Tadrous P.J. Diagnostic criteria handbook in histopathology: a surgical pathology vade mecum

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Eye and Ear 199

Tumours of the Orbital Tissues and Muscles

Any soft tissue tumour incl. granular cell tumour, RMS, liposarcoma, endothelial tumours, etc.

Mesenchymal chondrosarcoma

Lymphoma: usu. extranodal MZL, other types occur (e.g. FCL, DLBCL) but are less common

Retinoblastoma

Composed of neuroblasts from cellular layers of the retina

Growth may be in towards the centre of the vitreous (endophytic) or out through the wall of the globe

(exophytic) or both

Mitotically active small blue oval cell tumour

Solid sheets, necrosis with perivascular sparing, multifocality, Ca

± Fibrillary rosettes with (Flexner-Wintersteiner) or without (Homer-Wright) central lumena

Immuno: GFAP shows perivascular stromal astrocytes

d/dg retinoma (retinocytoma) is usu. small, less cellular and is composed of better differentiated

photoreceptor cells (more cytoplasm, smaller basal nuclei)

For details important for the report, see p. 44.

The Ear

Accessory Auricles (incl. Tragi)

Clin: like a FEP near the ear but present at birth ± other anomalies

Adnexa-containing skin and adipose ± central cartilage (d/dg FEP lacks adnexa/cartilage)

Chondrodermatitis Nodularis Helicis

Clin: painful ulcer on the helix, rarely >1cm, d/dg BCC/SCC

Ulcer with adjacent dermal vasc. ectasia ± actinic change ± PEH (! see clin. d/dg above)

Underlying granulation tissue and inﬂam

involves perichondrium with ﬁbrinoid and eosinophilic

degeneration of the cartilage

Malignant Otitis Externa (Necrotising External Otitis)

Pseudomonas aeruginosa cellulitis with poor circulation and ↓ PMN function (e.g. DM/elderly)

Acute and chronic inﬂam

, necrotic tissue (incl. bone and cartilage when there is osteomyelitis /

chondritis), granulation tissue, scarring, Gram −ve rods ++

Ulceration of the EAM ± PEH (! d/dg SCC which may also show necrotic tissue)

Aural Polyp (Inﬂammatory)

Youths, arise in middle ear (± non-ciliated columnar lining) but may protrude through the EAM

Variably mature granulation tissue, mixed chronic inﬂam

, plasma cells ± big Russell bodies, ± Ca

Cholesterol granulomas may be present (! do not confuse with cholesteatoma, vide infra)

Seek an infective aetiology (e.g. do a Gram and DPAS) and rule out the d/dg below

d/dg: bacillary angiomatosis, HX, RMS, paraganglioma, other neoplasm

Cholesteatoma (of the Middle Ear)

This is an acquired (epidermal) or congenital (epidermoid) inclusion cyst of the EAM or external

tympanic membrane that erodes into the bone around the middle ear

Bx usu. shows loose irregular ﬂakes of keratin but stratiﬁed squamous epithelium (non-dysplastic) is

required for diagnosis

d/dg SCC is dysplastic and may show desmoplasia or an inﬁltrative margin

d/dg keratosis obturans shows tightly-packed lamellar keratin ﬂakes

Otosclerosis (of the Endochondral Part of the Temporal Bone)

Early: resorption of the normal compact lamellar bone (± cartilage islands) by vascular ﬁbrous tissue

→ woven bone

Later: hypercellular, dense, sclerotic, darker-staining woven bone fuses the stapes to its footplate

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Eye and Ear 200

Neoplasms

Salivary gland and Schneiderian-type, SCAP, SCC, adenoCA, paraganglioma and soft tissue lesions

External ear: ceruminal gland adenoma/carcinoma

Apocrine-like cells containing intracytoplasmic brown pigment (ZN +ve and autoﬂuorescent)

Arch.: papillary, solid cords, cystic ± cribriform

Adenoma: well-circ. (no capsule), 2-cell type seen focally, ± minor atypia and few mitoses

Carcinoma: inﬁltrative, no myoepithelial layer, ± marked atypia/mitoses/ulcerat

d/dg rare .

. exclude metastatic (e.g. salivary) or middle ear 1

◦

Middle ear: middle ear adenoma

Plasmacytoid cells, ± pleom. but rare mitoses, ± NE nucleus, ± AB&DPAS+ve secretions

Arch.: single cell-lined acini, trabeculae, ‘back-to-back’, solid sheet; well-circ. (no capsule); sparse

stroma

Immuno: +ve for CK ± NE markers, −ve for vimentin (and −ve for S100 in 85% of cases)

d/dg carcinoid if NE +ve: most think you should call this ‘adenoma with NE differentiation’

Inner ear: endolymphatic sac papillary tumour (= ‘low grade adenocarcinoma of probable

endolymphatic sac origin’)

Clin: locally aggressive .

