Renal Cell Carcinoma

Slide 1 · Renal Cell Carcinoma

Pathogenesis • morphology • clinical correlations

A pathology teaching lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Distinguish major renal cell carcinoma subtypes by molecular and histologic features.

Explain how VHL inactivation alters hypoxia signaling and tumor vascularity.

Recognize the major familial predisposition syndromes.

Connect anatomic behavior with hematuria, venous invasion, and metastasis.

Interpret clinicopathologic clues in focused case examples.

Slide 3 · Renal carcinoma in context

RCC is the dominant malignant epithelial tumor of the adult kidney

RCC accounts for approximately 85% of adult renal cancers in the source textbook.

Renal pelvic urothelial carcinoma is a different epithelial malignancy.

Tumor classification integrates architecture with cytogenetic and genetic changes.

Slide 4 · Demographic profile

Most RCCs occur in the sixth and seventh decades.

The source reports an approximately 2:1 male predominance.

Most tumors arise sporadically rather than through inherited syndromes.

An appreciable minority presents before symptoms develop, because of incidental imaging.

Slide 5 · Risk factors: Exposure and host

Potentially modifiable factors

Tobacco use is emphasized as a major risk factor.

Obesity and hypertension have been associated with RCC.

Occupational/environmental exposures reported include petroleum products and heavy metals.

Renal disease settings

Chronic kidney disease and end-stage kidney disease increase risk.

Acquired cystic kidney disease is an important association.

Tuberous sclerosis is included among predisposition settings.

Slide 6 · A framework for renal carcinogenesis

Host and exposure

Genetic predisposition or acquired risk

Driver alteration

Tumor-suppressor loss or oncogene gain

Cellular program

Angiogenesis, growth, altered metabolism

Tumor phenotype

Subtype-specific morphology and behavior

Slide 7 · Sporadic and familial RCC

Sporadic carcinomas

Form the great majority of RCC cases.

Frequently involve somatic changes in subtype-specific drivers.

Most clear cell RCCs are sporadic.

Familial predisposition

Usually autosomal dominant in the syndromes discussed.

Often presents earlier in life.

Bilaterality and multiplicity can suggest inherited susceptibility.

Slide 8 · Inherited syndromes: Practical clues

Young age or multifocal bilateral disease warrants attention to hereditary susceptibility.

Extrarenal manifestations often identify a specific constitutional syndrome.

Inherited syndromes clarify the oncogenic pathways used by sporadic tumors.

Absence of family history does not exclude a genetically defined renal tumor.

Slide 9 · Four important hereditary associations

VHL syndrome

Renal cysts and often bilateral, multiple clear cell renal carcinomas.

FH deficiency

Leiomyomas and an aggressive FH-deficient renal cancer phenotype.

Hereditary papillary RCC

Multiple bilateral papillary tumors; Activating MET alterations.

Birt–Hogg–Dubé syndrome

Skin lesions, pulmonary cysts, and morphologically diverse renal tumors.

Slide 10 · VHL syndrome and renal tumors

Germline VHL defect

Autosomal dominant predisposition

Additional VHL loss

Tumor-suppressor function is lost

HIF dysregulation

Hypoxia-responsive programs persist

Clear cell RCC

May be multiple and bilateral

Slide 11 · FH-deficient renal cell carcinoma

The FH gene encodes fumarate hydratase, a Krebs-cycle enzyme.

Loss-of-function is associated with hereditary leiomyomatosis and RCC syndrome.

Skin and uterine leiomyomas may accompany the renal tumor.

The kidney tumor can be aggressive with a propensity for metastasis.

FH-deficient RCC may occur without an evident hereditary family history.

Slide 12 · FH loss links metabolism with carcinogenesis

FH loss

Deficiency of fumarate hydratase

Metabolic disruption

Krebs-cycle perturbation

Tumorigenic state

Altered cellular metabolic environment

Aggressive RCC

FH-deficient renal carcinoma

Slide 13 · Hereditary papillary renal carcinoma

Typically an autosomal dominant predisposition.

Multiple bilateral papillary renal tumors are characteristic.

Activating mutations of MET are the central genetic feature.

Tumors are often relatively low nuclear grade in the reported syndrome.

Slide 14 · Birt–Hogg–Dubé syndrome

Loss of folliculin function results from mutations of the BHD/FLCN gene.

Cutaneous findings include fibrofolliculomas and related papules.

Pulmonary cysts or blebs are part of the syndrome.

Renal tumors can show different morphologic patterns rather than one uniform subtype.

