Pathology of Kidney Presentation

1. Common Pathologies of
Kidney
Dr.Israt Zaman Akhi
MD(Phase A) Resident
Dept. of Pediatric Nephrology
NIKDU

2. Introductions
Kidney diseases can be described by dividing them into
four basic morphological components.
1.Glomeruli.
2.Tubules.
3.Interstitium.
4.Blood vessels.

3. Most glomerular diseases are immunologically mediated, on the other
hand tubular and interstitial disorders are frequently caused by toxic or
infectious agents.
Primary disorders of the blood vessels inevitably affects all the
structure supplied by these vessels.
In chronic kidney disease all four basic components are damaged
ultimately.

4. Pathologic Responses of the Glomerulus to Injury
 Various types of glomerulopathies are characterized by one or more of
four basic tissue reactions:
i. Hypercellularity
ii. Basement Membrane Thickening
iii. Hyalinosis
iv. Sclerosis

5. Hypercellularity
Some inflammatory diseases of the
glomerulus are characterized by an increase in
the number of cells in the glomerular tufts.
This hypercellularity results from one or more
of the following:
1.Proliferation of mesangial or endothelial
cells.
2. Infiltration of leukocytes.
3. Formation of crescents.

6. 1. Proliferation of mesangial or endothelial cells and Infiltration of
leukocytes includes
• Neutrophils
• Monocytes and
• In some diseases, lymphocytes.
The combination of infiltration of leukocytes and swelling and proliferation
of mesangial and/or endothelial cells is often referred to as endocapillary
proliferation

7. 3. Formation of crescents
• These are accumulations of cells composed of proliferating glomerular
epithelial cells (predominately parietal but including some visceral cells)
and infiltrating leukocytes.
• The epithelial cell proliferation that characterizes crescent formation
occurs following an immune/inflammatory injury involving the capillary
walls.
• Plasma proteins leak into the urinary space, where it is believed that
exposure to pro-coagulants such as tissue factor leads to fibrin deposition
include multiple proinflammatory cytokines.

8. • Activation of coagulation factors such as thrombin is suspected of being
a trigger for crescent formation, but the actual mechanisms are still
unknown.
• Molecules that have been implicated in recruitment of leukocytes into
crescents.

9. Formation of crescents

10. II- Basement Membrane Thickening:
• By light microscopy, this change appears as thickening of the capillary
walls, best seen in sections stained with periodic acid-Schiff (PAS).
• By electron microscopy , such thickening takes one of three forms:
• 1. Deposition of amorphous electron-dense material, most often immune
complexes on the
Endothelial side of the basement membrane or
Epithelial side of the basement membrane or
Within the basement membrane (GBM) itself.

11. 2. Fibrin, amyloid, cryoglobulins, and abnormal fibrillary proteins may also
deposit in the GBM.
3. Increased synthesis of the protein components of the basement occurs in
diabetic glomerulosclerosis.
4. Formation of additional layers of basement membrane matrices, which
most often occupy subendothelial locations and may range from poorly
organized matrix to fully duplicated lamina densa, as occurs in
Membranoproliferative glomerulonephritis.

12. Slides showing basement membrane thickening

13. Hyalinosis
• Hyalinosis denotes the accumulation of material that is homogeneous
and eosinophilic by light microscopy.
• Hyaline is an extracellular, amorphous material composed of plasma
proteins that have insudated from the circulation into glomerular
structures.
• When extensive, these deposits may obliterate the capillary lumens of the
glomerular tuft.

14. • Hyalinosis is usually a consequence of endothelial or capillary wall
injury and typically the end result of various forms of glomerular
damage.
• Sclerosis: It is characterized by deposition of extracellular collagenous
matrix and may be confined to mesangial areas.

15. Mediators of glomerular injury
• The mediators both cells & molecules are the usual suspects involved in
acute & chronic inflammation.
Cells:
1.Neutrophils & monocytes infiltrate the glomerulus in certain types of
glomerulonephritis.
2.Macrophage & T lymphocytes, which infiltrate the glomerulous in
antibody & cell mediated reactions.
3.Platelet may aggregate in the glomerulous during immune mediated
injury.