. → radical surgery. May be assoc

with VHL

Simple papillae with simple lining (ﬂat to columnar, may be clear ± intracytoplasmic DPAS +ve

material; only mild pleom. and rare mitoses)

Stroma: granulation tissue, haemosiderin ± Ca

(not psammomatous)

Thyroid follicle-like areas with DPAS +ve ‘colloid’ (not thyroglobulin)

Immuno: +ve for CK ± vimentin, EMA, S100, GFAP and NE markers; −ve for thyroglobulin

d/dg: mets (RCC, thyroid), 1

◦

middle ear adenoCA (more pleom, mitoses and inﬁltration; also use CPC

– esp. radiol.)

Bibliography

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edn, Thieme Medical Publishers Inc., NY.

Berns, S. and Pearl, G. (2006) Middle ear adenoma. Archives of Pathology and Laboratory Medicine, 130 (7), 1067–1069.

Demirci, H., Shields, C.L., Eagle Jr, R.C. et al. (2006) Report of a conjunctival myxoma case and review of the literature. Archives of Ophthalmology,

124 (5), 735–738.

Domizio, P., Lowe, D. and McCartney, A. (1997) Eye, in Reporting Histopathology Sections,1

edn (eds P. Domizio and D. Lowe), Chapman &

Hall Medical, London, pp. 356–365.

Firkin, B.G. and Whitworth, J.A. (1987) Dictionary of Medical Eponyms,1

edn, The Parthenon Publishing Group, Lancs., UK.

Hughes, G.R.V. (1977) Connective Tissue Diseases,1

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Norton, A.J. (2006) Monoclonal antibodies in the diagnosis of lymphoproliferative diseases of the orbit and orbital adnexae. Eye, 20 (10), 1186–1188.

Ruprecht, K.W. and Naumann, G.O.H. (1986) The Eye in Systemic Disease, in Pathology of the Eye,1

edn, (eds G.O.H. Naumann and D.J.

Apple), Springer-Verlag, NY, pp. 873–956.

Sternberg, S.S. (ed) (1997) Histology for Pathologists,2

edn, Lippincott Williams & Wilkins, Philadelphia.

Symmers, W. St. C. (ed) (1980) Systemic Pathology, Vol. 6, 2

edn, Churchill Livingstone, Edinburgh.

V¨olcker, H.E. and Naumann, G.O.H. (1986) Conjunctiva, in Pathology of the Eye,1

edn (eds G.O.H. Naumann and D.J. Apple), Springer-Verlag,

NY, pp. 249–316.

Wheater, P.R., Burkitt, H.G. and Daniels, V.G. (1987) Functional Histology: A text and colour atlas,2

edn, Churchill Livingstone, Edinburgh.

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Renal Medicine 201

15. Renal Medicine

Normal and Age-Related Changes

The blood supply of the tubules is mainly from the efferent arteriole (.

. any scarring glomerular disease

→ ischaemic tubules → interstitial ﬁbrosis and tubular atrophy)

Cellularity (in a 3 H&E section): capillary loops – 0 nuclei; mesangium – 2–4 nuclei

Adequacy of a renal Bx: need ≥20 glomeruli not to miss focal disease

Sclerosed glomeruli (= global acellular sclerosis): 5% till 30 years then [age/2]-10 gives the 90

centile (from Smith et al., 1989). Segmental sclerosis is not normally seen

Ageing: arterioles: hyaline change; arteries: ﬁbrous intimal thickening and reduplication of the IEL

Clinical Presentation and Syndromes

Nephrotic Syndrome

Proteinuria (3–10g/d), Oedema, Hypoalbuminaemia: [HT, ↓renal function, hyperlipidaemia, infec-

tions]

Macro: kidneys are large and pale (due to oedema) with yellow streaks in the cortex

Micro:  foamy M ± cholesterol granulomas

 hyaline and fatty droplets in PCT

 hyaline casts in DCT

 EM: effaced foot processes (pedicel ‘fusion’) due to cytoplasmic swelling

Causes:  1

◦

glomerular (minimal change disease, FSGS and all GN but crescentic)

 2

◦

to systemic disease (D.A.S.H.I.N.)

and drugs

Nephritic Syndrome

Oedema (± effusions), HT(± encephalopathy), Oliguria: [microhaematuria, protein, granular casts]

Causes: usu. glomerulonephritis of ADP / RPC / focal and segmental types

Asymptomatic Proteinuria

Causes: many, but if proteinuria is asymptomatic renal damage is usu. slight, early or not obvious

Painless Haematuria

With dysmorphic erythrocytes on urine cytology

Causes: IgA nephropathy and some hereditary nephritides (Alport’s and thin membrane disease)

