Benign Kidney Tumours

Includes 2017 CUA Guideline on Cystic Renal Lesions

Renal Cysts

• Most common benign renal lesion
• Increase in size and number over time

Pathogenesis

• Develop within renal tubules by pathogenetic processes that involve cellular proliferation, accumulation of tubule fluid within distended cavities, and remodeling of extracellular matrix§
• Risk factors for renal cysts (4):
  1. Increasing age
  2. Male gender
  3. Hypertension
  4. Renal insufficiency
• In patients with autosomal-dominant polycystic kidney disease (ADPKD), cyst formation is due to loss of PKD1 (polycystin-1 protein) or PKD2 (polycystin-2)
• Acquired renal cystic disease is associated with increased risk of RCC

Diagnosis and Evaluation

History and physical exam

• Usually asymptomatic
• Rarely, benign cystic lesions can cause pain and/or hypertension
• Symptoms can occur as a consequence of hemorrhage within the cyst or spontaneous or traumatic cyst rupture

Imaging

• Any renal lesion that is not a simple cyst should be further characterized with contrast-enhanced axial imaging to better characterize the cyst

Bosniak classification of renal cysts

• Originally devised using CT scans
  • Can be used in MRI, but MRI tends to exaggerate some findings related to cysts

Bosniak category	Key features	Risk of malignancy (5-15-55-90)	CT Appearance
I (simple cyst)	Usually round or oval shape Anechoic with posterior enhancement on US Regular contour with clear interface with renal parenchyma No septa, calcification or enhancement
II	Single thin septum (<1 mm) Fine calcification (often small, linear, parietal, or septal) No perceived contrast enhancement Hypderdense cyst <3 cm; >20 HU	5% Likely gross overestimation of the true risk, as most of the malignant category II lesions had features that made them too complex to be considered a true category II cyst
IIF	Cyst unequivocally categorized as category II or III cysts Multiple thin septae or a slightly thickened, but smooth septa Calcifications – thick or nodular No perceived contrast enhancement Hyperdense cysts ≥3 cm	8-27%
III	Uniform wall thickening and/or nodularity Irregular, thickened, and/or calcified septa Contrast-enhancing septa	54%
IV	Wall-thickening Gross, irregular, and nodular septal thickening Solid contrast-enhancing component, independent of septa	88%

• Proposed updated 2019 classification
• Radiopaedia article on Bosniak classification of renal cysts

Other

• Renal tumour biopsy (RTB)
  • Significantly less informative for the diagnosis of cystic lesions compared to solid lesions
  • Generally, not diagnostic for most Bosniak III cysts, as there is minimal targetable solid component
  • For Bosniak IV cysts, a biopsy of the solid component may be considered to confirm the presence of a malignant tumour and to help with decision-making in select cases (elderly, multiple comorbidities, unfit for treatment, etc)

Management

• Based on Bosniak classification[1]
  • Bosniak I and II
    • Follow-up not warranted
      • Majority will grow over time; growth should not necessarily be considered a sign a malignancy
      • Transformation into a more complex cyst is rare
    • Intervention only warranted if the cyst becomes symptomatic (bleeding, recurrent infection or pain)
      • Treatment options:
        1. Percutaneous management (aspiration +/- sclerotherapy)
        2. Cyst decortication
        3. Surgical resection
      • Percutaneous cyst decompression may be considered prior to offering definitive treatment as a means to confirm that the source of symptoms are cyst-related
  • Bosniak IIF
    • ≈15% of these category IIF cysts will progress in complexity (to Bosniak category III or IV)
    • Should be followed with imaging
      • Contrast-enhanced CT scan or MRI (not US) every 6 months for the first year. Cases without progression should be followed annually for at least 5 years
  • Bosniak III/IV
    • Surgical excision is generally suggested
    • Bosniak III
      • Given the low metastatic potential of cystic RCC, the panel feels that reduced surgical margins and controlled cyst decompression (if required) can be performed with low risk of tumour recurrence
      • For the same reason, active surveillance and thermal-ablation therapies (see below) may also be considered as appropriate treatment alternatives in select cases
    • Bosniak IV
      • Most of these malignant cysts are thought to have low metastatic potential and thus, more conservative management may be safely considered in select cases
    • 2017 AUA Localized RCC Guideline:
      • AS is an option as initial management, especially those <2cm
      • AS/expectant management should be prioritized when the anticipated risk of intervention or competing risks of death outweigh the potential oncologic benefits of active treatment
      • For patients in whom the
        • Risk/benefit analysis for treatment is equivocal and who prefer AS, physicians should repeat imaging in 3-6 months to assess for interval growth and may consider RMB for additional risk stratification.
        • Anticipated oncologic benefits of intervention outweigh the risks of treatment and competing risks of death, physicians should recommend active treatment. In this setting, AS with potential for delayed intervention may be pursued only if the patient understands and is willing to accept the associated oncologic risk.