16. 4. Resident glomerular cells, particularly mesangial cells, can be
stimulated to produce several inflammatory mediators including reactive
oxygen species, cytokines, chemokines, growth factors, NO,endothelin.
 Soluble mediators
1. Complement activation leads to the generation of chemotactic products
& formation of C5b-C9(the membrane attack complex). C5b-C9 causes
cell lysis & also stimulates mesangial cells to produce oxidant, protease &
other mediator.

17. 2.Eicosanoids,NO,angiotensin & endothelin are involved in the
hemodynamic changes.
3.Cytokine mainly IL-1 & TNF also cause glomerular injury.
4.Coagulation system is also a mediator of glomerular damage.

18. Immune mechanism of glomerular injury:
Antibody mediated injury.
In situ immune complex deposition
1. Fixed intensive tissue antigen
2. Planted antigen: May be exogenous & endogeneous.
Circulating immune complex deposition: May be endogeneous &
exogeneous.
Cell mediated immune injury.
Activation of alternative complement pathway.

19. Kidney Diseases
• Congenital disorders
• Glomerular diseases
• Tubulo-interstitial diseases
• Vascular diseases
• Urinary stones
• Cystic disease of kidney
• Obstructive uropathy
• Tumors

20. Congenital Anomalies
• Agenesis - Potter syndrome
• Dysplasia
• Simple cysts
• Polycystic kidney disease
• Horse shoe shape kidney
• Double ureter
• Bifid ureter
• Duplex kidney

21. Glomerular disease
• Acute proliferative glomerulonephritis
• Rapidly progressive(crescentic)GN
• Membranous Nephropathy
• Focal segmental glomerulosclerosis
• Membranoproliferative GN
• Dense deposit disease
• IgA nephropathy
• Chronic GN

22. Hereditary disorders
• Alport syndrome
• Thin BM disease
• Fabry disease

23. Systemic disease with glomerular involvement
• SLE
• Diabetes mellitus
• Amyloidosis
• Goodpasture syndrome
• Microscopic polyarteritis
• Wegener granulomatosis
• Henoch-schonlein purpura
• Bacterial endocarditis

24. Tubular and Interstitial Disease
• Acute Kidney injury (Acute Tubular Necrosis)
• Tubulo Interstitial Nephritis-
Pyelonephritis and Urinary Tract Infection
Acute Pyelonephritis
Chronic pyelonephritis and reflex nephropathy

25. Vascular Diseases:
• Benign Nephrosclerosis
• Malignant Hypertension and Accelerated
Nephrosclerosis
• Renal Artery Stenosis
• Thrombotic Microangiopathies and Other vascular
Disorder

26. Cystic Disease of Kidney:
• AD (Adult) polycystic Kidney disease
• AR (Childhood) Polycystic Kidney disease
• Cystic diseases of Renal Medula
Medulary Sponge Kidney
and Medulary Cystic Disease
• Acquired (Dialysis Associated) Cystic disease
• Simple Cysts

27. Tumors of the Kidney
• Benign tumors
Renal Papillary Adenoma
Angiomyolipoma
Oncocytoma
• Malignant Tumors
Renal cell carcinoma(AdenoCarcinoma)
Urothelial Carcinomas of the renal pelvis

28. Nephritic Syndrome
• It is characterized by inflammation of glomeruli.
Acute Proliferative(Post streptococcal) glomerulonephritis: It
usually appears 1 to 4 weeks after a streptococcal infection of
the pharynx(1-2weeks) or skin(3 to 4 weeks).It is caused by
nephritogenic strains of group A B-hemolytic streptococci; M
protein,strains 1, 4,12,25 & 49 are the most common.

29. Glomerular injury in PSGN result from deposition of immune complexes
in the glomerular capillaries. These immune complexes result in
activation of complement, infiltration of neutrophils, proliferation of
glomerular cells & expansion of mesangial matrix.
Molecular mimicry between streptococcal antigens & normal glomerular
antigens that reacts with antibodies against streptococcal antigens.

30. Morphology:
Light microscope: Enlarged hypercellular glomeruli is caused by
1.Infiltration by leukocytes- both neutrophil and monocyte.
2. Proliferation of endothelial and mesangial cell
3. In severe cases crescent formation
Immunofluorescence microscopy: Granular deposition of IgG,C3 and
occasionally IgM in the mesangium and along the GBM.It may be focal or
diffuse.