Hypertension

Causes are many: renal, vascular and systemic

Renal Failure or Impaired Renal Function

Causes of ARF: ATN, various GN, acute interstitial nephritis, vasculitides/CTD, Goodpasture’s disease

and myeloma

Causes of CRF: advanced chronic renal disease may be difﬁcult to diagnose but try to distinguish

between glomerulonephritic (e.g. IgA nephropathy) or non-glomerulonephritic (e.g. DM)

General Points on Histological Interpretation and Reporting

Stage: always give an estimate of the degree of irreversible chronic damage i.e. % scarring and tubule

atrophy (see the Banff system on p. 209 for a method) – in any disease, not just Tx rejection

Grade:givethen˜o and % of glomeruli showing ‘active lesions’ (for an example, see SLE, p. 204)

Report: a) what is present (cortex +/ medulla), b) the maximum n˜o of glomeruli on any single section,

the % sclerosed and a description of any glomerular lesions, c) any tubular lesion and % tubular loss,

d) state of the interstitium, e) the n˜o and type of blood vessels and any changes, f) immuno and EM, e)

conclusions

Diabetes, Amyloid, SLE, HSP, Infection, Neoplasia

Diagnostic Criteria Handbook in Histopathology: A Surgical Pathology Vade Mecum. Paul J. Tadrous



2007 by John Wiley & Sons, Ltd. ISBN: 978-0-470-51903-5

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Renal Medicine 202

Describe the location and pattern of immunostaining: linear / granular, mesangial / loops

Some IgM often deposits in the mesangial matrix and doesn’t mean much unless intense (→FSGS)

[NB: some regard FSGS as the severe end of a spectrum: minimal change disease →steroid dependent /

resistant minimal change disease with mesangial IgM →mesangial expansion with IgM (±C3 and mi-

nor amounts of IgA / IgD) +glomerular capillary hypercellularity (the so-called ‘mesangioproliferative

glomerulopathy’

or ‘IgM nephropathy’) → FSGS]

IgG/M deposition is usu. not signiﬁcant (=serum background-staining) unless the pattern is continuous

and linear +/ complement is also deposited but...

C3 can be unreliable with immunoperoxidase .

. use a panel that includes others e.g. C9 or C1q

The odd glomerular PMN may be seen in any proliferative lesion – it does not imply ADP GN

Glomerulonephritis

Clinical Perspective on GN

The nasty ones are RPC GN, membranoproliferative GN and FSGS. The others are usu. more indolent

and prognosis depends on the underlying cause

Look for cholesterol emboli (foam cells, fat stain +ve, birefringent fat on FS) if a ‘vasculitic’ FSGN is

proposed or in the d/dg of TMA. Cholesterol emboli usu. occur in vasculopaths (e.g. IHD), following

repair of an aortic aneurysm or following removal of a graft kidney from an atheromatous donor

The commonest 1

◦

glomerular causes of the nephrotic syndrome are:

 (child) minimal change / FSGS

 (adult) membranous / FSGS

The commonest cause of an RPC GN is P-ANCA +ve microscopic polyarteritis

HSP may present with an ADP GN picture (not just FSGN / RPC GN)

For an urgent Bx you must decide if the kidney is viable, whether the disease is acute / chronic, and

where the main seat of disease is (glomeruli, tubulointerstitium, vessels, etc.)

Chronic Glomerulonephritis

Macro: granular contracted kidney (for d/dg reﬂux nephropathy, see p. 213)

Hyalinised glomeruli

Interstitial ﬁbrosis, chronic inﬂammation and tubular atrophy

The type of preceding GN is usu. not recognisable but most are thought to be IgA nephropathy

Acute Diffuse Proliferative GN (Post-infective ADP GN)

Youths (but all ages), nephritic / subclinical, low C3, post infective (Strep./EBV/HCV/malaria)

Most youths recover but 50% of older patients develop RPC GN and die

Rx: not steroids

Macro: large and pale kidney with grey dot glomeruli in an expanded cortex.

Micro: large hypercellular glomeruli (incl. PMN, esp. if ≥5), ± a few crescents, ↑ mesangial cells

Immuno: granular IgG and C3

EM: subepithelial ‘humps’ (n˜o. ∝ severity)

Elsewhere: protein and RBC casts ± ischaemic tubules

Rapidly Progressive Crescentic GN

Older (but all ages), insidious malaise, oedema, dyspnoea

◦

Pauci-immune GN (= idiopathic) / post Strep.

have p-ANCA,

c-ANCA

◦

: Goodpasture’s (young M) / vasculitides (WG, S.H.I.P.

