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0 - Urology > 5 - Familial RCC, AML, Dx > Flashcards

5 - Familial RCC, AML, Dx Flashcards

1
Q

Ddx of renal mass

A

Benign:

1) Simple cysts (most common, 70%)
2) Oncocytoma
3) AML, fat free AML
4) Abscess, TB

Malignant:

1) RCC
2) UTUC
3) Lymphoma
4) Sarcoma, liposarcoma
5) Renal metastasis

(picture: % Ddx of renal cortical mass)

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2
Q

Classification of renal cysts

A

Based on contrast CT scan (the updated version contains MRI too) to look for “SICES” (Septum, Irregular thickening, Calcification, Enhancement, Solid component)

Note: only for complex cysts >1cm

Bosniak I: Simple benign cyst
- Hairline thin wall
- Density <20 HU
- No “SICES”

Bosniak II: Cystic lesions
- a few hairline thin septa
- fine calcification
- “perceived” enhancement (not measurable)
- no solid component
- Uniformly high attenuation lesions <3cm, well marginated, do not enhance (<3cm hyper dense cyst)

Bosniak IIF: minimally complex cyst
- multiple hairline thin septa
- minimal smooth thickening of wall/septa
- thick or nodular calcification of wall/septa
- “perceived” enhancement (not measurable)
- Totally intra-renal high attenuation lesion >3cm, do not enhance (>3cm hyper dense cyst)

Bosniak III: Indeterminate cystic mass
- Thick irregular/smooth walls or septa
- measurable enhancement

Bosniak IV: Likely malignant cyst
- all Bosniak III features
- with enhancing soft tissue components adjacent to, but independent of, the wall or septum

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3
Q

Management of renal cyst

A

Based on Bosniak Classification:

1) Cat I & II
- benign lesion no need FU

2) Cat IIF
- obtain prior studies to compare
- consider contrast MRI for further characterisation
- follow-up CT
- if still unable to differentiate IIF from III, then place to Cat III

3) Cat III, IV
- treat as malignancy (discuss surgery / local ablation / surveillance)
- if opted for active surveillance: then 6 month image then yearly images

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4
Q

What is the % malignancy in Bosniak IIF / III / IV lesions

A

IIF = 5 to 15%
- in a systematic review, <1% stable IIF cysts showed malignancy on FU

III = >50% (based on systematic review 51%)

IV = >90% (based on systematic review 89%)

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5
Q

What are the pathological Ddx of complicated cysts?

A

1) If malignant, most commonly ccRCC with pseudocystic changes and low malignant potential

DDx:
2) Cystic nephroma
3) Mixed epithelial-stomal tumour

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6
Q

A patient with ESRF on chronic dialysis is noted to have developed multiple renal cysts.

What is the likely diagnosis? What is the diagnostic criteria

A

Acquired renal cystic disease (ARCD) aka Acquired cystic kidney disease

Diagnosis: ≥3 renal cysts per kidney

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7
Q

Pathophysiology of Acquired cystic kidney disease

A

Seen in 50% patients with ESRF undergoing dialysis, usually more than 10 years of dialysis

Likely associated with uraemic toxins

As the cysts are noticed to regress after transplantation

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8
Q

What is the risk of RCC in the following conditions:

1) Acquired cystic kidney disease
2) AD PCKD

A

1) Acquired cystic kidney disease
- increased risk of RCC (type 1 papillary)
- incidence of renal malignancy in dialysis patient is 5-50 times greater

2) AD PCKD
- no increased risk of RCC

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9
Q

What is the usual pathology for Acquired cystic kidney disease associated RCC?

A

1) Predominantly type 1 papillary RCC

2) Followed by ccRCC

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10
Q

Management of renal tumour in acquired cystic kidney disease

A

Offer surgical excision if size ≥3cm

If less than 3cm then can consider monitoring or surgery

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11
Q

Tell me about the genetics of adult onset PCKD

A

PKD1 (85%)
- polycystin 1
- 16p13

PKD2 (15%)
- polycystin 2
- 4q21

Autosomal dominant
100% penetrance of gene, but phenotype may not

================
so many cysts!! ➔ 16p13
go play pool ➔ 4q21

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12
Q

Pathophysiology of adult PCKD

A

1) Polycystin 1 and 2 are normally transmembrane protein that inhibits cell proliferation

