Review on Angiomyolipoma (AML) www@AML Dr KP Wong Urology, PYNEH Joint Surgical Grand Round

Review on Angiomyolipoma (AML)www@AML

Dr KP WongUrology, PYNEH

Joint Surgical Grand Round

What is angiomyolipoma?

2nd commonest benign neoplasm in kidney

vessel

fat

smooth muscle

Imaging

How common? 1969: 8501 Autopsies without tuberous sclerosis

complex (TSC) 2 males (0.02%) 25 females (0.29%)

1995: Population based USG screening (Japanese Study) 13 out of 12970 males (0.1%) 11 out of 4971 females (0.22%)

pain

mass

haematuria

shock

haemorrhage

Lenk’s triad

1. Oesterling et al. The management of renal angiomyolipoma.J Urol, 135:121, 1986

Presentation

~59% symptomic on presentation

Presentation.

2. NELSON et al. Contemporary diagnosis and management of renal angiomyolipoma.J Uro 168:1315,

2002.

W - who is at risk ?

More common in Female ~86%

W - Who at risk @ AML

2. NELSON et al. Contemporary diagnosis and management of renal angiomyolipoma.J Uro 168:1315,

2002.

Tuberous Sclerosis Complex

Cortical tubers

Ash-leaf spots

W - Who at risk @ AML

2. NELSON et al. Contemporary diagnosis and management of renal angiomyolipoma.J Uro 168:1315,

2002.

~20% associated with Tuberous Sclerosis

W- who is at risk ?

Am I different from sporadic AML ?

In Which Way I was in difference?

Nature history - TSC

Young, Large, Multiple, more acute bleeding

2. NELSON et al. Contemporary diagnosis and management of renal angiomyolipoma.J Uro 168:1315,

2002.

Growth Characteristic - TSC Steiner et al.

35 patient: Follow up: 4 year

3. Steiner, et al. The natural history of renal angiomyolipoma. J Urol,150: 1782, 1993

67%

50%

21%28%

0%

20%

40%

60%

80%

100%

No. tumors thatgrow (%)

requir surgicalintervention

TSC

sporadic

W - When to intervent?

Symptomic vs Asymptomic

Intervention

Asymptomic AML no RCT available Limit prospective data, retrospective data:

symptomic or haemorrhage => likely larger tumorsLarger tumor => become symptomic with time

Large?

Tumor size → symptom Oesterling et al.

retrospective review (1948~ 1985) 253 patient: 8% from autopsy, 20% were TSC stratified into < 4cm (30%), > 4cm (70%)

1. Oesterling et al. The management of renal angiomyolipoma.J Urol, 135:121, 1986

Tumor size → treatment

43% 95%

1. Oesterling et al. The management of renal angiomyolipoma.J Urol, 135:121, 1986

Tumor size → symptoms Nelson et al.

Large tumors (>4cm) more likely symptomic

2. NELSON et al. Contemporary diagnosis and management of renal angiomyolipoma.J Uro 168:1315,

2002.

↑Need to intervene with larger tumor (>4cm)

Tumor size → treatment

2. NELSON et al. Contemporary diagnosis and management of renal angiomyolipoma.J Uro 168:1315,

2002.

Tumor size → Growth Steiner et al.

35 patient: Follow up: 4 year

3. Steiner, et al. The natural history of renal angiomyolipoma. J Urol,150: 1782, 1993

27%

46%

0%

10%

20%

30%

40%

50%

No. tumors that grow (%)

< 4cm

> 4cm

W - How to intervene?

Nephrectomy total

Nephron sparing approach Partial nephrectomy Enucleation of AML Cryotherapy (open or lap.) Trans-arterial embolization

Angiographic embolization

Emergency Avoid total nephrectomy Nephron sparing

Elective Reduce size

Efficacy Re-embolization ~14% Surgical intervention ~16%

Pre-embolization

Post-embolization

2. NELSON et al. Contemporary diagnosis and management of renal angiomyolipoma.J Uro 168:1315,

2002.

Take Home Message W – Who at risk

female Tuberous sclerosis complex

W - When to intervene Size:

W - How to intervene Nephron sparing approach would be choice of

management in AML

end

Q & A

More information

Presentation Histology Association

TSC LAM Malignant variant

Imaging

Intervention Consideration Surgical intervention Lap cryotherapy Embolization

Hormonal potentiation Molecular biology and

recent advance

Presentation

Presentation Classical triad

Flank pain, tender palpable mass, gross haematuria

Incidental finding Microscopic haematuria Others:

Renal failure, UTI, anemia

Presentation

Palpable mass – 20% Retroperitoneal hemorrhage – 15% Hypovolemic shock – 30% Renal insufficiency

Haemorrhagic aetiology

Wunderlich’s syndrome Spontaneous retroperitoneal haemorrhage

Trauma During pregnancy

haemorrhage

risk or haemorrhage: 25%~50% female 18%, male: 8%

6.KESSLER et al. Management of renal angiomyolipoma: Analysis of 15 cases. Eur Urol 33:572–5, 1998

7.WEBB et al. A population study of renal disease in patients with tuberous sclerosis. Br J Urol 74:151–4,1994

Growth Characteristic - Size Steiner et al.

