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Renal Medicine 209

Humoural Rejection (‘Antibody-Mediated Rejection’)

A term used to indicate Ab-mediated vascular damage occurring in acute and chronic rejection

Early (‘Acute Humoural Rejection’): interstitial oedema, PMN margination and accumulation in capil-

laries (peritubular and glomerular), glomerular ﬁbrin thrombi and endothelial swelling (=‘glomerular

solidiﬁcation’), peritubular capillary congestion. Fibrinoid necrosis and ischaemic tubular damage may

also be seen

Later (‘Chronic Humoural Rejection’): continued peritubular and glomerular capillary damage (lume-

nal dilatation and BM thickening and reduplication) → tubular atrophy and interstitial ﬁbrosis with

↑ intravascular mononuclear cells ± loss of peritubular capillaries

Immuno:  linear deposition of C4d lining the peritubular and glomerular capillaries (! may also be

seen in, e.g., LE [usu. granular] .

. not 100% speciﬁc, but it is usu. −ve in acute cellular

rejection)

 alternatively, C3 +/Igmaybe+ve in arterial walls (but C4d in arteries is non-speciﬁc)

 glomerular C4d is normal in FS but is pathological in parafﬁn sections (although the

pathology may be any immune complex deposition disease such as membranous GN)

d/dg acute cellular rejection or other causes of TMA (e.g. HUS): these are C4d −ve

Grading:  Type 1: +ve serology for donor speciﬁc HLA Abs (indicates performing a renal Bx)

 Type 2: C4d deposition on Bx but no other changes

 Type 3: C4d deposition on Bx plus other histological changes

 Type 4: clinical evidence of allograft dysfunction ± Types 1–3 (indicates Rx)

Banff (1996–1997) Grading of Renal Allograft Rejection

Acute rejection

Minor grades show acute cellular rejection (Borderline and Grades 1–2A)

More severe types show acute vascular rejection (Grades 2B and 3)

Borderline: subtle changes not deﬁnitive for rejection → Rx based on clinical criteria alone

Grade 1A: >25% of interstitium inﬂamed + moderate tubulitis

Grade 1B: >25% of interstitium inﬂamed + severe tubulitis

Grade 2A: >25% of interstitium inﬂamed + arterial endothelialitis upto moderate degree

Grade 2B: severe arterial endothelialitis (deﬁned as >25% lumenal area)

Grade 3: transmural or necrotising arteritis or interstitial haemorrhagic infarction without other cause

Chronic Allograft Nephropathy (chronic rejection)

Grade each component separately on a 4 point scale (0–3) as follows:

Glomerulopathy: % non-sclerosed glomeruli affected (cg0 =0%, cg1 ≤25%, cg2 26–50%, cg3 >50%)

Interstitial Fibrosis: % of cortical area (ci0 ≤5%, ci1 6–25%, ci2 26–50%, ci3 >50%)

Tubular Atrophy: % area of cortical tubules (ct0 = 0%, ct1 ≤25%, ct2 26–50%, ct3 >50%)

Vasculopathy: % narrowing of the lumen (cv0 = 0%, cv1 ≤25%, cv2 26–50%, cv3 >50%)

(=% lumenal narrowing by ﬁbrous intimal thickening in the worst affected vessel taking the area enclosed

by the IEL as the original lumen size)

Other changes

For example: pre-existent / recurrent disease, venulitis, ATN, drug toxicity (vide infra)

Infection e.g. polyomatubulointerstitial nephritis: look for inclusions in tubule cell nuclei – conﬁrmation

is by immuno nuclear +vity for SV40 large T Ag in tubular cells but this may be lost later on (so stain

a previous Bx if suspected)

Banff (2005) Changes Since 1997

Chronic Allograft Nephropathy has been dropped

Humoural Rejection (antibody-mediated rejection) has been included

For details see: Solez et al., 2007

Anti-Rejection Drug Toxicity

Calcineurin Inhibitors (= CNI, e.g. Cyclosporin and Tacrolimus [FK506])

Nodular hyaline deposits in afferent arterioles (usu. more focal and peripherally sited in the media cf.

arteriolosclerotic or DM changes which begin sub-intimally). Diffuse hyalinosis is non-speciﬁc

Microvesicular vacuolation of the PCTs (unlike d/dg hypokalaemia q.v.) ± eosinophilic inclusions