• Role of active surveillance for suspected cystic RCC
  • The vast majority of cystic RCCs are multilocular cystic RCCs (mcRCC) though all RCC subtypes may present in a predominantly cystic form
    • Cystic RCCs need to be distinguished from solid renal masses with necrotic components, which behave more aggressively
  • mcRCCs have low malignant potential
    • Better cancer-specific and overall survival compared with solid RCCs
      • There has yet to be a report demonstrating metastases or recurrence of mcRCCs.
      • One potential explanation for this indolent behaviour is that the majority of mcRCCs tumour volume is fluid and therefore the actual tumour burden is much lower when compared to similar sized solid tumours.
    • To reflect this indolent behaviour, the International Society of Urological Pathology (ISUP) now recommends calling these lesions multilocular cystic renal neoplasm with low malignant potential
    • As the outcomes of these tumours do not seem to be influenced by the overall lesion size, some have even suggested to abandon the current pathological T staging for mcRCC and to reassigned them a new stage called pT1c (c for cystic).
  • Given their relatively indolent behaviour, there is emerging evidence suggesting that these lesions (especially Bosniak classification III) can be safely managed by active surveillance
    • If active surveillance is considered, consider abdominal imaging every 6 months for the first 2 years, followed by yearly imaging thereafter, if the lesion is stable.
  • Triggers for intervention on active surveillance for suspected cystic RCC are yet to be clearly defined and validated, but may include (3):
    1. Progression from Bosniak III to IV
    2. Growth of solid nodule > 3 cm
    3. Fast-growing nodule
• Thermal-ablation therapies (RFA, cryotherapy)
  • Given the limited data, RFA should be limited to patients with small Bosniak category III and IV cysts who are poor operative candidates and in whom active surveillance is not being considered
  • The role of cryotherapy in the management of Bosniak III or IV cysts is not well-defined, only a few cases reports in the literature

Oncocytoma

Epidemiology

• More common in younger females and older patients with a small incidentally discovered renal mass

Pathology

• Derived from the collecting duct/distal renal tubules, similar to chromophobe and collecting duct RCC
  • Recall that clear cell and papillary RCC are derived from the proximal tubules
• Cells demonstrate an abundance of mitochondria
• Hemorrhage, extension into perinephric fat, vascular invasion, cellular atypia, prominent nucleoli, and pleomorphism may be seen in up to 1/3rd of patients, yet the clinical behavior in these cases is benign

Diagnosis and Evaluation

• Imaging
  • Clinically and radiographically indistinguishable from RCC
    • Classic findings of spoke-wheel pattern seen on angiography or stellate scar on cross-sectional imaging have a poor predictive value

INSERT FIGURE

• Scroll through CT of oncycytoma on Radiopaedia
  • Other
    • Biopsy
      • Can provide diagnosis
        • Histologically, difficult to distinguish oncocytoma from chromophobe and clear cell RCC, either with eosinophilic characteristics
      • Frozen section is unreliable and should not be used to guide treatment