31. • Electron microscopic findings: Discrete, amorphous, electron
dense deposit on the epithelial side of the membrane(like
humps).Subendothelial deposits are also commonly seen,
typically early in the disease course.

32. Figure: Acute Proliferative(Post streptococcal)
glomerulonephritis

33. Rapidly Progressive (Crescentic) Glomerulonephritis
• It is a syndrome associated with severe glomerular injury but does not
denote a specific etiologic from of GN.
• Pathogenesis: Although no single mechanism can explain all cases but in
most cases the glomerular injury is immunologically mediated.
• Several distinct pathogenic mechanisms describe below:
• 1.Anti-GBM antibody mediated disease-characterized by linear deposits
of IgG &,in many cases C3 in the GBM.

34. • 2.Diseases caused by immune complex deposition.RPGN can be a
complication of any of the immune complex nephritis,including;
PIGN,lupus nephritis,IgA nephropathy & HSP.
• 3.Pauci-immune RPGN-defined by the lack of detectable anti-GBM
antibodies or immune complexes by immunefluorescence & electron
microscopy.Most patients with this type of RPGN have circulating
antineutrophil cytoplasmic antibodies(ANCAs) that produce cytoplasmic
or perinuclear staining pattern & are known to play a role in some
vasculitis.

35. • Morphology: The kidneys are enlarged and pale, often with petechial
hemorrhage on the cortical surface.
• Light microscope: 1. Glomeruli often so focal and segmental necrosis and
show diffuse or focal endothelial and mesangial proliferation.
2. Crescents are formed by proliferation of parietal cells
and migration of monocytes and macrophage into the urinary space.
Neutrophil and lymphocyte may be present.
3. Fibrin strands are frequently prominent between the
cellular layer in the crescents.

36.  Immunofluorescence microscopy:
Granular immune deposit, in case of Goodpasture syndrome- linear
GBM fluorescence for Ig and complement.
In pauci immune cases Little or no deposition of immune reactant.
 Electron microscopic findings: show rupture in GBM, that allows
leukocytes, plasma protein. Coagulation factor , complement to reach the
urinary space, where they trigger crescent formation.

37. Nephrotic Syndrome:
• Caused by a derangement in glomerular capillary wall resulting in
increased permeability to plasma protein. The manifestation of the
syndrome include-massive proteinuria, hypoabuminemia, generalized
edema & hyperlipidemia.
• Causes of nephrotic syndrome:
• Primary glomerular diseases
• Minimal change disease.
• Membranous nephropathy
• Focal segmental glomerulosclorosis
• Membranoproliferative glomerulonephritis & dense deposit disease
• Others proliferative glomerulonephritides.

38. Systemic Diseases
• Diabetes mellitus
• Amyloidosis
• SLE
• Drugs(NSAID,penicillamine,heroin)
• Infections(Malaria,syphilis,hepatitis,B,C HIV)
• Malignant disease(Carcinoma,Lymphoma)

39. Minimal change disease:
• This relatively benign disorder is characterized by diffuse effacement of
foot processes of visceral epithelial cells(podocytes),detectable only by
electron microscopy, in glomeruli that appear virtually normal by light
microscopy.
It is most frequent cause of NS.
• Pathogenesis:
 The absence of immune deposit of glomerulus exclude classic immune
complex mechanism.
 According to current hypothesis it involves some immune dysfunction
that results damage visceral epithelial cells & causes proteinuria.

40. Morphology:
Light microscope:
Glomeruli are normal
Immunofluorescence microscopy:
Show no Ig or complement deposit.
Electron microscopic findings: The GBM appears normal and no
electron dense material deposited. The principal lesion is the visceral
epithelial cells which show a uniform and diffuse effacement of foot
processes.

41. Figure: Minimal change disease

42. Membranous Nephropathy
• Membranous nephropathy is characterized by diffuse thickening of the
glomerular capillary wall due to the accumulation of deposits containing Ig
along the subepithelial side of the basement membrane. .
• 75% of cases are primary. The remaining cases occur in association with
other diseases referred to as secondary.
• The most notable of these associations are-
1.Drugs-Penicillamine,gold,captopril,NSAID.
2.Malignant tumour-Carcinoma of colon & lungs, melanoma.
3.SLE-
4.Infections-Hepatitis-B,C,Syphilis,Malaria.
.