Myxoid and granular intimal thickening of arterioles

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Renal Medicine 210

Medial myocyte cytoplasmic vacuolation ± apoptosis

HT-like arteriolosclerotic changes

Alternating dense and rareﬁed (‘stripy’) stromal ﬁbrosis or patchy ﬁbrosis

Stromal +/ tubular calciﬁcations

± TMA (due to endothelial damage)

± Mild tubulitis (<4 cells)

± Renal changes of drug-induced DM

Juxtaglomerular apparatus hyperplasia

Target of Rapamycin Inhibitors (= TORi, e.g. Rapamycin)

Functional proteinuria

Myeloma-cast-like nephropathy (but the casts stain for CK, not light chains)

± TMA

Bibliography

Alsaad, K.O. and Herzenberg, A.M. (2007) Distinguishing diabetic nephropathy from other causes of glomerulosclerosis: an update. Journal of

Clinical Pathology, 60 (1), 18–26.

Bellamy, C.O.C. (2004) Microangiopathies & malignant vascular injury in the kidney. Current Diagnostic Pathology, 10 (1), 36–51.

Churg, J., Cotran, R.S., Sinniah, R. et al. (eds) (1985) Renal Disease Classification and Atlas of Tubulo-Interstitial Diseases,1

edn, Igaku-Shoin,

Tokyo.

Colvin, R.B. and Cornell, L.D. (2007) Renal transplant pathology: an update. Current Diagnostic Pathology, 13 (1), 15–24.

Corwin, H.L., Schwartz, M.M. and Lewis, E.J. (1988) The importance of sample size in the interpretation of renal biopsy. American Journal of

Nephrology, 8 (2), 85–89.

Cotran, R.S., Kumar, V. and Collins, T. (eds) (1999) Robbins Pathologic Basis of Disease,6

edn, W.B. Saunders Co., Philadelphia.

Furness, P.N. (2000) Renal biopsy specimens. Journal of Clinical Pathology, 53 (6), 433–438.

Ghadially, F.N. (1998) Diagnostic ultrastructural pathology: A self-evaluation and self-teaching manual,2

edn, Butterworth-Heinemann, Boston.

Howat, A.J., Thomas, C.M. and Coward, R.A. (2000) Immunoperoxidase for the demonstration of immune deposits in renal biopsies. Current

Diagnostic Pathology, 6 (2), 125–129.

Howie, A.J. (2005) Approach to diagnosis and pitfalls: the renal biopsy, in ACP Yearbook, Association of Clinical Pathologists, Hove, pp. 37–38.

Howie, A.J. (2001) Handbook of Renal Biopsy Pathology,1

edn, Kluwer Academic Press, Dordrecht.

Howie, A.J. (1997) Interstitial nephritis, in Recent Advances in Histopathology, Vol. 17 (eds P.P. Anthony, R.N.M. MacSween and D.G. Lowe),

Churchill Livingstone, Edinburgh, pp. 219–231.

Lucas, S. (2000) Update on the pathology of AIDS. Current Diagnostic Pathology, 6 (2), 103–112.

Luu, J., Bockus, D., Remington, F. et al. (1989) Tubuloreticular structures and cylindrical confronting cisternae: a review. Human Pathology, 20 (7),

617–627.

Roberts, I.S.D., Furness, P.N. and Cook, H.T. (2004) Beyond diagnosis: stage and grade in inflammatory renal disease. Current Diagnostic

Pathology, 10 (1), 22–35.

Roberts, I.S.D. and Solez, K. (2000) New developments in renal transplant pathology. Current Diagnostic Pathology, 6 (4), 219–228.

Smith, S.M., Hoy, W.E. and Cobb, L. (1989) Low incidence of glomerulosclerosis in normal kidneys. Archives of Pathology & Laboratory Medicine,

113 (11), 1253–1255.

Solez, K., Benediktsson, H. and Cavallo, T. (1996) Report of the third Banff conference on allograft pathology on classification of lesion scoring in

renal allograft pathology, July 20–24, 1995, Banff, Canada. Transplantation Proceedings, 28 (1), 441–444.

Solez, K., Colvin, R.B., Racusen, L. et al. (2007) Banff ‘05 Meeting Report: Differential diagnosis of chronic allograft injury and elimination of chronic

allograft nephropathy (‘CAN’). American Journal of Transplantation, 7 (3), 518–526.

Walker, P.D., Ferrario, F., Joh, K. et al. (2007) Dense deposit disease is not a membranoproliferative glomerulonephritis. Modern Pathology, 20(6),

605–616.