35 patient: Follow up: 4 year

3. Steiner, et al. The natural history of renal angiomyolipoma. J Urol,150: 1782, 1993

Growth Characteristic - Size

< 4cm > 4cm

No. tumors that grow (%) 27% 46%

Require surgical intervention (%)

7% 53.8%

Large AML (>4cm) enlarged more likely than small AML

Steiner et al. 35 patient: Follow up: 4 year

3. Steiner, et al. The natural history of renal angiomyolipoma. J Urol,150: 1782, 1993

Growth Characteristic - Size Steiner et al.

35 patient: Follow up: 4 year

3. Steiner, et al. The natural history of renal angiomyolipoma. J Urol,150: 1782, 1993

27%

7%

46%

53.80%

0%

10%

20%

30%

40%

50%

60%

No. tumors thatgrow (%)

Require surgicalintervention (%)

< 4cm

> 4cm

Histology

Classification

Hamartoma? Fat and smooth muscle not normal found in kidney

Choristoma? Neoplastic?

Clonal expansion LN invasion

Extra-renal AML Adrenal gland, Liver, ovary, fallopian tube, spermatic cord,

colon

History

1900: Grawitz a large renal tumor comprised of fat, muscle and blood

vessels

1911: Fisher Histopathology: Contains fat cell, smooth muscle cell,

blood vessel in different proportions

1951: Morgan Name: angiomyolipoma

vascular

fat

smooth muscle

Pathological evaluation Fatty – normal Vascular – thicken

wall, lower elastin content, surround by cuff of smooth muscle cell

Smooth muscle – normal spindle cell or rounded epithelioid cells

histological stain

anti-smooth muscle stain: spindle and epithelioid cell

S-100 antibodies: fat cell

HMB-45 : perivascular epithelioid cell derived lesion

Histological examination

Percutaneous biopsy Tumor spread Complication Subsequent management

FNAC Correctly Dx: 5/8 Melanosome associated protein HMB-45: 7/8

Association of AML

Association

Association Tuberous Sclerosis complex Lymphangionleiomyomatosis (LAM)

40 % of TSC (young female)Rare for sporadic case - 60% associated with AML

Tuberous Sclerosis complex

Autosomonal dominant Mutation in TSC1 or

TSC 2 gene Incidence of AML in

TSC – 55~75%

Tuberous Sclerosis Complex

Tuberous Sclerosis Complex

Dermatological Ash-leaf spots Shagreen patch Adenoma sebaceum Ungal fibromas

Neurological Cerebral cortical tubers Epilepsy, infantile spasm Neruobehavorial disorder

Renal AML epithelial cyst, polycystic

kidney, RCC

Pulmonary Lymphangio-leiomyomatosis

Cardiac Rhabdomyomas

Growth Characteristic - TSC Steiner et al.

35 patient: Follow up: 4 year

3. Steiner, et al. The natural history of renal angiomyolipoma. J Urol,150: 1782, 1993

Growth Characteristic - TSC

TSC sporadic

No. tumors that grow (%)

67% 21%

requir surgical intervention

50% 28%

Steiner et al. 35 patient: Follow up: 4 year

3. Steiner, et al. The natural history of renal angiomyolipoma. J Urol,150: 1782, 1993

Growth Characteristic - TSC Ewalt et al.

60 children with TSC: 4 year FU50% had renal AML at initial stage During Fu, 40.7 % of children without AML at initial stage had

AML

De Luca et al. 51 patient with sporadic AML: 5 year Fu

92% without growth

AML with TSC enlarged more likely than sporadic AML

4. Ewalt, et al. Renal lesion growth in children with tuberous sclerosis complex. J Urol, 160: 141, 1998

5. De Luca et al. Management of renal angiomyolipoma: a report of 53 cases. BJU Int, 83: 215

Am I different from sporadic AML ?

In Which Way I was in difference?

When will disease be present?

Lymphangioleiomyomatosis (LAM)

Lymphangioleiomyomatosis (LAM)

Male Biopsy document LAM: 3 with TSC, 1 without TSC

Tuberous sclerosis complex 40% of TSC: had LAM 1% of TSC: symptoms

Sporadic Sporadic: rare < 1000 case 60% of LAM: had AML

Lymphangioleiomyomatosis (LAM)

Pathology Smooth muscle infiltration Cystic destruction of lung

Symptoms: Progressive SOBOE Recurrent pneumothorax Abdominal & thoracic

lymphadenopathy Abdominal tumor, e.g. AML,

lymphangiomyoma

Lymphangioleiomyomatosis (LAM)

Treatment – antagonism of estrogen action Progesterone im Oral progrestin GnRH agonist