43. • Pathogenesis: It is a form of chronic immune complex mediated disease.
Primary membranous nephropathy ,thought to be of unknown cause. It is
now considered to be an autoimmune disease linked to certain HLA
alleles such as HLA DQA1 & caused in most cases by antibodies to a
renal autoantigen.

44. Morphology:
Light microscope: The glomeruli either appear normal in the early stages of
the disease or exhibit uniform, diffuse thickening of the glomerular capillary
wall.
Immunofluorescence microscopy: Granular deposits contain both
immunoglobulin and complement. As the disease progresses segmental
sclerosis may occur.
 Electron microscopic findings: Irregular electron dense thickening is
seen.Deposit containing immune complex between the GBM and the
overlying epithelial cells, with effacement of podocyte foot processes. These
appear as irregular spike protruding from the GBM.

45. Focal Segmental Glomerulosclerosis:
• It is the common cause of nephrotic syndrome in adults.
• Pathogenesis: The characteristic degeneration & focal disruption of
visceral cells with effacement of foot processes. Epithelial damage is the
hallmark of FSGS. Different mechanisms are responsible for such
epithelial damage including circulating factors and genetically determined
defects affecting components of the slit diaphragm complex.
The first relevant gene NPHS1 maps to chromosome 19q13 & encode the
protein nephrin.
A distinctive pattern of autosomal recessive FSGS result from mutation in
the gene NPHS2 maps to chromosome 1q25-q31.

46. Morphology
Light microscope:
1. Focal & segmental lesions may involve only a minority of the
glomeruli.
2.In the sclerotic segment there is collapse of capillary loops, increase in
matrix & segmental deposition of plasma protein along the capillary wall.
Lipid droplets & foam cells are often present.
 Immunofluorescence microscopy:Ig M & C3 may be present in the
sclerotic areas & in the mesangium. In addition pronounced hyalinosis &
thickening of afferent arterioles may be found. In time it leads to total
sclerosis of glomeruli with tubular atrophy & interstitial fibrosis.
 Electron microscopy: Both sclerotic & nonsclerotic areas show diffuse
effacement of foot processes & may also be focal detachment of epithelial
cells & denudation of the underlying GBM.

47. Membranoproliferative Glomerulonephritis:
• It is considered a pattern of immune mediated injury rather than a specific
disease.
• MPGN into two groups-
• 1.Type-I:deposition of immune complexes containing IgG & complement.
2.Type-II:Dense deposit disease,in which excessive activation of alternative
complement pathway. Decrease serum C3 but normal C1 & C4.
• Pathogenesis:
There is evidence of immune complexes in the glomerulus & activation of
both classical & alternative complement pathway.The antigen involved in
idiopathic MPGN are unknown.In many cases they are belived to be protein
derived from infectious agent such as Hepatitis B,C virus.

48. Morphology
 Light microscopy:
The glomeruli are large & hypercellular. Lobular appearance of glomeruli is
due to the proliferating mesangial cells & increased mesagial matrix.
The GBM is thickened & shows a double contour or tram-track appearance
due to duplication of GBM.
Electron microscopy:
In type I MPGN , discrete subendothelial electron dense deposit are present.
In type II ,lamina densa of the GBM is transform into a irregular ribbon like
homogeneous extremely electron dense material of unknown compostion.
Immunofluorescence:
Ig G & C3 are deposited in a granular pattern & early complement
component(C1q & C4 ) are often present.

50. IgA nephropathy(Berger Dz):
It is characterized by the presence of prominent Ig A deposit in the
mesangium. It is the most common type of glomerulonephropathies
worldwide.
• Pathogenesis:
 It is a hereditary or acquired defect in the normal formation or attachment
of galactose containing sugar chain to the hinge region of the IgA molecule.
 The glomerular deposit consist predominantly IgA molecule with
aberrant glycosylation. The deposited IgA & IgA immune complexes
activate mesangial cell to proliferate, increase amount of ECM & secrete
numerous cytokines & growth factor.
 These causes,inflammation of glomeruli & activation of complement
pathway. Hence the presence of C3 & the absence of C1q & C4 in glomeruli
are typical of this disorder.

51. Morphology
 Light microscope:
The glomeruli may be normal or may show mesengial widening due to
cell proliferation ,accumulation of matrix or immune- deposit &
endocapillary proliferation, segmental proliferation.
 Immunofluorescence:
Mesangial deposition of IgA with C3 & properdin & lesser amount of
IgG & IgM.
 Electron microscope :
Electron dense deposit predominantly in the mesangium & sparse
capillary wall deposit may be found.