)

Rx: immunosuppression → temporary remission else RF in days–months (ANCA +ve cases may be

curable)

Macro: ± large and pale kidney with grey dot glomeruli and petechiae

Micro:  diffuse segmental proliferation & cellular crescents (in >70% of glomeruli)

 ± haemorrhagic necrosis of capillaries → scarring (d/dg TMA / HUS – see p. 207)

Immuno: crescents contain ﬁbrin but not Ig

EM: crescents do not contain immune complexes

!do not confuse with mesangioproliferative glomerulonephritis (p. 203)

SLE, HSP, Infective endocarditis, microscopic Polyarteritis (malaise, purpura, arthralgia)

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Renal Medicine 203

Elsewhere: as for ADP but more severe. Reporting of the vasculitides should incl. % active tubular

inﬂam

/necrosis and % glomeruli that are/have:

◦

normal,

◦

segmental scars,

◦

crescents,

◦

necrosis

Membranous GN

Older men, insidious nephrotic syndrome, ± microhaematuria (never gross)

◦

idiopathic (majority)

◦

to Sarcoid, Infection (malaria, HBV, syphilis), Neoplasia, Drugs (gold, penicillamine, ACEI)

Rx: diuretics not steroids; over 10 years 50% → CRF

Macro: nephrotic changes (see p. 201)

Micro:  no proliferation

 hyaline BM thickening → narrow loop lumens →↓ GFR

 silver ‘spikes’ in vertical section / bubbly ‘chain-mail’ in tangential section

Immuno: peripheral granular IgG (± C3) in situ complex formation

EM: multiple, almost conﬂuent, subepithelial deposits

Elsewhere: tubular atrophy and scarring, nephrotic changes (see p. 201), changes of any 1

◦

disease

Membranoproliferative GN Types I – III (MPGN or ‘Mesangiocapillary GN’)

nephrotic / nephritic (esp. type II) / asymptomatic proteinuria, low C3

◦

(most are now known to be post HCV cryoglobulinaemia) / 2

◦

(infective endocarditis, malaria, HCV)

Type II may be familial (assoc

with partial lipodystrophy and Factor-H deﬁcient TMA)

Rx: symptomatic, not steroids; most → CRF. Type II may recur in a transplanted kidney.

Micro:  (diffuse prolif

, accentuated lobulation, narrowed loops) →↓ cells, ↑ hyaline → GS

 double contour BM (also seen in PET and many causes of glomerular TMA)

 crescents are more common with type II

Immuno: C3 and IgG +/ IgM, granular and peripheral (i.e. involving capillary loops)

EM: I – discrete subendothelial immune complex deposits, mesangial interposition and subendothe-

lial new BM formation

II – ‘dense deposit disease’ – due to underlying defect of the BM. BM splits around dense deposits

(=BM material damaged by circulating anti-C3bBb Ab i.e. ‘nephritic factor’). NB: Only 25%

show MPGN by LM – most show mesangial prolif

, ADP or cresentic GN

III – very rare, subendothelial and subepithelial deposits

Mesangial Proliferative GN (Mesangioproliferative GN)

↑ Cellularity ±↑matrix in the mesangium without capillary loop involvement

Common with IgA nephropathy (more common than FSGN) and SLE

Many other causes e.g. the healing phase of ADP GN

Focal Segmental GN (FSGN)

◦

(= IgA nephropathy = Berger’s disease),

common adult GN, recurrent haematuria ± nephritic

syndrome, assoc

with IgA mucositis / liver disease (some only diagnose Berger’s in the absence of

this)

◦

to WG, S.H.I.P. and Goodpasture’s; (H. is a variant of Berger’s disease, I. is assoc

with low C3)

Rx: immunosuppression in some cases (!but see d/dg below); upto 50% → CRF

Micro:  focal and segmental prolif

± ﬁbrinoid necrosis / thrombosis (d/dg TMA/HUS q.v.)

 ± RBC in Bowman’s space / tubules

 ± small cellular crescents

Immuno: 1

◦

: IgA and C3 (mesangial)

◦

: H. as for 1

◦

, I. shows IgG, P. pauci-immune, S. full house

EM: subendothelial and mesangial deposits

Elsewhere: infarcts and vasculitis (in the case of microscopic polyarteritis)

d/dg: cholesterol emboli: these can mimic vasculitic rash and give FSGN – !do NOT immunosuppress

IgA nephropathy is also known as mesangial IgA disease as deposits are usu. mesangial and often large, appearing as eosinophilic

PA S +ve tiny drops on LM. IgA/M in the capillary loops or mesangial IgG are poor prognostics. Grade should include % gloms with:

◦

cellular crescents, and

◦

segmental necrosis. Percent of cortical myoﬁbroblasts by SMA immuno correlates with advancing

stage

often with IgM, full house occurs in 25% of Berger’s – then go by predominant staining: predominantly IgA favours Berger’s,

predominantly IgG favours lupus (a ‘mixed’ GN morphology also favours SLE)

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Renal Medicine 204

Focal Segmental Glomerulosclerosis (FSGS)

Nephrotic, HT and microhaematuria common (2

◦

to parenchymal loss); FSGS circulating factor

◦

(idiopathic) / 2

◦

(HIV, IVDA ‘heroin nephropathy’); most → CRF after years; recurs in Tx

Macro: changes of the nephrotic kidney (see p. 201)