Management

• Options include observation, thermal ablation, or surgery
  • If surgery, partial nephrectomy preferred given benign nature and very low probability of recurrence
  • If observation, should be followed with the same imaging protocols used for untreated, low risk (cT1, NO, Nx) renal cancer patients.
    • Benign tumors can exhibit substantial growth patterns over time that may threaten destruction of the renal unit by compression/invasion of surrounding parenchyma and vascular structures
    • Although the accuracy of percutaneous biopsy has improved substantially in the past several years, the pathologic differentiation between oncocytoma and oncocytic neoplasms (e.g., chromophobe renal cell carcinoma) and renal cell carcinoma can at times be difficult, with the true pathology of the mass only coming to attention by rapid tumor growth.
    • The purpose of routine imaging of these benign neoplasms is, therefore, to capture undue tumor growth and allowing for expedient surgical/ablative intervention and avoidance of radical nephrectomy.
    • AUA Guidelines for the follow-up of renal cancers and untreated low-risk tumors, including oncocytoma, include:
      • History and physical examination
      • Basic laboratory testing to include blood urea nitrogen (BUN)/creatinine, urine analysis (UA), and estimated glomerular filtration rate (eGFR)
      • Continued renal imaging (US, CT or MRI scan) at least annually, and annual chest X-ray (CXR) to assess for pulmonary metastases.

Angiomyolipoma

Epidemiology

• Sex
  • Predominantly found in females
    • Strongly expresses estrogen receptor β, progesterone receptor, and androgen receptor suggesting a potential hormonal influence
• Age
  • Rare before puberty
  • Decreased incidence of sporadic AMLs with increased age
• Most often sporadic but can also be associated with autosomal dominant tuberous sclerosis complex (TSC)
  • 20-30% of AMLs occur in patients with TSC
  • 50% of patients with TSC develop AMLs
  • See Kidney Cancer Pathology and Familial Syndromes Chapter Notes for further details on TSC

Pathology

• Thick-walled poorly organized blood vessels, smooth muscle, and varying levels of mature adipose tissue
• Benign lesion, but can have extra-renal occurrences indicating multicentric origin rather than malignancy with metastasis
  • Malignant epithelioid variant can metastasize and cause death
• Positive immunoreactivity for HMB-45 (human melanoma black 45) is characteristic for AML

Diagnosis and Evaluation

History and Physical Exam

• Clinical Presentation
  • Spontaneous perirenal hemorrhage
    • Renal neoplasm most commonly associated with spontaneous perirenal hemorrhage, closely followed by RCC
    • Aneurysmal dilation is found in 50% of AMLs; size of aneurysm correlates with risk of rupture
    • Wunderlich syndrome, which is a massive spontaneous non-traumatic retroperitoneal hemorrhage (from any cause), is the most significant complication of AML
    • Pregnancy increases risk of AML hemorrhage

Imaging

Stellate scar in right renal mass. Source: Wikipedia

• The only benign renal tumour that is confidently diagnosed on imaging
  • Presence of fat (≤-20 HFU) within a renal lesion is considered a diagnostic landmark
    • Other lesions that can contain fat (2):
      • Liposarcoma
        • Should be considered in the differential of a fat-containing retroperitoneal tumour
        • Can distinguish from RCC by whether mass originates from kidney or retroperitoneum, the latter of which may displace kidney
      • Fat-containing RCC
        • In RCC, the fat is thought to be a reactive process related to tumor necrosis.
    • ≈5% of AML’s are fat poor
      • Fat-poor AML can be difficult to distinguish from RCC
      • Calcification is virtually never seen in association with AML
        • Clinical implication: presence of fat with calcification is suggestive of RCC
  • MRI can be used in difficult cases when the lesion has minimal fat
    • A T2-weighted image with fat suppression is most likely to identify macroscopic fat and confirm the diagnosis of an angiomyolipoma (AML).

