Two11 97A Malignant Renal Tumors - Basics

• Strongly enhancing mass - 
• Clear cell RCC
• Angiomyolipoma
• Oncocytoma
• Papillary RCC (occasionally)
• Chromophobe RCC (occasionally)

• Moderately enhancing mass - 
• Papillary RCC
• Chromophobe RCC
• Clear cell RCC (occasionally)
• Oncocytoma
• Fat-poor angiomyolipoma
• Adenoma/metanephric adenoma
• Unifocal lymphoma

Multiple large, well-circumscribed, round pulmonary metastases that appear not unsurprisingly like cannonballs. (तोप को ball). Metastases with such an appearance are classically secondary to -

• - renal cell carcinoma
• - choriocarcinoma

• Triple phase CECT of abdomen and chest for the diagnosis and staging of renal tumours - EAU. In usual practice, we do CT chest if disease is T2 or more
• Use magnetic resonance imaging to better evaluate venous involvement - recent literature says  it is equal as compared to CT
• Do not use PET

CE USG was found to be better than CT in diagnosis of malignancy in complex renal masses / equvocal renal masses which are not even clear in CT or MRI - Recommened by EAU

• Noncontrast - fat, calcification, hemorrhage detection 
• 20 -  30 seconds -  arterial
• 30-70 -  corticomedullary, assess hypervascular enhancement of lesion, differentiate tumor from pseudotumor 

(for fast memorization, use 0, 40, 80 seconds and 8 minutes, for non contrast, corticomedulary, nephrogenic, and excretory phase) 

80 to 120 - Nephrographic, best for renal tumors, tumor detection, thrombus detection

3 minutes - excretory, TCC detection


Reaches to bladder in 20-30 minutes, absence of contrast excretion 24 hours after intravenous contrast injection indicates non functioning kidney

Enhancement >15HU is RCC, If we take 20HU as cutoff, some RCC may be missed. So, we take cutoff of 15 as cutoff, and evaluate the lesions so that we dont miss any probable malignant lesions. Clear cell RCC enhance >100HU on contrast enhancement. To take the papillary variants and chromophobe variants, which enhance 15-20 HU, this cutoff has been taken

• Note 
• - Absence of contrast excretion 24 hours after intravenous contrast injection indicates a nonfunctioning kidney. 

Always do the all the phases, as near to surgery as possible. Suhasha Acharya, case of osteosarcoma mets to the Kidney with IVC thrombus, missed , after 1 month of surgery, was found to have 8 cm pelvic bone mass. She had preoperative CT chest and upper cuts of MRI, so pelvis mass was missed. USG was done to rule out pelvic tumors, but missed bone mass.

• 
• Ball-type lesions - present as expansile masses, deforming the renal contour.
• Bean-type lesions - do not deform the renal contour and the bean-shape of the kidney is preserved. The bean-type masses are invisible on unenhanced images and are best appreciated on nephrographic and excretory phase images. Collecting system elements are destroyed by the bean-type masses
• Look the PCS in excretory phase, to look for the PCS -  to differentiate RCC and UTUC

• For cystic and indeterminate solid tumors 
• can be used in impairment 

• 
• In prostate cancer, T2 phase is more important, in RCC, T1 is more important 

• Gadolonium contrast, if very enhancement, clear cell, if not so enhancement - then papillary
• Enhancement of greater than 20% with intravenous  gadolinium-based contrast on MRI is suggestive of RCC

Although MRI has been recommended as the test of choice for IVC thrombus at most centers, many studies have demonstrated that a properly performed multiplanar CT also provides sufficient information for surgical planning, and it has become the preferred diagnostic study at many centers.