Micro:  juxtamedullary large glomeruli with focal and segmental hyaline obliteration

 becomes global and diffuse with time

 silver stain highlights segmental scars

Immuno: IgM and C3 granular/nodular. Lack of IgG helps exclude the resolving phase of ADP GN

Elsewhere: nephrotic changes, tubule atrophy (and large thyroidal tubular casts and inﬂammation in

the ‘collapsing FSGS’ variant often assoc

with HIV)

Minimal Change Disease (Lipoid Nephrosis)

Nephrotic syndrome, usu. in children, selective albuminuria, no HT / haematuria

◦

(most) / 2

◦

(atopy/allergy/lymphomas/other malignancy)

Rx: spontaneous resolution or steroids; may relapse (and some may progress to FSGS)

Macro: changes of the nephrotic kidney (see p. 201)

Micro: ﬁxed dilated capillaries and nephrotic changes (see p. 201)

Immuno: −ve

EM: pedicel ‘fusion’ or ‘effacement’ (= cytoplasmic swelling) assoc

with loss of polyanion

The Kidney in Systemic Disease

Diabetic Nephropathy

Clin. progression is: asymptomatic proteinuria → HT and nephrotic → CRF (granular contracted

kidney)

Hyaline arteriolosclerosis: worse in afferent cf. efferent (and both are worse cf. HT / old age)

Nodular glomerulosclerosis (Kimmelstiel-Wilson lesion) is more characteristic of DM, but diffuse

glomerulosclerosis is more ∝ to renal function. Sclerosis is assoc

with microangiopathy elsewhere

(e.g. retina)

Immuno: glomerular and tubular BM: linear IgG (but not C3); sclerotic lesions: IgM, C3,  and 

all ±ve

EM: pedicel ‘fusion’, ↓ podocytes per glomerulus, ± mesangial bundled diabetic ﬁbrillosis

Other lesions: ﬁbrin cap, capsular drop, mesangial expansion, glomerular capillary microaneurysm,

renal artery atheroma, renal papillary necrosis, UTI / acute pyelonephritis, interstitial scarring

d/dg nodular glomerulosclerosis: other hyaline deposits (e.g. amyloid, ﬁbrillary glomerulopathy, MIDD,

macro/cryoglobulins), advanced MPGN, idiopathic nodular glomerulosclerosis

HIV Nephropathy

FSGS (q.v. – esp. the collapsing FSGS variant)

EM: tubuloreticular structures and cylindrical confronting cisternae (esp. the latter)

Rx-related effects and opportunistic infections e.g. CMV

Systemic Lupus Erythematosus and the 2003 ISN/RPS Lupus Nephritis Classes

Class 1: glomeruli normal by LM but immuno shows mesangial deposits

Class 2: mesangial disease only (hypercellularity) by LM with mainly mesangial deposits by immuno/EM

Class 3: focal GN: global/segmental, active (proliferative) +/ chronic (sclerosing)

Class 4: diffuse GN: global (≥1/2 the tuft is involved in ≥50% of the affected glomeruli)/segmental,

active +/ chronic

Class 5: membranous GN ± advanced sclerosis

Class 6: chronic GN (‘advanced sclerosis’): ≥90% of the glomeruli are totally sclerosed and inactive

Rx: aims to transform 3/4 (proliferatives) to 1, 2 or 5

There may be more than one class in a given biopsy (e.g. class 2 and 5)

Any ‘active lesions’ make the class 2 (if focal) or 3 (if diffuse): i.e. PMN/leukocytoclasia, crescents

with some cellularity, hyaline ‘wire loop’ lesions (due to massive subendothelial deposits), lilac haema-

toxyphile bodies, hyaline/ﬁbrin thrombi or segmental ﬁbrin

‘Diffuse’ disease is deﬁned as ≥50% of glomeruli are involved (in the past, >80% was used)

Give the n˜o and % of glomeruli with:

◦

any active lesion,

◦

crescents and

◦

ﬁbrinoid necrosis

Interstitial nephritis may be the more predominant disease

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Renal Medicine 205

± Lupus vasculopathy: hyaline deposits and myocyte dropout in media and intima of terminal inter-

lobular arteries and afferent arterioles, immuno +ve for Ig, complement and ﬁbrin (d/dg TMA which

may also occur due to antiphospholipid Abs but has a better prog.)

Immuno:  full house i.e. IgG/A/M, C3, C4, C1q complex (mesangial/subendothelial/epithelial)

 mixture of GN patterns favours LE (e.g. membranous with hypercellular mesangium)

 mesangial immune deposits favour LE (but IgA may be Berger’s disease)

 presence of IgA/M without IgG is unlike lupus and the aetiology should be questioned

Renal Amyloidosis

◦

; pericapillary deposition and obliteration (nephrotic → CRF)

Can get spiking of BM in amyloid (d/dg membranous GN)

Nodular deposits (d/dg DM, light chain, advanced mesangiocapillary GN)

Negative Congo Red does not rule out amyloid – even if properly done – .