Slide 15 · Hereditary syndromes compared

Syndrome

Gene / pathway

Diagnostic context

von Hippel–Lindau

VHL; HIF signaling

Cysts; multifocal/bilateral clear cell RCC

FH-deficient RCC

FH; metabolic enzyme

Cutaneous/uterine leiomyomas; aggressive RCC

Hereditary papillary

MET activation

Bilateral multifocal papillary RCC

Birt–Hogg–Dubé

BHD / folliculin

Skin papules, lung cysts, renal tumors

Slide 16 · Principles of subtype classification

Histology is interpreted together with cytogenetic and genetic findings.

Clear cell, papillary, and chromophobe RCC are major categories.

TFE3-rearranged RCC and collecting duct carcinoma are less common examples.

Sarcomatoid change may arise across several RCC subtypes; It is not a single lineage.

Slide 17 · Major renal cell carcinoma subtypes

Subtype

Approximate share

Hallmark

Clear cell

70–80%

VHL/3p abnormalities; clear nests

Papillary

10–15%

7/17 gains; papillae; MET subset

Chromophobe

~5%

Multiple chromosome losses; perinuclear halo

Collecting duct

≤1%

Medullary glands with desmoplasia

Slide 18 · Clear cell RCC: The predominant subtype

Constitutes approximately 70–80% of RCC in the source.

Believed to arise predominantly from proximal tubular epithelium.

Usually presents as a solitary unilateral tumor.

Growth patterns include nested, tubular, solid, and pseudopapillary forms.

VHL pathway loss is a central oncogenic event.

Slide 19 · Clear cell RCC: Gross architecture

Gross-anatomic interpretation

Polar tumor location

Distortion of renal outline

Necrosis and hemorrhage may coexist

Simplified kidney cross-section: Diagrammatic location and spread (not a gross specimen)

Slide 20 · Clear cell RCC: Gross specimen clues

A rounded, well-demarcated cortical tumor may distort the kidney.

Bright yellow coloration reflects lipid accumulation in tumor cells.

Hemorrhagic and gray-white necrotic regions are frequent.

The tumor may contain cystic areas or more extensive hyalinization.

Gross appearance alone does not establish histologic subtype.

Slide 21 · Clear cell RCC: Nested architecture

What to recognize

Cells are polygonal or rounded.

Clear or granular cytoplasm reflects lipid and glycogen content.

Fine branching vessels separate tumor nests.

Nuclear atypia varies from mild to striking.

Schematic architecture only — not a histologic specimen

Slide 22 · Why does clear cell cytoplasm look clear?

Neoplastic cells accumulate lipids and glycogen.

Routine tissue processing removes much of the cytoplasmic lipid.

The remaining pale cytoplasm creates the diagnostic “clear cell” appearance.

This cytoplasmic phenotype must be interpreted with architecture and context.

Slide 23 · VHL: The two-hit tumor-suppressor model

First VHL event

Deletion or inherited defective allele

Second VHL event

Mutation or epigenetic silencing

VHL loss

Ubiquitin ligase function impaired

HIF persistence

Growth and angiogenic programs increase

Slide 24 · Oxygen sensing: Intact VHL versus loss

With functional VHL

In the presence of adequate oxygen, HIF is targeted for proteolysis.

HIF-dependent transcription is restrained.

This oxygen-sensitive mechanism limits angiogenic signaling.

With VHL inactivation

HIF degradation becomes impaired even with adequate oxygen.

Persistent HIF stimulates transcription of target genes.

VEGF and growth-promoting programs become inappropriately active.

Slide 25 · VHL loss leads to angiogenesis

VHL inactivated

Reduced HIF degradation

HIF accumulation

Hypoxia signaling persists

VEGF expression

Angiogenic program activated

Tumor vasculature

Conspicuous delicate vascular network

Slide 26 · HIF controls more than angiogenesis

HIF-dependent gene expression includes VEGF, a major angiogenic factor.

Insulin-like growth factor-1 is among growth-promoting outputs noted in the text.

HIF interacts with MYC-driven metabolic programs.

The biological outcome is a microenvironment that favors tumor growth.

Slide 27 · Clear cell RCC: Genotype to phenotype

Genetic findings

3p25.3 loss includes the VHL locus.

Somatic VHL mutation or silencing can remove the second allele.

Alterations in chromatin-regulatory genes are also frequent.

Morphologic outputs

Lipid-rich cells create the pale, yellow gross cut surface.

Clear cells grow in nests with a delicate vascular meshwork.

The tumor can show necrosis, hemorrhage, and venous invasion.

Slide 28 · Epigenetic remodeling in clear cell RCC

Genomic studies have identified mutations involving histone-modification regulators.

Epigenetic dysregulation provides an additional route to abnormal gene expression.