Weening, J.J., D’Agati, V.D., Schwartz, M.M. et al. (2004) The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney

International, 65 (2), 521–530.

Whittaker, M.A., Bass, P.S. and Rogerson, M.E. (2003) Systemic lupus erythematosus and the kidney-lupus nephritis, in Progress in Pathology,

vol. 6 (eds N. Kirkham and N. Shepherd), Greenwich Medical Media, Ltd, London, pp. 29–50.

Web sites

University of Pittsburgh, Transplant Pathology Internet Service, http://tpis.upmc.edu/ (accessed April 2007).

Schrier, R. (ed) Atlas of Diseases of the Kidney, http://www.kidneyatlas.org/toc.htm (accessed March 2007).

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Urological 211

16. Urological

Normal Testis

Normal Morphology of Spermatogenesis

Sertoli Cells

Oval/triangular pale vesicular nuclei, may be folded

Prominent central round to oval nucleolus

Nucleolus ﬂanked at poles by heterochromatin which accentuates the oval/fusiform shape

Indistinct cytoplasm (± Charcot-B¨ottcher needle crystalloids basally in mature cells)

Spermatogonia

Basally located, undergo mitosis

Round-ovoid nucleus (≈ 2× the diameter of a lymphocyte)

Type A:  moderately condensed chromatin with small peripheral nucleoli +/ nuclear vacuole

 pale and dark subtypes

Type B: more open chromatin with a central nucleolus, no nuclear vacuole

Primary Spermatocytes

Larger than spermatogonia, span the thickness of the tubule and increase in size with meiotic stage

Rounded nuclei show ﬁlamentous chromosomes with increasing degrees beadedness and thickness

with meiotic stage (preleptotene, leptotene, zygotene, pachytene and diplotene)

Abundant cytoplasm

Secondary Spermatocytes

Too short-lived for reliable identiﬁcation, look similar to early spermatids

Spermatids

Central location, smaller than 1

◦

spermatocyte (≈ diameter of a lymphocyte)

Condensed chromatin, round to oval nucleus

Spermatozoa

Small pointy nuclei, very condensed chromatin

Sertoli cells

Spermatozoa

Spermatids

1° Spermatocytes

Pale & Dark Type A Spermatogonia Type B Spermatogonia

FIGURE 16.1 Spermatogenesis

TABLE 16.1

Immuno of Sertoli and Leydig cells

Antibody Leydig Sertoli

inhibin A, ++

S100, calretinin

PGP 9.5, NSE + (& spermatogonia) −

3OHSD +−

WT1 −+(mature & immature)

p27

kip

−+(mature only)

Sertoli and Leydig Cells

Leydig cells may normally be found

within tubules, within the tunica al-

buginea testis and in the paratestic-

ular soft tissues around nerve twigs

Immuno: (see Table 16.1)

See also sections on Sertoli Cell

Nodule/‘Adenoma’, p. 227

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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Urological 212

Epididymis and Vas Deferens

Post-pubertal epithelium may show eosinophilic DPAS +ve nuclear inclus

s (! these are not viral)

Johnsen’s Score for Seminiferous Tubules (Assessment for Infertility/Subfertility)

Adequacy: a Bx with <50 tubules is considered inadequate for scoring by some authorities

The score correlates with sperm count and certain sub-fertility conditions

The average score over all tubules in the section should be calculated (excluding tangential cuts and

damaged tubules at the edge of the Bx)

The original study used a ×10 objective in general (×25 to conﬁrm spermatozoa or if poor ﬁxation)

The term ‘many’ is not deﬁned numerically but >10 per tubule cross section is a reasonable guide

TABLE 16.2 Johnsen scoring

Spermato- Spermato- Sertoli

Score Spermatozoa Spermatids scytes gonia Cells

Other Features

10 many many present present present open lumen & uniform

germinal layer

9 many many present present present disorganised germinal

layer (sloughing /

lumen obliteration

)

8 <5–10/tubule many present present present

7 none many present present present

6 none <5–10/tubule present present present

5 none none ≥5/tubule present present

4 none none <5/tubule present present

3 none none none present present

2 none none none none present

1 none none none none none = acellular tubule

Based on: Johnsen SD. Testicular biopsy score count - a method for registration of spermatogenesis in human testes:

normal values and results in 335 hypogonadal males. Hormones (1970); 1:2–25.