. need EM

d/dg ﬁbrillary and immunotactoid glomerulopathies, cryoglobulinaemia

Myeloma Kidney

May lead to ARF/CRF

Myeloma cast nephropathy

BJP is toxic to tubule epithelial cells and casts

erode tubules → giant cell

and PMN inﬂam

d/dg innocuous hyaline casts: in myeloma at least some of the casted tubules will not have a ﬂat, atrophic

lining; these are the innocuous ones. Pure Tamm-Horsfall casts are intensely DPAS +ve (but weakly

+ve if diluted by paraproteins)

d/dg TORi toxicity post-Tx (see p. 210)

Paraprotein deposition

Amyloid /  light chains are deposited in vessels, glomeruli, tubules (light chain nephropathy)

Nephrocalcinosis

in tubule epithelial cells and BM → interstitial ﬁbrosis and chronic inﬂam

→±CRF

Associated features

Plasma cell inﬁltrates, urate crystals (gout), nephrotoxic effects of drugs

Light Chain Nephropathy

Due to nonﬁbrillary light chains (unlike amyloid)

Nephrotic / proteinuria, HT, CRF; myeloma may or may not be present

LM: lobular accentuation and PAS +ve

mesangial nodules () [also in glomerular and tubule BM]

Immuno:    (may be −ve as Fc may be missing .

. urine may also be −ve for light chains)

d/dg membranous GN / DM nodular GS (if ?DM but no hyaline arterioles, consider light chain disease),

amyloid, advanced mesangiocapillary GN

d/dg other forms of MIDD i.e. heavy chain or mixed light chain and heavy chain deposition disease

Hereditary Nephritis

Alport’s Disease

AD/XL; both sexes: haematuria; males: proteinuria, ↓renal function, spherophakia, nerve deafness

LM: normal / FSGN

Immuno: −ve

EM: multilamination / splitting / trabeculation / fragmentation of glomerular capillary, tubular and

Bowman’s capsular BM (! may be focal and also reported in d/dg post Strep. ADP GN, Berger’s disease

and thin membrane disease)

Thin Membrane Disease (Benign Familial Haematuria)

Usu. AD but non-familial cases occur; variable haematuria, ↑ incidence of HT, ± other renal disease.

LM: minimal change or ↑ sclerotic glomeruli / mesangial thickening

EM: thin glomerular BM must be measured carefully (! tangential artefacts), lamina densa is preserved

These acellular casts (BJP & Tamm-Horsfall protein) may stain for amyloid. The  and  immuno is hard to interpret. Glomerular

capillaries may be involved (‘hyaline thrombi’) in Waldenstr¨om’s

giant cells can appear intratubular as well as interstitial

silver stain negative (unlike d/dg ↑ mesangial matrix)

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Renal Medicine 206

Fabry’s Disease

Treatable XL recessive lysosomal storage disease (glycosphingolipid accumulates in many organs –

esp. epithelial, endothelial and smooth muscle cells incl. cornea, synovium and solid organs)

LM: foam cells (podocytes) in the glomeruli, endothelial and epithelial (incl. tubular) cells show PAS

+ve vacuoles; immuno is −ve

EM: myeloid bodies (= irregular lamellated lipid inclusions) in the podocytes or tubular epithelium

Is assoc

with multiple angiokeratomas of the skin (angiokeratoma corporis diffusum)

MPGN II: (see p. 203)

Tubulointerstitial and Vascular Disease

Potassium Deﬁciency (Hypokalaemia)

Macrovesicular vacuolation of PCT cells (unlike d/dg cyclosporin toxicity – p. 209)

Acute Pyelonephritis

PMN in tubules

Acute Tubular Necrosis

Clin.: ARF ± oliguria → normal in days/weeks (but 50% mortality)

Aetiology: ischaemic (medical/surgical/obstetric), nephrotoxic (drugs/chemicals/pigments)

Macro: pale oedematous cortex and dark congested medulla (enhanced corticomedullary differentia-

tion)

Micro:

 interstitial oedema and focal Ca

(oxalate)

 focally dilated tubules with sloughing of PCT brush border (PCTs look like DCTs)

 ± necrosis of tubule epithelial cells ± tubulorrhectic inﬂam

 after 1 week: mitoses and regenerative atypia

 ‘tubular cell unrest’ (anisocytosis of tubular cells)

 ± mild tubulitis (i.e. < 4 mononuclear cells, see p. 208)

 casts in DCT (protein or granular)

 in renal Tx kidneys, ATN may show:

 more interstitial inﬂam

and calciﬁcations

 less ‘unrest’, casts and brush border damage

 foci of full-cross sectional tubule necrosis

Renal Papillary Necrosis (Causes)

◦

diabetes mellitus

◦

analgesic nephropathy

◦

vascular occlusion e.g. sickle cell disease, leukaemia, etc.