VHL/HIF remains a core pathway but is not the entire molecular explanation.

Altered chromatin regulation contributes to biologic heterogeneity.

Slide 29 · Clear cell RCC: Integrated mechanism

VHL loss → persistent HIF signaling → angiogenic and growth-promoting transcription

The vascular phenotype and molecular pathway reinforce one another.

Histologic identity still rests on the combined morphology and context.

Targeted therapy rationale follows pathway biology, not morphology alone.

Slide 30 · Papillary RCC: General profile

Accounts for roughly 10–15% of RCCs.

Architecture may be papillary, tubulopapillary, or solid.

Sporadic and familial forms both occur.

Multifocal tumors are more frequent than in clear cell RCC.

The characteristic cytogenetic pathway differs from 3p/VHL loss.

Slide 31 · Papillary RCC: Epithelial fronds

What to recognize

Papillae contain fibrovascular cores.

Cuboidal or low-columnar epithelial cells cover the fronds.

Foamy macrophages may occupy papillary stalks.

Psammoma bodies may occur.

Schematic architecture only — not a histologic specimen

Slide 32 · Papillary RCC: Gross features

Can be bilateral or multifocal.

Larger lesions are commonly hemorrhagic and cystic.

The architecture includes papillae but is not limited to them.

Foamy histiocytes and psammoma bodies reinforce the microscopic impression.

Slide 33 · Papillary RCC: Cytogenetic associations

Gain of chromosome 7

A recurrent finding in both familial and sporadic papillary RCC.

Gain of chromosome 17

Frequently observed in sporadic papillary RCC.

Loss of Y chromosome

Additional recurring alteration in tumors from male patients.

MET activation

Germline event in hereditary papillary RCC; Somatic in a subset.

Slide 34 · MET activation in hereditary papillary RCC

MET gain of function

Receptor tyrosine kinase activated

HGF–MET signaling

Growth factor receptor program

Cell behavior

Growth, motility, invasion, morphogenesis

Renal tumor

Papillary carcinoma predisposition

Slide 35 · Papillary RCC: Familial versus sporadic

Hereditary cases

Germline MET activation defines classic hereditary papillary carcinoma.

Often multifocal and bilateral.

Chromosome 7 gain is described.

Sporadic cases

Frequently show gains of chromosomes 7 and 17.

Loss of chromosome Y may occur in men.

MET mutations affect only a subset.

Slide 36 · Papillary adenoma: Close morphologic mimic

Small cortical papillary adenomas can resemble low-grade papillary RCC.

The source describes lesions typically less than 1.5 cm.

They may share gains of chromosomes 7 and 17 with papillary RCC.

Size, context, and recognized diagnostic criteria are essential to classification.

This is a practical overlap within the renal neoplasm spectrum.

Slide 37 · Chromophobe RCC: Defining profile

Represents approximately 5% of RCCs.

Believed to arise from collecting-duct intercalated cells.

Tumor cells have conspicuous membranes and pale eosinophilic cytoplasm.

A perinuclear halo is a common cytologic feature.

Prognosis is generally more favorable than clear cell or papillary RCC.

Slide 38 · Chromophobe RCC: Cell borders and halos

What to recognize

Large polygonal epithelial cells form solid sheets.

Cell borders are particularly conspicuous.

Perinuclear halos interrupt pale eosinophilic cytoplasm.

Chromosome loss is a major molecular correlate.

Schematic architecture only — not a histologic specimen

Slide 39 · Chromophobe RCC: Chromosomal pattern

The hallmark is extensive chromosomal loss with marked hypodiploidy.

This differs from the 3p/VHL loss pattern of clear cell RCC.

It also differs from the recurrent gains in papillary RCC.

Interpret chromosomal data together with cell morphology.

Slide 40 · Chromophobe RCC versus renal oncocytoma

Chromophobe carcinoma

Prominent membranes and perinuclear halos.

Multiple chromosome losses are characteristic.

Despite relatively favorable prognosis, it remains malignant.

Renal oncocytoma

Benign epithelial neoplasm with eosinophilic, mitochondria-rich cells.

Often homogeneous tan or mahogany-brown grossly.

Overlapping oncocytic appearance can complicate histologic assessment.

Slide 41 · TFE3-rearranged renal cell carcinoma

Genetically defined by rearrangements involving TFE3 at Xp11.2.

Often encountered in younger patients.

Different partner genes may produce different architectural patterns.

Histology may be nested, solid, or tubulopapillary.

TFE3 overexpression reflects the underlying rearrangement.

Slide 42 · TFE3-rearranged RCC: Diagnostic reasoning

Clinical context

Young patient with a renal epithelial malignancy.