∗

said to be indicative of distal obstruction

Developmental Anomalies

Renal Dysplasia (Multicystic Dysplasia, Cystic Dysplastic Kidney)

Neonate/infant, usu. unilateral; most are obstructive (assoc

with valves/atresia/reﬂux), a minority are

syndromic/inherited

Macro: irregular nodularity

Lobular disarray (jumbled mix of cortical and medullary structures)

Stromal cartilage (helpful but not always seen)

Primitive tubules

Ducts/ductules lined by simple cuboidal/columnar epithelium and surrounded by ﬁbromuscular or

mesenchymatous stroma. Some may be cystic hence the alternative names for this condition

± Nodules of blastema (may be preneoplastic → Wilms’ tumour)

Some residual normal parenchyma may be present

Renal Hypoplasia

Small kidney

≤5 calyces

Normal histology

Autosomal Dominant Polycystic Kidney Disease (ADPCKD, Adult-type)

Children/middle-aged, ± infection, HT (± complications), nephrolithiasis, renal failure

Bilateral huge kidneys with surface bosselations

Spherical cysts enlarge throughout the cortex and medulla

Lined by ﬂattened or PCT-like epithelium ± papillaroid hyperplasia

Filled with serous/haemorrhagic/gelatinous material ± superposed infective changes/stones

Occ. glomeruloid tufts project into the lumen from the cyst wall (this feature may predominate in

childhood cases = one form of ‘glomerulocystic disease’)

Normal parenchyma in between

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Urological 213

± Cysts in other organs (liver, pancreas, spleen, lung)

± Berry aneurysms

d/dg renal dysplasia: can be a problem if young and asynchronous development (i.e. unilateral)

Autosomal Recessive Polycystic Kidney Disease (Infantile-type)

Less severe form: infant/children, ± HT (± complications), ± portal HT due to liver changes

Severe (fatal) form: ± Potter’s triad (oligohydramnios, pulmonary hypoplasia, uro/renal dysgenesis)

Bilateral huge kidneys without surface bosselations and without lobular disarray

Elongated, slit-like cysts radiate from medulla to cortex (± medullary dilatation)

Lined by ﬂattened or cuboidal (collecting-duct) epithelium

Normal (but ﬁbrotic/atrophic) parenchyma in between

± Cysts in liver (but usu. not other organs – else consider a different diagnosis)

± Berry aneurysms

Liver shows dilated biliary structures and ﬁbrosis (periportal and perivenular) and may amount to

congenital hepatic ﬁbrosis or Caroli disease ± 2

◦

ascending cholangitis/sepsis changes

Medullary Sponge Kidney

Adults, bilateral, urinary Sx ± nephrolithiasis/pyelonephritis

Cysts in renal papillae (may contain calciﬁc concretions)

Simple cuboidal/columnar lining

Epididymal Cysts and Testicular Appendage Anomalies

The appendix epididymis is cystic with a low columnar internal lining and ﬁbrovascular wall lined

externally by serosa

The appendix testis (Morgagni) is a solid polyp with a ﬁbrovascular core and columnar (non-ciliated)

external lining

They are located close to each other on the superior pole of the testicle and may tort/enlarge

Maldescended Testis (Cryptorchid Testis)

≈ Normal histology until after puberty but may show:

 ﬁbrous thickening of the tunica albuginea testis

 reduced numbers of germ cells

 small ± annular tubules

Small size (and small seminiferous tubules)

Fibrous thickening of the tunica albuginea testis

Atrophy and loss of spermatogenic cells with persistence of Sertoli cells

± Tubules lined by immature (long and thin with small nucleus) Sertoli cells – may form aggregates

(Pick’s tubular ‘adenomata’ – vide infra under ‘Sertoli Cell Nodule’, p. 227)

Stromal ﬁbrosis with ‘apparent’ Leydig cell hyperplasia

Peritubular ﬁbrosis

± Germ cell neoplasia (intratubular germ cells may be sparse but can be seen at any age)

Inﬂammatory Conditions

Chronic Pyelonephritis and Reﬂux Nephropathy

Interstitial ﬁbrosis and chronic inﬂam

± intratubular PMN

Loss of some tubules and dilatation of others with hyaline casts (‘thyroidisation’)

Glomeruli show periglomerular ﬁbrosis and clusters of obsolete glomeruli

d/dg reﬂux nephropathy cf. chronic GN:

 changes worst at the poles in reﬂux nephropathy

 reﬂux show dilated, distorted and thickened calyces apposed to scarred parenchyma

 in reﬂux the scarring is asymmetrical and irregular

inability to contribute to the amniotic ﬂuid volume by urination → oligohydramniotic restrictive environment → squashed face