◦

urinary tract obstruction

◦

haemorrhagic necrosis of papillae in the newborn

Interstitial Nephritis

Interstitial scarring (ﬁbrosis) as seen in any GN with a chronic component contains a chronic inﬂam-

matory inﬁltrate which does not imply interstitial nephritis

Granulomas in the kidney are not usu. related to drugs (cf. in the liver)

The three main aetiological categories are:

◦

Drugs

‘Acute’ interstitial nephritis

For example, due to penicillin or quinine; mediated by anti-tubule Abs

Mixed chronic inﬂam

cell inﬁltrate (incl. eosinophils) with tubule destruction

Glomeruli are spared (or involved by a drug-induced TMA)

Analgesic nephropathy

Papillary necrosis with overlying chronic inﬂam

inﬁltrate

± Metaplastic bone / Ca

Glomeruli are spared

◦

Radiation

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Renal Medicine 207

Radiation nephropathy

Vascular changes incl. ﬁbrinoid necrosis (without severe HT) – see also p. 72

Stromal ﬁbrosis and tubular atrophy

Glomerular capillary loop thickening and fusion

◦

Metabolic:

Urate nephropathy (gout)

Fibrosis, tubule atrophy and medullary stromal urate crystals ± renal urate calculi

Medullary collecting tubule uric acid crystals and giant cell reaction

Atrophy of corresponding nephrons (→ granular contracted kidney)

Superimposed HT changes

Nephrocalcinosis

Intra- and extratubular Ca

Cystinosis

Multinucleated podocytes

Thrombotic Microangiopathy (TMA)

TMAs are non-inﬂammatory thrombotic vasculopathies (d/dg vasculitis – ! although some TMA lesions

may be seen downstream of classical vasculitides). The thrombi are +ve for FVIIIRA

Clinically thrombocytopenia, red cell fragmentation and ↑LDH (due to tissue hypoxia) may be seen

(= TTP if there is deﬁciency of FVIIIRA proteases or = HUS if there is ARF)

May predominantly affect glomeruli, afferent arterioles and other small arteries/arterioles ∝ cause

Arteriole-capillary TMA: platelet-rich thrombi ± lumenal microaneurysmal dilatation. May heal by

re-endothelialisation (→ subendothelial hyaline humps) ± recanalisation (→ glomeruloid structures)

Glomerular TMA:

 normal cellularity or ↑ PMN but not otherwise inﬂam

and no immune deposits. May lead to

glomerular sclerosis or cortical necrosis if severe

 bloodless glomeruli with ﬁbrin thrombi and an eosinophilic ‘double contour’ on H&E (thick-

ening of capillary wall and subendothelial space expansion – ! do not confuse with BM double

contouring on silver stains [which, if present, usu. indicates a more chronic and less destructive

course])

 engorged and partly necrotic glomeruli (‘glomerular paralysis’) due to distal thrombosis

Small artery-arteriole severe TMA (‘malignant vascular injury’) is essentially the same lesion as found

in malignant HT with myxoid and proliferative endarteritis, ﬁbrinoid necrosis and variable thrombosis

and occurs in malignant HT, HUS and PSS renal crises (= PSS + HT + ARF). Assoc

focal tissue

ischaemia/necrosis is more common with this form

Causes include: drugs (incl. quinine, OKT3, cyclosporin and tacrolimus), post Tx humoural rejection,

Type II MPGN (and other causes of factor-H deﬁciency), bacterial toxins (Shigella, E.coli phage),

radioRx, chemoRx (esp. mitomycin C), antiphospholipid Ab syndromes (± SLE) and anti-endothelial

Ab states (e.g. post Strep. pneumoniae), viruses (HIV, CMV, parvovirus B19), pregnancy / puerperium,

paraneoplastic, any cause of TTP / HUS and idiopathic

In glomerular TMA, accompanying mesangiolysis and BM reduplication is not usu. seen with infective

toxin-assoc

cases but may be seen with the other causes (and also in PET)

Effects (∝ cause and severity): resolution, glomerular sclerosis, tubular damage ± RF

d/dg: vasculitis (inﬂam

, immune markers, CPC), chronic allograft glomerulopathy (also has other

changes of chronic rejection), DIC (platelet poor, FVIIIRA −ve thrombi and moribund patient)

d/dg PET (large and bloodless glomeruli due to endothelial swelling occluding the lumens, double

contour BM due to mesangial interposition, glomerular capillary partial prolapse into the PCT – but

no arterial/arteriolar changes of TMA, also PET changes resolve 3–6 months post partum)

d/dg venous thrombosis (go by CPC if a thrombosed vein is not sampled)

d/dg hyaline glomerular thrombi of light chain or Waldenstr¨om’s type (glomerular hypercellularity and

immuno for IgM// and CPC)

d/dg cholesterol emboli (vide supra under ‘Clinical Perspectives on GN’ on p. 202)

Renal Transplant and Rejection Pathology

General Considerations

Rejection changes are widespread but can be focal .

