

but upto 20% of cases may be focally +ve for EMA

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Lymphoreticular 118

Lymphocyte Depleted HL (LDHL)

Rarest type, extranodal sites or retroperitoneal LN preferred

Predominance of classical H/RS (or pleomorphic variant) cells to background lymphocytes

Diffuse ﬁbrosis subtype: low cellularity, H/RS cells rare, ﬁne ﬁbrosis with proteinaceous material

Reticular subtype: numerous H/RS with bizarre forms (= ‘Hodgkin’s sarcoma’)

d/dg NSHL: if there is nodular sclerosing ﬁbrosis don’t call it LDHL (it is NSHL, probably grade II)

d/dg ALCL: LDHL should have CD15 +ve H/RS cells and the diagnostic features of ALCL are absent

Interfollicular HL

A name given to HL (of various subtypes) that occurs in the interfollicular regions of a LN

It is accompanied by follicular hyperplasia so may be mis-diagnosed as reactive

Sentinel Node Pathology

Melanoma

Most mets are in the subcapsular sinus and ≈ all are S100 +ve

Benign naevus cells are co-present in >10% cases and are usu. HMB45 −ve but will give a +ve

tyrosinase test on PCR (hence limitations of non-histological methods for SN assessment)

‘Enhanced histopathology’ (multiple levels and immuno) of SN is predictive of local LN ﬁeld mets

Lymphadenectomy of SN +ve cases only: spares unnecessary morbidity

Lymphadenectomy of SN +ve cases only: may be therapeutic (but ? survival advantage)

≈ 20% of SN show mets by enhanced histopathology (∝ Breslow thickness and Clark level)

≈

of these also have +ve LN other than the SN

Breast

Similar clinical points and +vity stats as for melanoma (SN immuno for CK is esp. sensitive in ILC)

Good for local control by selective axillary clearance or radioRx for SN +ve cases

It can also identify internal mammary LN +ve cases (worse prognosis)

Per-operative assessment by imprint cytology (= ‘dabs’) or FS is becoming popular

Colorectal

High level of false −ves in literature (>10%) mean that routine sampling of SN for enhanced

histopathology is not justiﬁed outside research

SN mapping may be useful to guide surgery by identifying unexpected lymphatic drainage routes

Other Lesions and Reactions of Lymph Nodes

Benign LN Inclusions

! A source of overdiagnosis of malignancy on FS

Epithelial:  peri/intra-parotid / submaxillary LN – salivary duct inclusions

 axillary LN – breast epithelium, usu. cystic +/ squamous / apocrine change

 periaortic LN – M¨ullerian metaplastic epithelium

 mesenteric LN – colonic glands

 pelvic / inguinal LN – tubal-type epithelium without stroma, usu. women

Mesothelial:  mediastinal LN

 epithelioid cells in sinuses

 bland nuclei, low NCR, well-deﬁned cell borders ± windowing

 immuno: mesothelial (see p.89 and p.360)

Naeval:  usu. intracapsular / intraseptal in axillary LN (!d/dg single ﬁle ILC cells)

 inguinal / neck LN – sinus naevocytes drained from congenital naevi

Decidual: ! do not mistake for metastatic SCC

Haemopoietic: megakaryocytes are AE1/AE3 −ve (d/dg carcinoma)

the original skin naevus may show intravascular naevocytes