Morphologic spectrum

Nested, solid, or tubulopapillary architecture; Not pathognomonic alone.

Molecular definition

Rearrangement involving the TFE3 gene at Xp11.2.

Slide 43 · Collecting duct carcinoma: A rare aggressive pattern

Roughly 1% or less of renal epithelial tumors in the source.

Arises from collecting duct structures in the renal medulla.

Infiltrative glands are set in abundant desmoplastic stroma.

The epithelium is markedly atypical; Hobnail lining can be seen.

Anatomic location and stromal response are important clues.

Slide 44 · Collecting duct carcinoma: Medullary glands

What to recognize

Medullary location is an important context clue.

Irregular glands or channels infiltrate stroma.

The tumor epithelium is highly atypical.

A conspicuous desmoplastic reaction surrounds glands.

Schematic architecture only — not a histologic specimen

Slide 45 · Renal medullary carcinoma: Important association

Medullary carcinoma as morphologically similar to collecting duct carcinoma.

The association with sickle cell trait is diagnostically important.

The designation should not be inferred solely from medullary location.

This differential requires integrated clinical and pathologic assessment.

Slide 46 · Morphology-based subtype comparison

Feature

Clear cell

Papillary

Chromophobe

Dominant pattern

Nests and delicate vessels

Papillae / tubules

Solid sheets

Cytoplasm

Clear or granular

Usually cuboidal cells

Pale eosinophilic

Key clue

Fine vascular network

Foamy macrophages

Perinuclear halos

Genetic theme

3p / VHL

7/17 gains; MET subset

Multiple losses

Slide 47 · Sarcomatoid change: A cross-subtype warning

Sarcomatoid transformation can occur in several RCC subtypes.

It is associated with a markedly adverse prognosis.

The finding describes dedifferentiation rather than a separate tubular cell lineage.

Areas of spindle-cell morphology require correlation with an epithelial RCC component.

Slide 48 · RCC and renal vein invasion

Gross-anatomic interpretation

Renal vein invasion

Extension toward the vena cava

Potential intravascular tumor column

Simplified kidney cross-section: Diagrammatic location and spread (not a gross specimen)

Slide 49 · Why venous invasion matters

Clear cell RCC may extend as a solid tumor column within the renal vein.

Contiguous intravascular growth can reach the inferior vena cava.

Rarely, extension may approach the right side of the heart.

Venous spread changes surgical and prognostic assessment.

Do not equate visible venous extension with distant metastasis.

Slide 50 · How RCC extends locally

Expanding tumors distort the renal parenchyma and may approach the capsule.

Bulging into the calyceal system may produce collecting-system involvement.

Advanced tumors may extend into the renal pelvis or ureter.

Anatomic tumor extent is distinct from the histologic subtype.

Slide 51 · The classic clinical triad

Hematuria + flank pain + palpable mass

All three occur together in only a minority of cases (~10% in the source).

Hematuria may be intermittent or only microscopic.

Absence of the complete triad does not exclude substantial disease.

Slide 52 · Hematuria: The key local symptom

Hematuria as a reliable clinical clue.

Bleeding may be intermittent and escape attention.

Microscopic hematuria can precede obvious urinary symptoms.

An occult lesion may grow for years before becoming clinically apparent.

Slide 53 · Why RCC is often discovered incidentally

Many tumors produce no local signs at early stages.

Cross-sectional imaging is frequently performed for unrelated reasons.

Incidental CT or MRI therefore detects a growing share of RCCs.

Imaging discovery does not replace tissue-based subtype classification.

Slide 54 · Constitutional manifestations

Fever, malaise, weakness, and weight loss can dominate the presentation.

Advanced disease may cause systemic symptoms before focal renal symptoms.

This clinical diversity contributes to RCC being a “great mimic.”

Constitutional findings are nonspecific and require clinical context.

Slide 55 · Paraneoplastic manifestations: Map the syndrome

Hematologic

Polycythemia, eosinophilia, or leukemoid reactions

Mineral and vascular

Hypercalcemia and hypertension

Hepatic / endocrine

Hepatic dysfunction, Cushing syndrome, or sexual-hormone effects

Protein deposition

Amyloidosis may occur

Slide 56 · Two systemic manifestations to recognize

Polycythemia

Renal neoplasm can be associated with inappropriate hormone production.

Unexpected erythrocytosis may accompany an occult tumor.

Correlate blood findings with renal imaging and clinical context.

Hypercalcemia

A recognized systemic syndrome of RCC.

Can contribute to nonspecific weakness and systemic illness.

Requires evaluation beyond the local renal tumor findings.