2) Mutation in PKD1 or PKD2 leads to abnormal polycystin

2) Therefore proliferation pathways are unopposed, and cysts forms

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13
Q

How to diagnose AD PCKD

A

USG diagnostic criteria:
1) Positive family history
- ≥2 unilateral or bilateral renal cysts before 30
- ≥2 cysts in each kidney between 30-59
- ≥4 cysts in each kidney >60

2) No family history
- ≥3 unilateral or bilateral renal cysts before 30
- ≥2 cysts in each kidney between 30-59
- ≥4 cysts in each kidney >60

3) No cyst by age of 30: Considered not involved

➔ if in doubt, genetic testing for 16p13 and 4q21 can be considered

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14
Q

Tell me the extra-renal associations of AD PCKD

A

1) Cerebral Berry Aneurysm
2) CNS arachnoid cysts
3) Liver and pancreatic cysts
4) Mitral valve prolapse
5) Colonic diverticulum
6) Abdominal wall and inguinal hernia
7) Seminal vesicle cysts ➔ sub fertility

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15
Q

Oncocytoma epidemiology

A
  • benign tumour
  • comprising 3-7% of all solid renal tumours
  • M:F = 2:1 (twice as common in male)
  • Simultaneously with RCC in 7-32% of cases
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16
Q

Oncocytoma CT features

A
  1. Spoke-wheel pattern enhancement on contrast CT or angiogram
  2. Central stellate scar
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17
Q

Oncocytoma presentation

A
  1. Mostly asymptomatic with incidental finding
  2. rarely Loin pain / haematuria
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18
Q

Histological findings of oncocytoma

What stain?

A

Comprise of aggregates of eosinophilic cells, arising from intercalated cells of the collecting duct.

Cells are packed with mitochondria

Mitosis is rare, large nucleoli are present.

➔ CD117 (C-Kit) +ve
➔ CK7 -ve

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19
Q

Chromosomal abnormality of oncocytoma

A

1) Loss of Y chromosome

2) Loss of heterozygosity at chromosome 1 and 14

20
Q

Oncocytoma management

A

Active surveillance because:
- no malignant potential (if confirmed)
- slow progression with annual growth rate <14mm

➔ no need FU after nephrectomy if histology returns to be oncocytoma

21
Q

What is the significance of renal Bx pathology of oncocytoma?

A

Poor concordance rate with histology => if renal biopsy showed oncocytoma, only 60% is oncocytoma in surgical specimen

i.e. renal Bx cannot differentiate oncocytoma from:
1) Chromophobe RCC
2) Type 2 papillary RCC or oncocytic variant of papillary RCC
3) Glandular variant of ccRCC with eosinophilic characteristics

22
Q

What are angiomyolipoma?

A

Benign renal mesenchymal tumour, composed of:
- thick walled vessels
- smooth muscles
- adipose tissue

23
Q

How to classify AML? What are the differences?

A

Sporadic vs. Syndromic (i.e. TSC related)

1) F:M = 4:1 vs 2:1
2) Middle age onset vs childhood
3) Growth rate 5% vs 20%
4) Single & unilateral vs Multiple & bilateral
5) Treat with SAE or PN if size >4cm vs treat with MTORi if size >3cm

24
Q

What’s the name of the feared complication of AML?

A

Wunderlich Syndrome which is the spontaneous rupture and haemorrhage causing massive retroperitoneal bleeding

It is characterised by the Lenk’s triad of:
- flank pain
- flank mass
- hypovolemic shock

25
Q

Radiological features of AML

A

CT: presence of fat component within a renal lesion (HU -50 to -100)

USG: bright echo-pattern without acoustic shadow (vs stone)

26
Q

Stain for AML

A

HMB-45
(Human Melanoma Black)

27
Q

What are the risk factors for bleeding in AML?