• E. Clear cell carcinoma
• Microscopic intracytoplasmic lipids have been found in 59% of clear cell carcinomas, which allows it to be differentiated from other renal cell carcinoma cell types

urothelial cancer, lymphoma, infectious processes, and high-grade or sarcomatoid RCC commonly demonstrate infiltrative growth patterns and indistinct borders on imaging

Unlike upper tract urothelial carcinomas, most RCCs are not grossly infiltrative, with the notable exception of collecting duct carcinoma and sarcomatoid variants

Poor PS can be used to segregate patients when deciding whether to obtain a bone scan for metastatic RCC. Shvarts and colleagues (2004) a have shown that patients with good PS (ECOG PS = 0), no evidence of extraosseous metastases, and no bone pain were extremely low risk for bone metastasis and did not benefit from bone scanning. They recommended a bone scan for all other patients, and the incidence of bone metastasis in this group was >15%

Unlike for most other malignancies, application of FDG PET/CT is limited for RCC, mainly due to physiological excretion of FDG from the kidneys, which decreases contrast between renal lesions and normal tissue, and may obscure or mask the lesions of the kidneys. 

FDG PET/CT can be effectively used for postoperative surveillance and restaging with high sensitivity, specificity, and accuracy, as early diagnosis of recurrent/metastatic disease can drastically affect therapeutic decision and alter outcome of patient - ref? 

124I-girentuximab, which targets carbonic anhydrase IX primarily present on clear cell RCC, and PSMA (epithelial membrane target) remain in development for clear cell RCC.

Smoking - RR 2.5, strongest risk factor for RCC is tobacco exposure

Obesity - RR increases by 1.07 for each additional unit of BMI, mechanism - increased IGF-1, increased estrogen level, increased arteriolar nephrosclerosis, local inflammation

HTN - mechanism - HTN induced renal injury, changes in renal tubules increases susceptibility to carcinogens

ESRD - RR is 5-20 folds higher than general population

4-6% of patients with RCC have a familial syndrome

• Clear - 3p25-26
• HPRCC (Type 1)  - 7,17 trisomy, loss of Y 
• HLRCC (Type 2) - 1q42-44, site of the fumarate hydratase (FH) gene
• SDH-RCC
• BHD - 17p, 12q
• Cowden - PTNE - 10q

All Autosomal dominant

Familial - HLRCC, SDH-RCC, [@ Succinate Sucks, Leio लियो ज्यान लियो  

Medullary > collecting duct > Clear > Papillary > Chromophobe

Correlate Medullary with sickle cell - hypoxia in medulla - sickling

More recent reports have demonstrated a good prognosis for a subset of patients with SDH-RCC, particularly when low-grade features predominate. Tumors with high-grade, coagulative necrosis, or sarcomatoid features are more likely to behave aggressively.

• HPRCC does not develop tumours in other organ systems
• The autosomal dominant mode of transmission
• VHL is caused by inactivation or mutation of a tumour suppressor gene, whereas HPRC is caused by activation of an oncogene.

• Penetrance for RCC in HLRCC is lower than for the cutaneous and uterine manifestations, with only a minority (20%) of patients developing RCC.
• In contrast, almost all individuals with this syndrome will develop cutaneous leiomyomas and uterine fibroids (if female), usually manifesting at the age of 20 to 35 years.
• A high proportion of women have had a hysterectomy for fibroids before formal diagnosis of HLRCC

• HLRCC are unusual for familial RCC in that they are 
• - often solitary and unilateral
• - more likely to be aggressive than other forms of familial RCC

- Aggressive form of type 2 papillary renal cell cancer. Collecting duct RCC - additional histological subtype indicative for the syndrome.

• Cutaneous fibrofolliculomas
• Lung cysts
• Spontaneous pneumothoraces, and a variety of renal tumors

The renal tumors typically include chromophobe RCC, oncocytomas, and hybrid oncocytic tumors that exhibit features of both of these entities. 

Derived from the distal nephron 17 chromosome - produce folliculin which interfere mTOR pathway. When folliculin is inactivated, mTOR activated

Fibrofolliculomas are 2 to 4 mm in diameter, dome-shaped, yellowish or skin-colored papules usually located on the head, neck, and upper trunk. Characteristics of BHD.