Slide 57 · RCC: Metastatic behavior

Renal cell carcinoma may metastasize before local symptoms develop.

The text reports radiologically evident metastasis in approximately 15% at diagnosis.

Lung and bone are major sites of distant involvement.

Other metastatic destinations include nodes, liver, adrenal glands, and brain.

Slide 58 · Clinical progression is not always linear

Silent renal mass

May be discovered incidentally

Intravascular spread

Renal vein or vena cava involvement

Hematogenous spread

Lung and skeletal metastases

Systemic disease

Constitutional or paraneoplastic signs

Slide 59 · Common metastatic sites

Site

Clinical implication

Lungs

Frequent distant target; chest assessment is important

Bone

May present with pain or pathologic fracture

Regional lymph nodes

Locoregional dissemination

Liver, adrenal, brain

Potential extrapulmonary disease sites

Slide 60 · Prognosis: Stage and spread matter

Absence of distant metastasis is associated with substantially better survival.

Extension to renal vein or perinephric fat worsens prognosis.

Sarcomatoid differentiation is an adverse microscopic feature.

Histologic type contributes to risk but cannot replace anatomic assessment.

Slide 61 · Prognostic assessment: Separate the axes

Anatomic extent

Organ-confined versus local extension and venous invasion

Distant dissemination

Metastatic disease fundamentally changes prognosis

Histologic biology

Subtype and sarcomatoid differentiation affect behavior

Clinical state

Symptoms and systemic effects influence clinical management

Slide 62 · Treatment principles in the source

Surgery is central for localized RCC.

Nephron-sparing surgery is recommended for small T1a lesions where feasible.

Additional tumors may be suitable for renal-preserving resection if technically possible.

VEGF/kinase-directed agents and immunotherapy are discussed for advanced disease.

Drug sequencing and current treatment algorithms require separate guideline verification.

Slide 63 · A case of hematuria without the triad

A 62-year-old has episodic microscopic hematuria and no palpable renal mass

Would absence of flank pain and a palpable mass exclude RCC?

What investigation commonly reveals clinically silent renal tumors?

Which renal tumor can invade the renal vein while remaining relatively well circumscribed?

Slide 64 · Case resolution: Hematuria and a renal mass

No: The complete triad occurs in only a minority of patients.

Cross-sectional imaging often detects occult renal masses.

Clear cell RCC has a notable tendency for renal vein invasion.

The combination of imaging findings and pathology establishes tumor context.

Slide 65 · A case of bilateral papillary tumors

A young adult has multiple papillary renal tumors in both kidneys

Which inherited syndrome becomes a major consideration?

Which proto-oncogene is characteristically activated?

Which chromosomal gains commonly characterize the papillary pathway?

Slide 66 · Case resolution: Hereditary papillary RCC

Hereditary papillary renal carcinoma should be considered.

Activating MET mutations define the classical familial form.

Chromosome 7 gain is seen; Sporadic tumors often also gain chromosome 17.

Multifocality and bilaterality are important clinical clues.

Slide 67 · High-yield differential: RCC versus pelvic urothelial cancer

Renal cell carcinoma

Tumor of renal parenchymal epithelial lineage.

Clear cell, papillary, chromophobe, and other subtypes.

Venous invasion and distant spread are important behaviors.

Renal pelvic urothelial carcinoma

Originates from urothelium of the collecting-system pelvis.

May cause early hematuria or urinary obstruction.

Histologically parallels urothelial neoplasia of the bladder.

Slide 68 · Morphology → mechanism → clinical behavior

Clear cell

VHL/HIF dysregulation → vascular clear-cell nests → venous invasion

Papillary

Chromosome 7/17 changes ± MET → papillary cores → often multifocal

Chromophobe

Multiple chromosomal losses → pale cells with halos → favorable relative outcome

Collecting duct

Medullary origin → desmoplastic infiltrating glands → aggressive presentation

Slide 69 · Five principles to retain

Histology and genetics jointly define RCC subtypes.

VHL loss stabilizes HIF and links clear cell RCC to angiogenesis.

MET activation characterizes classic hereditary papillary RCC.

Chromophobe RCC has prominent membranes, perinuclear halos, and multiple losses.

Venous invasion and occult metastatic spread are central to clinical assessment.

Slide 70 · References

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. Chapter 20: The Kidney. Renal cell carcinoma, pp. 863–865.

Adjacent source context: Renal papillary adenoma and renal oncocytoma, pp. 862–863; urothelial carcinoma of renal pelvis, p. 865.

Textbook Fig. 20.46 summarizes the genetic patterns of clear cell and papillary RCC.

Textbook Figs. 20.47–20.48 depict gross and histologic RCC morphology.