Other

• Biopsy
  • Consider biopsy if imaging findings equivocal

Management

• Consider size of the tumour, presence of symptoms, and patient factors
  • Most studies have focused on a 4-cm cut point but size represents a continuum of risk
• Asymptomatic, smaller tumors (typically <4 cm)
  • Observation (preferred) with repeat initial imaging at 6 to 12 months to define the growth rate and clinical significance.
    • Repeat imaging can be lengthened once stability has been established, with follow-up performed only annually or biannually for smaller tumors
    • Solitary, sporadic AMLs have a mean growth rate of 5%/year; multifocal AMLs and those in patients with TSC have mean growth rate of 20%/year
• Symptomatic or larger tumors (>4cm)
  • Consider intervention taking into account the patient’s age, comorbidities, and other related factors
    • A proactive approach should also be considered In (2):
      1. Females of childbearing age
      2. Patients with limited access to surveillance or to emergency care
• Options for intervention (4):
  1. Partial nephrectomy
  2. Selective embolization
     • Disadvantages
       • Many require repeat procedures
       • Risk of complications from procedure
         • Overall complication rate with embolization in some series is 10%, similar to rates of partial nephrectomy
           • Potential complications of embolization include hemorrhage, abscess formation, or sterile liquefaction of the tumor requiring percutaneous drainage or surgical intervention.
       • Extended follow-up after selective embolization is needed, which would not be required after partial nephrectomy
  3. Thermal ablation
     • Limited data on efficacy
       • Follow-up remains short, the evaluation of success remains poorly defined, and the duration for continued radiographic surveillance is unknown, thus committing the patient to multiple, long-term imaging
  4. Sirolimus
     • Has been investigated and can be used to reduce size of AML for possible surgery later

Papillary Adenoma

Epidemiology

• Incidence increases with age, male gender and acquired renal cystic disease that results in ESRD

Pathology

• Papillary architecture
• Lesions should be histologically ≤ 5mm and well circumscribed
• May be linked to development of papillary RCC and may represent a pre-malignant precursor

Diagnosis and Evaluation

• Commonly found at autopsy

Management

• Diagnosis remains controversial and many believe that all solid renal epithelium-derived masses are potentially malignant and should undergo treatment

Metanephric Adenoma

Epidemiology

• Rare
• Female predominance (F:M 2:1), peak incidence in the 5th decade, usually found incidentally

Pathology

• Wilms tumour marker WT1 is frequently expressed
• Α-Methylacyl-CoA racemase is poorly expressed, but highly expressed in papillary RCC
• S-100 protein is very high in metanephric adenoma, weak in Wilms tumour, and absent in papillary RCC

Diagnosis and Evaluation

• Polycythemia occurs in 10% of patients and may due to the production of erythropoietin and other cytokines by the tumor
• Primarily a pathologic diagnosis due to lack of highly predictive clinical and radiographic criteria; most patients will require surgical excision because of concern for malignancy

Cystic nephroma

• Complex cystic lesions that are typically classified as Bosniak II to III
• Appear to be genetically related to mixed epithelial and stromal tumors (MESTs) but generally have a somewhat different radiographic appearance.
  • Unlike MESTs, which contain a solid stromal component and often appear as solid or Bosniak IV lesions on cross-sectional imaging, cystic nephromas are typically characterized as complex cystic lesions without a solid component.
• Epidemiology
  • More common among females (F:M 8:1)
  • Diagnosis peaks primarily in the first 3 year of life predominantly in boys, and again in the 4th-5th decades (bimodal distribution)
• Management
  • Cannot reliably differentiate cystic nephroma from cystic RCC in adults or Wilms tumour in children, therefore often treated with surgery.
    • Because of concern for cystic Wilms tumor, most children with cystic nephromas continue to be managed by radical nephrectomy, whereas a nephron-sparing approach with partial nephrectomy, if feasible, is an option in adults

Mixed mesenchymal and epithelial tumours

• Female predilection and history of hormonal ablation therapy in male patients, combined with the frequent expression of estrogen and progesterone receptors, suggest that the sex-steroid hormones might play a role in the pathogenesis of these rare lesions

Mixed epithelial and stromal tumours

• Epidemiology
  • Rare; female predominance with a diagnostic peak in the 5th decade; should be considered in perimenopausal women receiving hormone therapy
• Pathology
  • Variable mix of epithelial and mesenchymal components
• Typically benign clinical course, but malignant transformations and recurrence have been described
• Radiographic appearance is of a complex cystic renal mass (Bosniak III to IV), indistinguishable from cystic RCC, therefore usually managed with surgical approach