• 50% lifetime risk of female breast cancer
• 34% lifetime risk of RCC,
• 10% lifetime risk of epithelial thyroid carcinoma

[@ cowten - pten - Chromosome 10]

A form of modified cellular metabolism based on aerobic fermentation found in cancer cells, which tend to favor anaerobic glycolysis rather than the oxidative phosphorylation pathway which is the preference of most other cells of the body

• 
• Found in HLRCC, SDH-RCC

Expression of multidrug resistance - Contributes to chemorefractory nature of RCC

Immunogenic 

Angiogenic

Dependence on mTOR pathway

• CMP - From PCT 
• CMC  - From Collecting duct
• Post neuroblastoma RCC 
• Mucinous tubular and spindle cell carcinoma 

Cystic RCC has better prognosis compared to solid RCC

• Previously, Sarcomatoid was kept as separate entitity, but now it is commented as presence and extent of sarcomatoid differentiation. 
• Sarcomatoid lesions represent poorly differentiated regions of other histologic subtypes of RCC rather than independently derived tumors
• Sarcomatoid differentiation is characterized by spindle cell histology, positive staining for vimentin, infiltrative growth pattern, aggressive local and metastatic behavior, and poor prognosis.
• Invasion of adjacent organs is common

Sarcomatoid differentiation is most commonly found in association with clear cell and chromophobe RCC

• Clear cell - 70-80%
• Papillary - 10-15%
• Chromophobe - 5% 
• Collectig duct - 1%
• Medullary - Rare

• Clear cell - golden yellow, highly vascular, necrosis
• Papillary - Pale brown (beige) - fleshy color, frequent hemorrhage (that may appear cystic  radiologically), multicentricity, less vascular due to lack of VHL mutation
• Chromophobe, oncocytoma - Tan colored [@ Does not like color, is black] 
• Collecting duct - centrally located tumor with infiltrative border
• Medullary carcinoma - arise from the calyceal epithelium near the renal papillae but is often highly infiltrative

• Clear - round, abundant cytoplasm
• Type I papilary - Basophilic 
• Type II Papillary - eosinophilic 
• Chromophobe - transparent cytoplasm with Plant cell appearence, stain Hale colloid iron

Plant cell like - flocculent cytoplasm (pale or reticulated, not-optically clear as in clear cell RCC) that condenses around the edges, giving the appearance of thick prominent cell borders ("plant cell-like")

• Extremely rare <100 cases reported 
• Typically diagnosed in young African Americans, often in the third decade of life.
• Extremely aggressive, nearly all patients metastatic 
• Does not respond to chemo/immunotherapy 
• Occurs almost exclusively in association with sickle cell trait

People with sickle cell trait carry only one copy of the altered hemoglobin gene and rarely have any clinical symptoms related to the disease. In contrast, people with sickle cell disease carry two copies of the altered hemoglobin gene.

Most collecting duct carcinomas are centrally located and exhibit an infiltrative growth pattern and aggressive clinical course, but this is also true for poorly differentiated TCCs of the renal pelvis or centrally located sarcomatoid RCC.

Ulex europaeus lectin is expressed by the normal collecting duct, and tumor staining suggests origin from this structure.

Collecting duct RCC is not typically responsive to chemotherapy

Expressed always in Clear cell RCC, rare in other variants 

Also called as MN9 

In normal renal parenchyma, expression is suppressed by wild type VHL protein

• Nucleus - 10-20 micron
• Nuclear outline - round uniform to bizzare 
• Nucleoli - Absent to Prominent

Fuhrman's system was the most frequently used system for more than three decades but was not reliable for  chromophobe RCC and has not been validated for the newer subtypes of renal carcinoma.

Validated for clear cell and papillary RCC and is now the recommended grading system for RCC 

• 1 Nucleolus are absent or inconspicuous and basophilic at 400× magnification 
• 2 Nucleoli are conspicuous and eosinophilic at 400× magnification and visible but not prominent at 100× magnification
• 3 Nucleoli are conspicuous and eosinophilic at 100× magnification
• 4 There is extreme nuclear pleomorphism, multinucleated giant cells, and/or rhabdoid and/or sarcomatoid differentiation

• Note - 
• - Sarcomatoid and rhabdoin (S/R) RCC are highly aggressive tumors and most patients with S/R RCC present with metastatic disease. Emerging evidence suggests immune checkpoint inhibitors are particularly effective for these tumors.