A

1) TSC

2) Size
- Classically cut-off of 4cm defined by Oesterling (1986) as 9% haemorrhagic shock vs. 0% in <4cm
- Latest EAU Guideline Panel meta-analysis (Fernandez-Pello) suggested 4cm should not be used as trigger for active Tx per se
- Some new study suggested 6cm as cut-off

3) Intralesional blood vessel or aneurysm >5 mm in greatest width

4) Growth rate >2.5mm per year

5) Pregnancy or hormonal therapy

6) Uncontrolled hypertension and coagulopathy

28
Q

Indications for active intervention for AML

A

1) High bleeding risk
- size: classically >4cm (latest EAU meta-analysis suggested 4cm should not be used per se)
- growth rate >2.5mm per year
- intralesional blood vessel or aneurysm >5mm
- women of child bearing age due to risk of pregnancy
- uncontrolled hypertension or coagulopathy

2) Symptomatic

3) Patients with limited access to emergency service or high risk occupation

29
Q

Management of sporadic AML

Tell me the pros and cons

A

Based on indication +/- size
(Oesterling classical series: 9% vs 0% haemorrhage using 4cm as cut-off)

1) Active surveillance if <4cm and no indication
- regular USG surveillance

2) Selective arterial embolisation
+) around 25% decrease in size
-) secondary treatment in 30%

3) Partial or radical nephrectomy
+) most effective treatment in terms of recurrence
+) secondary treatment rate <1%
-) more invasive, higher risk

30
Q

Tell me about the genetic basis of TSC

A

➔ Autosomal dominant
➔ mutations in the tumour suppressor genes:

1) TSC1 in 20%
- 9p34
- Hamartin

2) TSC2 in 80%
- 16p13
- Tuberin

31
Q

Pathophysiology of TSC

A

Mutations in tumour suppressor genes TSC1 (9p34) and TSC2 (16p13), which codes for hamartin and tuberin

Normally hamartin-tuberin complex inhibits the mTOR pathway which regulates cell proliferation and growth

Therefore the mutation will affect the normal cell proliferation and growth, increasing expression of HIF-alpha and PDGF /VEGF, and lead to harmatomas and AML

32
Q

What are the clinical presentation of TSC?

A

Relevant to urologist for presence of AML

Classical Vogot’s Triad: MR, seizure, adenoma sebaceum (which is only seen in 1/3)

MAJOR FEATURES:
1) Skin
- adenoma sebaceum
- Shagreen patch
- Ash leaf spot (hypopigmented macule)
- peri-ungal fibroma
2) CNS
- cortical tuber ➔ causing seizure
- sub-ependymal nodule
- sub-ependymal giant cell astrocytoma
3) Eye: retinal hamartoma
4) Cardiac: rhabdomyoma
5) Lung: LAM (lymph-angioleio-myomatosis)
6) Renal: AML

MINOR FEATURES:
- confetti skin lesion
- cerebral white matter migration lines
- bone cysts
- retinal achromic patch
- dental enamel pits
- gingival fibroma
- harmatomatous rectal polyps
- non-renal hamartoma

33
Q

Clinical diagnostic criteria for TSC

A

2 majors (or 1 major and 2 minors)

MAJOR FEATURES:
1) Skin
- adenoma sebaceum
- Shagreen patch
- Ash leaf spot (hypopigmented macule)
- peri-ungal fibroma
2) CNS
- cortical tuber ➔ causing seizure
- sub-ependymal nodule
- sub-ependymal giant cell astrocytoma
3) Eye: retinal hamartoma
4) Cardiac: rhabdomyoma
5) Lung: LAM (lymph-angioleio-myomatosis)
6) Renal: AML

MINOR FEATURES:
- confetti skin lesion
- cerebral white matter migration lines
- bone cysts
- retinal achromic patch
- dental enamel pits
- gingival fibroma
- harmatomatous rectal polyps
- non-renal hamartoma

34
Q

How to manage TSC associated AML?

A

Active surveillance if <3cm

Medical therapy if >3cm
- with mTOR inhibitor (everolimus) based on EXIST-2 trial

Active intervention if >4cm / no response to everolimus
- SAE
- Partial nephrectomy if possible

35
Q

Evidence of Everolimus for AML

A

EXIST-2 trial, 4 year update in 2017
- Renal AML
- 58% achieved AML response (≥50% reduction)
- 97% experienced reduction in renal lesion volumes at some point during the study period
- No AML bleeding or nephrectomies were reported

36
Q

What is everolimus? What is the mechanism and side effects?

A

mTOR inhibitor (mammalian target of rapamycin)
➔ for TSC associated AML

Blocks the mTOR pathway, thus blocking the downstream HIF and VEGF and PDGF, and stopping the dysregulated cell proliferation

Side effects:
- Mucositis / stomatitis
- Endocrine: DM / hyperlipidemia
- Pneumonitis
- Nephrotoxicity
- immunosuppression
- myelosuppression

37
Q

What are the familial RCC syndromes? What are their respective RCC and mutations?