52. Hereditary Nephritis
• It refers to a group of heterogeneous familial renal diseases associated
with mutations in collagen genes that manifest primarly with glomerular
injury.
• Alport syndrome:
When it is fully developed is manifested by hematuria with progression
to CRF ,accompanied by nerve deafness & eye disorders.
• Pathogenesis :
 The disease manifestations are due to mutation in one of several
genes coding for subunit of the collagen IV molecules, which resulting
in defective assembly of type IV collagen which is crucial for the
function of GBM ,lens of eye & cochlea.

53. Morphology:
 Electron microscope:
The GBM shows irregular foci of thickening alternating with
attenuation & splitting & lamination of the lamina densa which produce
basket-weave appearance.
 Immunofluorescence:
Absent or borderline basement membrane lesion due to antibodies to
α3,4 & 5 collagen fail to stain.

54. Chronic Glomerulonephritis:
• Chronic GN refers to end stage glomerular disease that may result from
specific types of GN or may develop from without antecedent history of any
of the well recognized forms of acute GN.
• Morphology:
The kidneys are symmetrically contracted and have diffusely granular
cortical surface.
On section:
 The cortex is thinned & increase in pelvic fat.
 The glomerular histology depends on the stage of the disease. In early
stage the glomeruli show evidence of primary disease.
 Eventually causes obliteration of glomeruli, increase mesagial matrix,
arterial & arteriolar sclorosis may be conspicuous.

55. Acute Tubular Injury/Necrosis:
• It is a clinicopathologic entity characterized clinically by acute renal
failure & often, but not invariably, morphologic evidence of tubular injury,
in the form of necrosis of tubular epithelial cell.
• Pathogenesis: The critical events in both ischemic & nephrotoxic .ATI are
believed to be.
1.Tubular cell injury:
Tubular epithelial cells are sensitive to ischemia & are also vulnerable to
toxin. Ischemia causes structural & functional alteration in epithelial cells,
resulting in abnormal ion transport across the cell.
2.Disturbence in blood flow.

56. Morphology:
It is characterized by focal tubular epithelial
necrosis at multiple point along the nephron with large skip areas
in between often accompanied by rupture of basement membrane
& occlusion of tubular lumens by casts.

57. Pyelonephritis:
Morphology:
 Acute pyelonephritis:
The hallmark of acute pylonephritis are patchy interstitial suppurative
inflammation, intratubular aggregates of neutrophils, neutrophilic tubulitis
& tubular necrosis. The suppuration may occur as discrete focal abscesses
or large wedge like areas & can involve one or both kidneys.
 Chronic pyelonephritis:
The hallmark of chronic pyelonephritis are course discrete
corticomedullary scar overlying dilated, blunted or deformed calyces &
flattening of papillae.

58. • It is one of the most common diseases of the kidney & is defined as
inflammation affecting the tubules, interstitium & renal pelvis.
• Pathogenesis:
Acute pylonephritis is generally caused by bacterial infection &
associated with UTI. Mostly caused by the Gm (-) bacilli that are normal
inhabitants of the intestinal tract.
The microbes move from the bladder to the kidneys by following
mechanisms-
1. Urinary tract obstruction & stasis of urine
2. Vesicoureteral reflux.
3. Intrarenal reflux.

59. Acute pyelonephritis Chronic
pyelonephritis

60. Autosomal Recessive (Childhood) polycystic kidney Disease:
• Autosomal recessive (childhood) polycystic kidney disease is genetically
distinct from adult polycystic kidney disease.
Perinatal, neonatal, infantile & juvenile subcategories have been defined,
depending on the time of presentation & presence of associated hepatic lesions.
• Genetics & pathogenesis:
In most cases, the disease is caused by mutations of the PKHD1 gene,
which maps to chromosome region 6p21-p23.The PKHD1 gene encodes
fibrocystin.

61. Morphology:
The kidneys are enlarged & have a smooth external appearance.
On cut section:
Numerous small cysts in the cortex & medulla give the kidney a sponge
like appearance. Dilated elongated channels are present at right angle to
the cortical surface, completely replacing the medulla & cortex.
On microscopic examination:
There is cylindrical or sacular dilatation of all collecting tubules.The
cyst have a uniform lining of cuboidal cells.