. consider sampling effect

Some of the changes may have been present in the donor (! overrating rejection severity)

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Renal Medicine 208

Effect of opportunistic infections (e.g. CMV or polyoma)

Effects of drugs (e.g. see CNI and TORi on pp. 209–210) incl. TMA ± HUS

Recurrence of 1

◦

renal disease in the graft



Obstructive effects: lymphatics distended with protein, dilated ducts in the outer cortex ± a foreign

body-type granulomatous response to disrupted tubules

For details and illustrations see: http://tpis.upmc.edu/ and specialist texts

Tubulitis

Deﬁned according to the N˜o. of mononuclear cells per 10 tubular epithelial cells (or per tubule cross

section) in the worst affected tubules as:

do not include areas with interstitial ﬁbrosis

and tubular atrophy because these may have

non-speciﬁc lymphocytic inﬁltration

 mild tubulitis: 1–4 mononuclear cells

 moderate tubulitis: 5–10 mononuclear cells

 severe tubulitis: >10 mononuclear cells

! If patient is on CAMPATH1 anti-lymphocyte Rx, the above deﬁnitions may be meaningless

d/dg: mild tubulitis (<4 cells) may occur in non-Tx kidneys and non-rejection states e.g. mild ATN or

cyclosporin toxicity; other d/dg incl. viral infection (esp. CMV or polyoma)

Preservation Injury

ATN-like changes in the tubules (see p. 206)

Hyperacute Rejection (hours–days)

Ab-mediated (humoural) damage to endothelia → arterial thromboses

Glomerular congestion and glomerular capillary thromboses, PMN ± necrosis

Interstitial tissue infarcts and haemorrhage, PMN margination in peritubular vessels

Immuno: −ve or linear deposits of IgG ± IgM; +ve for C3 and ﬁbrin in small vessel walls (not limited

to glomeruli)

‘Accelerated acute rejection’ is a variant of this humoural rejection manifesting as episodes of ↓ renal

function over the ﬁrst few days. ‘Delayed accelerated acute rejection’ is the same as accelerated rejection

but starts after a few weeks (this happens when the prior exposure to the offending Ags occurred a long

time before transplantation)

d/dg other causes of thromboses: cold-ischaemia-induced graft vascular endothelial damage (shows

less active inﬂam

cf. rejection), systemic vasculitis, DIC, calcineurin-inhibitor toxicity (use CPC)

! Do not confuse with the acute and chronic forms of ‘Humoural / Ab-Mediated Rejection’ that occurs

later and is deﬁned by C4d deposition and circulating anti-donor HLA / ABO Abs described below

Acute Cellular Rejection (weeks–years)

Glomeruli spared (unless co-existent vascular rejection – vide infra) d/dg PTLPD which

Mixed mononuclear interstitial inﬁltrate (predom. T8) ± granulocytes is destructive and

Tubulitis (vide supra)



B-cell predominant

Interstitial ﬁbrosis and oedema

Acute Vascular Rejection (weeks–years)

Endothelialitis (MPS intimal thickening, lymphocytes, endothelial cell swelling and shedding)

Transmural vasculitis (± ﬁbrinoid necrosis)

± Glomerulopathy (endothelial swelling, ﬁbrin thrombi, platelet aggregates)

± Acute cellular rejection changes (vide supra)

Chronic Rejection (months–years)

Vascular changes: ﬁbrous concentric intimal thickening hyperplasia not attributable to other causes

(e.g. donor HT), variable lumenal narrowing ± IEL breach ± foam cells ± mononuclear cells (NB:

acute vascular rejection changes may be superimposed). The changes may be segmental. d/dg HT:

reduplicative multilayering of the IEL and lack of intimal foam / mononuclear cells all favour HT

Tubular atrophy (i.e. thickened BM or < 50% of normal) and interstitial ﬁbrosis with lymphocytic

inﬁltration

Chronic allograft glomerulopathy (glomerular sclerosis, ±lymphocytic inﬁltration ±glomerular TMA-

like changes; for Banff scoring look for ↑ mesangial matrix and thickened BM ± double contours in

capillary loops [the latter increase with severity]) – d/dg mesangiocapillary GN (but the Tx lesions are

usu. focal ) or other lesions if your examination is by LM alone

Banff criteria: EITHER new (non-pre-existent) vasc. lesions OR the glomerulopathy are sufﬁcient to diag-

nose chronic rejection, but if LM alone is used then

ONLY new vascular lesions are acceptable