A

1) VHL (von Hippel-Lindau) Disease
- 3p25
- ccRCC

2) Hereditary papillary RCC
- 7q31
- type 1 papillary RCC

3) Hereditary leiomyomatosis and RCC
- 1q42
- type 2 papillary RCC

4) Birt-Hogg-Dube syndrome
- 17p11
- Chromophobe RCC / Oncocytoma

5) Others
- Cowden syndrome

38
Q

Tell me about hereditary leiomyomatosis and RCC

A

Genetics:
- autonomic dominant
- 1q42
- Fumarate hydratase mutation

Features:
1) Type 2 papillary RCC, very aggressive (usually young male)
2) Painful cutaneous leiomyoma
3) Uterine fibroids

Tx: usually prompt treatment is needed for RCC, not for NSS

39
Q

Tell me about hereditary papillary RCC

A

Genetics:
- Autosomal dominant
- 7q31
- Activation of c-MET proton-oncogene

Features:
1) Bilateral and multifocal type 1 papillary RCC:
- usually elderly
- no other organ involvement

Tx: for NSS

40
Q

Tell me about Birt Hogg Dube syndrome

A

Genetics:
- autosomal dominant
- 17p11
- BHD tumour suppressor gene (FLCN) for folliculin, which forms a protein complex that interferes with mTOR pathway

Features:
1) Chromophobe RCC / oncocytoma which can be mixed (<50yo, multiple, bilateral)
2) Painless firbofolliculoma, ≥5
3) Pulmonary cysts, pneumothorax

41
Q

What is the gene and pathophysiology of VHL?

A

Genetics:
- autosomal dominant
- 3p25
- VHL suppressor gene

Pathophysiology:
- Knudsen’s two-hit hypothesis: Require only one more somatic mutation to promote carcinogenesis, one VHL allele is inherited with mutation
- Inactivation of VHL
- Loss of VHL protein
- Accumulation of HIF-2a
- Leads to over-expression of VEGFR, PDGF, TGF-alpha etc, causing angiogenesis and cell proliferation

42
Q

Features of VHL syndrome

A

“HIPPEL”

  • Haemangioblastoma (CNS or retinal)
  • Increase risk of ccRCC
  • Pheochromocytoma
  • Pancreatic cysts
  • Eye (Retinal angioma), Ear (Endolymphatic sac tumor), Epididymal cystadenoma
  • Liver cysts
43
Q

Diagnostic criteria for VHL

A

1) With family history
- One major feature (CNS or retinal hemangioblastoma / RCC / Pheochromocytoma)

2) Without family history
- Two major features (e.g. two hemangioblastoma or 1 hemangio + one visceral tumour)

44
Q

Tell me about the subtypes of VHL

A

Type 1 and 2B have higher risk of ccRCC

Type 1:
- high risk of RCC and haemangio
- low risk of pheo

Type 2: high risk of pheo
- 2A: high risk of haemangio, low risk of RCC
- 2B: high risk of RCC and haemangio
- 2C: low risk of RCC and haemangio

45
Q

How common is ccRCC in VHL? How is it presented?

A
  • Seen in 50% of patient ➔ commonest cause of death
  • Onset age ~30 year old
  • Multiple, bilateral RCC
46
Q

How to manage RCC in VHL patient?

A

1) Genetic counselling, relative testing
2) Consider screening for extra-renal causes
- MRI for CNS haemangioblastoma
- urine catecholamine for pheochromocytoma

3) When renal lesion <3cm
- regular monitor
- use USG if <2cm
- use contrast CT if >2cm

4) When renal lesion >3cm ➔ NSS
- due to Walther study showing <3cm has 0% metastasis but >3cm has 25% metastasis

±5) HIF-2α inhibitor (Belzutifan) to stop progression

47
Q

What medication is used in VHL?

A

Belzutifan published in Lancet 2022

  • Phase II
  • Single arm
  • one or more RCC (size >1cm on CT or MRI) but not larger than 3cm

➔ 49% stable disease, 49% partial response, 0% progression
➔ during treatment: median growth −3.7 mm per year

0 - Urology (32 decks)

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