Leiomyoma

• Characteristic appearance of a small exophytic renal mass with or without enhancement arising from renal capsule, but conclusive radiologic differentiation from RCC is not possible
• Pathology demonstrates intersecting fascicles of smooth muscle with no evidence of hypercellularity, pleomorphism, or mitotic activity

Other benign renal tumours

• Hemangioma, lymphangioma, juxtaglomerular cell tumour, renomedually interstitial cell tumour, intrarenal schwannoma, and solitary fibrous tumour; cannot be reliably distinguished radiographically from malignant lesions
• Juxtaglomerular cell tumor (also known as reninoma)
  • Characterized by hypersecretion of renin
  • Diagnosis and Evaluation
    • History and Physical Exam
      • Symptoms include hypertension, headaches, polydipsia, polyuria, and myalgia
    • Labs
      • HYPOkalemia

Questions

1. What are the risk factors for cyst formation?
2. Describe the Bosniak classification and the risk of malignancy of each category?
3. As the the 2017 CUA Guidelines on Cystic Renal Lesions, what is the management of each Bosniak class?
4. How does the prognosis for a multilocular cystic RCC compared to a solid RCC
5. What are the triggers for intervention for a Bosniak III cyst managed with active surveillance?

1. When should thermal ablation be considered for management of a complex renal cyst?
2. Which form of thermal ablation has been better studied for the treatment of complex renal cysts, RFA or cryotherapy?
3. Which kidney tumours demonstrate an abundance of cellular mitochondria?
4. What imaging characteristic is a diagnostic landmark for AML?
5. Which pathologic stain is diagnostic for AML?
6. When should intervention be considered for AML?
7. What is the clinical presentation of a patient with a juxtaglomerular cell tumour?

Answers

1. What are the risk factors for cyst formation?
   1. Age
   2. Male Gender
   3. Hypertension
   4. CKD
2. Describe the Bosniak classification and the risk of malignancy of each category?
   • I: simple cyst
   • II: thin septum, fine calcification; risk of malignancy 5%
   • IIF: thick septae, thick or nodular calcifications; risk of malignancy 30%
   • III: enhancing septae; risk of malignancy 55%
   • IV: enhancing solid component; risk of malignancy 90%
3. As the the 2017 CUA Guidelines on Cystic Renal Lesions, what is the management of each Bosniak class?
   • I and II: no follow-up
   • IIF: follow-up with imaging; imaging every 6 months in the first year then yearly for 5 years
   • III and IV: excise
4. How does the prognosis for a multilocular cystic RCC compared to a solid RCC
   • Multilocylar cystic RCC has favourable prognosis
5. What are the triggers for intervention for a Bosniak III cyst managed with active surveillance?

1. 1. Progression from Bosniak III to IV
   2. Growth of solid nodule >3cm
   3. Fast-growing nodule

1. When should thermal ablation be considered for management of a complex renal cyst?
   • Patients with small Bosniak category III and IV cysts who are poor operative candidates and in whom active surveillance is not being considered
2. Which form of thermal ablation has been better studied for the treatment of complex renal cysts, RFA or cryotherapy?
   • RFA
3. Which kidney tumours demonstrate an abundance of cellular mitochondria?
   • Oncocytoma
4. What imaging characteristic is a diagnostic landmark for AML?
   • Presence of fat (≤-20 HFU)
5. Which pathologic stain is diagnostic for AML?
   • HMB-45
6. When should intervention be considered for AML?
   1. Symptoms
   2. Tumour size >4cm
   3. Given risk of bleeding, which is increased in pregnancy, consider proactive approach in women of childbearing age or those with limited access to surveillance or emergent care
7. What is the clinical presentation of a patient with a juxtaglomerular cell tumour?
   • Hypertension with hypokalemia and associated symptoms of polydipsia, polyuria, myalgia, and headaches

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 56