(Potter’s facies with beaked nose, etc.) and squashed thorax →pulmonary hypoplasia (respiratory distress of immature lungs prevents

these neonates surviving)

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Urological 214

Xanthogranulomatous Pyelonephritis

! Can be misdiagnosed (clin. and pathologically) as RCC (clear cell and sarcomatoid types)

! Can co-exist with RCC or metastatic cancer

Assoc

with obstruction (e.g. calculus) and infection (Proteus spp. & E.coli)

Macro: mass lesion, yellow, destroying renal parenchyma

Micro: a mass of foamy M plus lymphocytes, plasma cells and occ. giant cells

d/dg RCC:  lack of reticular capillary vascular pattern of clear cell RCC

 presence of a mixed inﬂam

inﬁltrate

 foamy rather than clear cytoplasm

 M immuno rather than RCC immuno

Granulomatous Pyelitis

A rare complicat

of chronic renal outﬂow obstruction with some degree of pelvicalyceal dilatation

Pelvis may contain calciﬁc/necrotic material (−ve for TB/fungi by culture)

Granulomatous inﬂammation in the pelvis (but not granulomatous interstitial nephritis)

d/dg TB, fungi, other infective agents

Malakoplakia

Lamina propria of bladder/ureter, substance of kidney, GIT/other organs ± assoc

malignancy

M with abundant granular eosinophilic cytoplasm (Hansemann cells) containing:

◦

Michaelis-Gutmann bodies:  lamellar, haematoxyphile and refractile

 mineralised (von-Kossa) and iron

◦

non-mineralised, PAS +ve globules

◦

iron granules

Other chronic inﬂam

cells are also present

d/dg: signet ring carcinoma on FS (but mucin vacuoles are not refractile)

Interstitial Cystitis (± Hunner’s Ulcer)

Diagnosis of exclusion with characteristic clin. and cystoscopic features

Urothelial denudation ± ulceration

Lamina propria oedema, congestion, ﬁbrosis ± focal RBC extravasation

Chronic inﬂam

: lymphocytes ± M, eos., plasma cells

↑Mast cells in muscle and lamina propria: some say the ratio count (detrusor muscle vs. lamina propria)

is helpful, others report that it is useless in distinguishing interstitial cystitis from controls

Painful Bladder Syndrome

Def

: >3 months of urinary Sx with suprapubic pain and sterile urine

Apparent discontinuity of the BM

↑ T-cells in the lamina propria

↑ Blood vessels in the lamina propria

↑ Perimuscular collagen (EVG)

Eosinophilic Cystitis

Assoc

with allergy or prior trauma

Transmural eosinophils + ﬁbrosis

Granulomatous Cystitis

BGC (non-caseating, lymphoid follicles, ± crystals in the giant cells)

Schistosomiasis

Chemotherapy-Induced Change in the Bladder

Haemorrhagic cystitis

Haemorrhage ++, oedema and congestion of the lamina propria

Ulceration/sloughing of the urothelium

Urothelial atypia (vide infra)

Regenerative changes: ﬁbroblastic/histiocytic reaction in the stroma, mitoses in the epithelium (!)

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Urological 215

Urothelial atypia

Cytomegaly

Nuclear pleomorphism and hyperchromasia

d/dg CIS:  upper layers worst affected (cf. full-thickness in CIS)

 good cohesion (! but not in haemorrhagic cystitis)

 lack of mitoses (! but get mitoses in regenerative phase of haemorrhagic cystitis)

Radiation Cystitis

Acute (months)

Epithelial sloughing and cytological atypia:

 cytomegaly with ill-deﬁned hyperchromatic chromatin

 nuclear and cytoplasmic (mucin −ve) vacuolation

 d/dg carcinoma (vide infra under urothelial CIS, pp. 219–220)

Lamina propria oedema (→ cystoscopic cobbles = ‘bullous cystitis’)

Microvascular engorgement and dilatation

Chronic (years)

Fibrinoid ulcers ± focal cytol. atypia (a rare PEH-like proliferation may be seen. This is limited to the

superﬁcial lamina propria, has variable squamous metaplasia, normal NCR and no ↑ in mitoses)

Stromal ﬁbrosis (incl. muscularis propria)

Bizarre stromal cells (multinucleated radiation ﬁbroblasts)

Proliferative endarteritis

Granulomatous Prostatitis

Idiopathic (most common type, 70%)