Reversible Airflow limitation Bronchodilator

Lung transplantation

epithelioid subtype

histological classification

classical vascular, smooth muscle and adipose

epithelioid variant of angiomyolipoma large component of epithelioid cell

epithelioid subtype

more aggressive

recur after resection fatal

diagnostic imaging

Imaging - US

Mark hyperechoic signal and acoustic shadowing 8~47% RCC also

hyperechoic Some proportion of

AML not highly hyperechoic

Imaging - CT AML:

Fat contain renal lesion (< -15 HU)

Some lesion contain minimal fat

Malignant tumor (RCC): Tissue necrosis with lipid

formation, intratumoral bone metaplasia => areas of calcification (rare in AML)

Imaging – MRI AML

High signal intensity on T1 image

Low intensity on T2 image

RCC Low signal intensity

on T1 image High intensity on T2 Contrast MRI

Imaging – MRI

T1 imageT2 image

Consideration on intervention

Selective of intervention Multiple factor

symptom Lesion size Tuberous sclerosis Pregnancy plan Occupation, activity Renal reserve Co-morbidity Reliability and compliance

TSC and associated feature

Symptomic

Choice of treatment

Observation & Fu

Stenier et al

Sporadic < 4cm

Yearly imaging

> 4cm Asymptomic or mild:

semiannual USGrowth: surgerySevere symptoms:

surgery

TSC < 4cm

Semiannual USGrowth: Surgery

> 4cm Surgery

Surgical management

Intervention

Pre-embolization post-embolization

Surgical management

Indication Significant haemorrhage Haematuria Symptoms not responsive to conservative Tx Local tissure or vascular invasion Suspicion of malignancy after imaging

Total nephrectomy

Indication: Whole kidney replaced by AML Solitary AML near hilum or risk for partial than

complete nephrectomy Suspicion of malignancy Reperitoneal haemorrhage, unsuccessful or

unavailable embolization

laparoscopic cryoablation

Gregory et al.Laparoscopic Cryoablation of Renal Angiomyolipoma. J Uro. 176, 1512-1516, 2006

7 patient Average size – 4.2cm 3 minor complication in 2 patient Operative time – 170 miniutes, Blood loss of

116 cc Average decreased in CrCl 8.6 ml/min

Gregory et al.Laparoscopic Cryoablation of Renal Angiomyolipoma THE JOURNAL OF UROLOGY

Vol. 176, 1512-1516, October 2006

Angiographic embolization

Indication: Acute hemorrhage Symptomic tumor with limit renal reserve or

poor operative candidate Prophylatic treatment for asymptomic tumor

Materials: Gelatin sponge, alcohol, iodized oil, polyvinyl

alcohol particles, metal coils

Angiographic embolization

Pre-embolization post-embolization

Angiographic embolization

Pre-embolization post-embolization

Angiographic embolization

Pre-embolization post-embolization

Angiographic embolization Post embolization syndrome: 85% Complication: 10% of case

Abscess formation 5% Pleural effusion 3%

2. NELSON et al. Contemporary diagnosis and management of renal angiomyolipoma.J Uro 168:1315,

2002.

Kothary et alRenal Angiomyolipoma: Long-term Results after Arterial Embolization J Vasc Interv

Radiol 2005; 16:45–50

Retrospective review, mean Fu 51.5 months 19 patient (TSC: 10/19) 30 renal AML (TSC:21/30)

Recurrence 31.6% of patient (6/19) 30% of AML (9/30) – all from TSC group (9/21)

Time from embolization to recurrence Mean: 81.3 months (range: 36~132 months)

Angiographic embolization Efficacy

Difficult to assess in absence of controlled studies

Re-embolization ~14% Surgical intervention ~16%

2. NELSON et al. Contemporary diagnosis and management of renal angiomyolipoma.J Uro 168:1315,

2002.

Angiographic embolization

Pros Option in emergency

setting Nephron sparing

Cons no tumor diagnosis Difficult in Follow up Possibility of

revascularization

Pre-embolization

post-embolization

Angiographic embolization

Adipose tissue Not sign affected

Angiomyogenic component Responsed

Size Decrease is variable

Enhancement Decreased or absent

Pre-embolization

Post-embolization

Durability of embolization ?

Efficacy Durability Re-embolization rate

Conservative Treatment

Avoid contact activities which flank/abdominal impact is likely

Repeat yearly or half yearly CT or US

Horomal potentiation

Hormonal potentiation

Progestrone and estrogen receptor in smooth muscle cell nuclei of some AML

Cases of rapid growth during pregnancy

Hormonal therapy: Early stage => not well defined

Molecular biology recent advance

Molecular biology Tuberous sclerosis complex

TSC1 on chromosome 9q34 TSC2 on chromosome 16p13 => produce Tuberin

Tumor suppressor Gene AML tissue with TSC2 mutation: lack tuberin expression Heterozyogosity at ½ of TSC loci: consistent finding at TSC

associated AML

Other genes Loss of TSC2 heterozygosity in only 10% of sporadic AML

Animal modal in AML

Akt singaling pathway in tuberous sclerosis Rat with hepatic tumor (HMB45 positive)

Rapamycin: Quenches S6K phosphorylation Shrinkage of inappropriate cell growth Shrinkage of renal tumor in mice