62. Autosomal dominant(Adult) polycystic kidney
Disease
• Autosomal dominant(adult) polycystic kidney disease is a hereditary
disorder characterized by multiple expanding cyst on both kidneys that
ultimately destroy the renal parenchyma & cause renal failure.
• Genetics:
A wide range of different mutations occur in the PKD1 & PKD2 genes. The
PKD1 gene is located on chromosome 16p13.3.It encode large integral
membrane protein named polycystin1.
The PKD2 gene located on chromosome 4q21 & encode polycystin 2.
• Pathogenesis:
The pathogenesis of disease is not established, but currently favored
hypothesis places the cilia chromosome complex of tubular epithelial cells at
the center of the disorder .

63. Morphology:
The kidneys are bilaterally enlarged & enormous sizes.
 On microscopic examination:
 Functioning nephrons are dispersed between the cyst.
 The cyst may be filled with a clear serous fluid or with turbid, red to
brown, sometimes hemorrhagic.
 Occasionally, papillary epithelial formations & polyps project into
the lumen.

64. Figure: polycystic kidney

65. Renal Artery Stenosis:
• Unilateral renal stenosis is responsible for 2% to 5% of hypertension.
• Pathogenesis:
HTN secondary to renal artery stenosis is caused by increased production of
renin from the ischemic kidney.
The most common cause of renal artery stenosis is narrowing at the region of
the renal artery by an atheromatous plaque. This occurs more frequently in men,
& the increases with advancing age & DM.
• Morphology:
 There is fibromascular dysplasia of the renal artery. Fibromascular thickening
that may involve the intima, the media, or the adventitia.
 The ischemic kidney is reduced in size & shows signs of diffuse ischemic
atrophy ,with crowded glomeruli, atrophic tubules, interstitial fibrosis & focal
inflammatory infiltrates.

66. Neoplasm of the kidney:
• Both benign & malignant neoplasms occur in the kidney. Malignant
neoplasms are of great importance clinically. The most common malignant
tumor is renal cell carcinoma, followed by Wilms tumor which is found in
children.
• Morphology:
 Renal cell carcinomas may arise any portion or the kidney, but more
commonly affect the pole. Clear cell carcinoma mostly arise from proximal
tubular epithelium.
 They are bright yellow gray white spherical mass that distort the renal
outline. There are large areas of gray-white necrosis & foci of hemorrhagic
discoloration.

67.  The growth patterns varies from solid to trabecular or tubular.
Papillary carcinoma composed of cuboidal or low columnar
cells arranged in papillary formations. Interstitial foam cells are
common in the papillary cores. Psammoma bodies may be
present.

68. Figure: Neoplasm of kidney

69. Bladder Neoplasm
Bladder cancer accounts for approximately 7% of cancers.
Pathogenesis: Several acquired genetic alterarions have been observed in
urothelial carcinoma,many of which lead to constitutive activation of growth
receptor signaling casecade.
Morphology: The appearance of urothelial tumors varies from papillary to
nodular or flat.
Papillary carcinoma 1.Low grade papillary carcinoma: The cells are evenly
spaced(i.e maintain polarity) & cohesive.There is mild degree of nuclear
atypia consisting of scattered hyperchromatic nuclei,infrequent mitotic
figure predominantly toward the base.

70. • 2.High grade papillary carcinoma: Contain dyscohesive cells with large
hyperchromatic nuclei.Some of the cells are highly anaplastic.Atypical
mitotic figure are frequent.Architecturally,there is disarray & loss of
polarity.
• 3.Carcinoma insitu(flat urothelial carcinoma):Presence of cytologically
malignant cells within a flat urothelium.

72. Cystitis
• The common etiologic agents of cystitis are the coliforms or
example.E.coli,proteus enterobacter. Womens are more likely to develop
cystitis as a result of their shorter urethra. Tuberculous cystitis is almost
always a sequel to renal TB.
• Morphology: Most cases of cystitis produce nonspecific acute or
chronic inflammation of the bladder.
• In acute cystitis: There is hyperemia of the mucosa & neutrophilic
infiltrate,sometimes associated with exudate.
• In chronic cystitis : Mononuclear cells are infiltrated.