Iatrogenic (TURP/Teﬂon/silicone)

 xanthoma/xanthogranuloma – d/dg hypernephroid Gleason 4/5 adenocarcinoma

 others: reactive atypia and ↑ cellularity d/dg high grade carcinoma

Infective (TB, Brucella, Histoplasma, Schistosoma, VZV)

Systemic disease (Wegener’s, Churg-Strauss, Sarcoid, RhA)

Malakoplakia (see p. 214)

Wegener’s, RhA and post-TURP can look similar to each other with palisaded granulomas

Granulomatous Orchitis

Adult, pain, ± PMHx UTI/trauma. Clinical d/dg neoplasia

Macro: homogeneous (d/dg lymphoma)

Tubulocentric mixed chronic inﬂam

inﬁltrate with epithelioid M ± giant cells

± Focal necrosis

Granulomatous nature of the inﬂam

may not be obvious

d/dg: lymphoma (but lymphoma has relative sparing of the tubules and is more monotonous)

d/dg: granulomas associated with seminoma or a speciﬁc infection

d/dg: idiopathic (spermatogenic) – exclude other causes ﬁrst

Penile Lesions

Zoon’s balanitis (Balanitis circumscripta plasmacellularis)

Red patch(es) in old uncircumcised men (clin. d/dg erythroplasia of Queyrat)

Plasma cell-rich band-like dermal inﬂam

± siderophages

Lichen sclerosus (Balanitis xerotica obliterans, BXO)

White plaques on glans +/prepuce; assoc

with phimosis, CIS and some forms of invasive SCC

Early: lichenoid (± vacuolar) interface change, orthohyperkeratosis, atrophy of stratum spinosum

Later: band-like or patchy lymphoid-rich inﬂam

descends to the mid-dermis leaving the intervening

dermis hyalinised, oedematous (± dilated microvasculature) and epidermis atrophic or hypertrophic

Other sites incl. the vulva and breast in women and back where follicular plugging is also a feature

d/dg: other lichenoid inﬂammatory dermatoses (pp. 297–298), morphoea (p. 301)

Syphilis

See p. 296.

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Renal Tumours (Benign)

Renal Oncocytoma

Solid, tubular, tubulocystic or trabecular nests of oncocytes (mitochondia +++ on EM)

Stroma: abundant oedematous, hyaline/myxoid

Acceptable:  focal nuclear pleomorphism and large nucleoli (grading is inappropriate)

 a few cases invade the perinephric fat

 microvascular invasion

Unacceptable:  mitoses are very rare and never atypical or present in an area of nuclear atypia

 clear cell areas, papillary growth pattern, sarcomatoid change

Immuno/stain: −ve for CK7, ‘RCC MA’, MOC31 and mucin (by Hale’s); ±ve (weak/patchy) for CD10

and vimentin; +ve for EMA, AE1/AE3 and c-kit; Ber-EP4 is usu. weak/−ve

d/dg chromophobe carcinoma or oncocytic conventional Renal Cell Carcinoma (RCC)

Cystic Nephroma (Multicystic Nephroma)

See ‘Renal Cell Carcinoma (Conventional)’, below

Renal Adenoma

<5mm and is of papillary non-clear cell type (by deﬁnition)

No clear cell/chromophobe/collecting duct areas and no sig. atypia/mitoses

Cytogenetics same as papillary renal cell carcinoma

Most common tumour at PM, often in scarred areas (.

. most do not progress to pap. RCC)

Angiomyolipoma

HMB45 +ve PEComa (for a more complete description, see p. 326)

◦

abnormal vessels

◦

myoid spindle cells

◦

fat (but can lack fat spaces and can be very cellular)

Can mimic RCC and some foci can be pigmented (d/dg pigmented RCC, melanoma)

Epithelioid variant may show malignant behaviour

50% have tuberose sclerosis (TS), 75% of TS have angiomyolipoma

Metanephric Adenoma

F  M, middle age, incidental

Macro: upto 8 cm 

Packed round tubules in the renal cortex

Empty lumens

May have papillary areas (and spindle ﬁbrous component = metanephric adenoﬁbroma)

Renal Tumours (Malignant)

Renal Cell Carcinoma (Conventional)

Cells (clear/granular/oncocytic/spindle): contain glycogen, fat, ± abnormal mitochondria, no mucin

Arch.: solid, alveolar, glandular (= tubular), papillary (in <75% of the tumour)

Sarcomatoid change is ‘RCC MA’ −ve and may incl. osteosarcoma, chondrosarcoma and RMS areas

May have extensive rhabdoid features (! do not confuse with RMS-like sarcomatoid change)

Pushing margin (else consider sarcomatoid change)

Stroma: inconspicuous with a rich delicate microvascular network

Focal cystic change has no prognostic signiﬁcance

Multilocular cystic variant (good prog.):

 no expansile solid clear cell nodules present

 little groups of clear cells in the septa

 d/dg multicystic nephroma (benign): no little groups clear cells in the septa

d/dg simple cysts lined by a single layer of clear cells = simple cysts not RCC

d/dg melanoma: ! some RCC are pigmented (have Fe −ve lysosomal pigment, not melanin)

d/dg mucinous tubular spindle cell CA (vs. sarcomatoid change): this has bland spindle cells in fascicles

± myxoid with a minor component of epithelium (tubules are rare). It is low grade malig. and its d/dg

incl. mixed epithelial stromal tumour and xanthogranulomatous inﬂam

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Papillary Renal Cell Carcinoma (= Chromophil Carcinoma)

Def

: the tumour must be >70–75% papillary (cf. clear cell) and ≥5mm.(NB: the ‘solid variant’

has alveolar/glomeruloid areas which are taken as ‘papillary’ for the purposes of this percentage as are

other papillary variant architectures such as elongated trabeculoid papillae)

Cells: low grade nuclei with cuboidal cytoplasm (Type 1) or columnar ± higher grade, focal necrosis

and more mitoses (Type 2, worse prog.). The cytoplasm is usu. eosinophil, amphophil or basophil

Stroma: foamy M in papilla cores ± psammoma bodies; not desmoplastic (cf. collecting duct CA)

Extensive haemorrhage/cyst formation

Complicates end stage kidneys (dialysis/post Tx) – these also predispose to ureteric carcinoma

d/dg conventional RCC (most are CK 7 −ve cf. papillary which are usu. CK 7 +ve incl. solid type)

d/dg collecting duct CA, chromophobe CA, papillary TCC, papillary mets

Differential Diagnosis of Conventional Renal Cell Carcinoma

Immuno for clear cell/papillary RCC:  +ve for CK, EMA, vimentin, CD10 and ‘RCC MA’

 c-kit, MOC31, S100 and CEA are usu. −ve

‘RCC MA’ is also +ve in breast and parathyroid epithelial tumours, cystic nephroma, mesothelioma

Adrenocortical carcinoma: EMA +ve favours renal cell and excludes adrenal, CK +vity too but less

so. For an immuno panel and more information, see table 19.1 on p. 276.

Melanoma: EMA +ve and CK +ve favour renal cell and excludes melanoma

Other carcinomas: CK and vimentin +vity is unusual in other carcinomas (except endometrial)

Translocation carcinoma: esp. in children, pale/clear cells but with nests/papillae ±psammoma bodies;

has der(17)t(X;17)(p11.2:q25) and has nuclear immuno +vity for TFE3 (related to ASPS)

Collecting Duct Carcinoma

Macro: the tumour is centred on the medulla

Cells: high grade (unlike papillary carcinoma), eosinophilic cytoplasmic globules, hobnailing

The rare low grade type has cuboidal cells with prom. nucleoli, tubulocystic arch. ± lumenal mucin

Mixed solid and tubulopapillary pattern

Dysplastic changes in adjacent collecting ducts

Stroma: desmoplastic (± PMN) associated with an inﬁltrating ductal carcinoma component

Its metastases may be microcystic

Stains: +ve for mucin, some HMW CK and Ulex europaeus lectin; −ve for vimentin and ‘RCC MA’

d/dg:  any papillary lesion (vide supra) esp. pelvic TCC spreading up ducts

 metastatic carcinoma

 overlap with renal medullary carcinoma

Renal Medullary Carcinoma

Variant of collecting duct carcinoma seen in association with sickle trait (not sickle cell disease)

Inﬂammatory stroma

Infarcts/ischaemic areas

Chromophobe Carcinoma

Macro: oncocytoma-like (i.e. brown with central stellate scar

), cystic change is rare

Two cell types:  oncocytic (may have high grade nuclei but often low grade)

 cells with pale staining granular cytoplasm (unless eosinophilic subtype), perinu-

clear halo (koilocytoid) and peripheral condensation to highlight cell borders (=

plant-like in the paler ones)

Nuclei: wrinkled ± grooved, always ﬁnd at least some binucleate/multinucleate forms

Cells are of variable size (‘mosaic’ pattern)

Microvessels are of variable thickness (with some thick vessels)

May have a papillary pattern and sarcomatoid change is relatively common

Stains: Hale’s colloidal iron (mucin) diffuse strong reticular cytoplasmic staining (cf. focal, weak,

dust-like for all others), also AB +ve; lipid and glycogen −ve

Immuno: vimentin −ve; Ber-EP4 and MOC31 usu. +ve. CK and EMA patchy +ve (incl. ‘membranous’

+vity for CK7). Diffuse cytoplasmic MUC1 +ve (cf. membranous in papillary/conventional)

. CD10

a central scar just means its a slow growing tumour and can be seen in any type

see Llinares et al., 2004

PIC

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Urological 218

−ve except in an aggressive subset (cf. +ve for papillary/clear cell or ±ve in others incl. oncocytoma).

‘RCC MA’ is usu. −ve (95% of cases). c-kit and Kidney-speciﬁc cadherin +ve (−ve in most other

renal tumours except oncocytoma)

EM: perinuclear microvesicles (? mitochondrial membrane derived). These don’t survive wax process-

ing so take fresh tissue directly into glutaraldehyde at time of cut-up

Prognostic Factors

Stage (esp. LN/mets), grade (Fuhrman), margins, histotype:

?14q- in clear cell (a bad prognostic); ?proliferation status

good chromophobe

papillary

clear cell

bad collecting duct

Cytogenetics

Oncocytoma : Y-, 1-

Papillary adenoma/carcinoma : Y-, trisomy 7, trisomy 17

Clear cell : 3p- (VHL oncosuppressor – not seen in other histotypes)

Collecting duct : 1-, 6-, LOH on 8p/13q

Chromophobe : 1-, 2-, hypodiploid

Fuhrman Grading of Nuclei

The original study was based on 103 patients with a minimum of 4 years F/U

Nuclear grade predicted mets better than (each of): size, stage, cell type, cytoarchitecture

Grade according to the worst focus (not the predominant grade)

TABLE 16.3 Fuhrman grading

Grade Nuclear size Nuclear shape Nucleoli

I ≈ 10  round & uniform small/absent

II ≈ 15  irregularity visible with ×40 objective frequently seen with ×40 objective

III ≈ 20  obvious irregularity large (seen with ×10 objective)

IV ≥ 20  as for III + bizarre/multilobed forms

and heavy chromatin clumps

large (seen with ×10 objective)

Based on: Fuhrman SA, Lasky LC, Limas C. Prognostic signiﬁcance of morphologic parameters in renal cell carcinoma.

AmJSurgPathol.(1982); 6:655-663.

Metastatic Tumours

Common sources are lung/stomach; also pancreas, adrenal (by direct spread), contralateral kidney (via

renal veins), breast and melanoma (± glomerular emboli)

There may be interstitial inﬁltration with glomerular sparing

Extensive vascular invasion favours a 2

◦

origin

Coexistence of usual-type 1

◦

tumour or preneoplastic metaplasia favours 1

◦

Frozen Sections

Usu. done for margins on partial nephrectomies or to diagnose a mass in a potential donor kidney

Problems include crushed tubules/detached groups of cells ?benign/malignant: go by architecture and

cytology (esp. nuclear features of atypia)

Cysts: if clear cell lining more likely RCC (! but see ‘d/dg simple cyst’ on p. 216) but if granular

eosinophilic cells consider ‘atypical cyst’ (the patient need not have VHL)

Fatty masses: d/dg angiomyolipoma (look for eosinophilic granular cells), fat necrosis, angiosarcoma

If not conﬁdent request additional tissue

Urothelial Tumours

Nephrogenic Adenoma / Metaplasia (NA)

Affects any urothelial-lined structure, esp. bladder and urethra and may extend into prostate

Immuno: +ve (PAX2, AMACAR, CK7, EMA, CA-19.9, CA-125); ±ve (CK20, ‘RCC MA’, CD10);

−ve for basal cells and p53, p63, Ki-67, PSA / PSAP

d/dg prostatic CA: NA has oedematous/inﬂam

stroma, intracellular mucin +ve, PSA/PSAP −ve

d/dg clear cell carcinoma: +vity for Ki-67 and p53 favours CCC. See also table 16.4

Inverted Papilloma

Clin.: male, 50’s, BOO/haematuria; macro: polypoid/nodule

Normal overlying urothelium, minimal exophytic component

Anastomosing trabeculae with palisading, eddies, cysts and glandular areas