Malignant Neoplasms

Slide 1 · Malignant Neoplasms of the Kidney

Renal cell carcinoma: carcinogenesis, morphology, and clinicopathologic interpretation

Medical pathology lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Classify malignant renal epithelial tumors using morphology and molecular alterations.

Explain how VHL loss stabilizes HIF and promotes clear cell carcinogenesis.

Recognize major hereditary syndromes and their renal tumor associations.

Link gross and microscopic findings to clinical manifestations and routes of spread.

Interpret major prognostic patterns and distinguish RCC from renal pelvic urothelial carcinoma.

Slide 3 · Two major epithelial locations

Renal tubular epithelium

Renal cell carcinoma

Renal pelvic urothelium

Urothelial carcinoma

Most of this lecture: Renal cell carcinoma. Pelvic tumors are contrasted briefly, then taught separately.

Slide 4 · The clinical burden of renal cell carcinoma

Adult renal cancers

~85%

Represented by RCC

New US cancers

~3%

RCC contribution

Sex ratio

2 : 1

Male predominance

Textbook epidemiologic estimates (11th edition); Figures may change across populations and years.

Slide 5 · Age distribution and clinical context

RCC occurs most often in the sixth and seventh decades of life.

Men are affected approximately twice as often as women.

Many cancers are sporadic and arise without a recognizable inherited syndrome.

Hereditary disease commonly presents at a younger age and may be bilateral or multifocal.

Slide 6 · Tobacco exposure: The principal risk factor

Tobacco exposure

Higher RCC risk

Risk recognition and prevention

Smoking as the most significant risk factor and reports an approximately twofold incidence among cigarette smokers.

Slide 7 · Recognized risk contexts

General risk associations

Occupational or environmental

Obesity; Stronger association noted in women.

Hypertension.

Unopposed estrogen therapy.

Asbestos exposure.

Petroleum products.

Heavy metals.

Slide 8 · Renal disease also changes cancer risk

Chronic kidney disease

ESKD or acquired cysts

Increased RCC susceptibility

Robbins additionally identifies tuberous sclerosis as an increased-risk condition.

Slide 9 · Sporadic and inherited renal cancer

Sporadic cases

Hereditary cases

Comprise the large majority of RCC.

Often solitary and unilateral.

Acquired somatic changes may target the same genes as familial disease.

About 4% of RCC in the source.

Often present at younger age.

Bilateral, multiple neoplasms are characteristic of several syndromes.

Slide 10 · When should an inherited syndrome be considered?

A young patient with a renal malignancy warrants evaluation of hereditary context.

Multiple or bilateral renal tumors increase suspicion of a familial predisposition.

Associated skin, pulmonary, or uterine findings can provide syndromic clues.

The specific histologic and molecular subtype helps direct further classification.

Clinical interpretation based on Robbins pp. 863–864; No formal genetic-testing algorithm supplied.

Slide 11 · Hereditary RCC syndromes: Molecular map

Syndrome

Altered gene

Renal/other clue

von Hippel–Lindau

VHL

Multiple, bilateral RCCs and renal cysts

FH-deficient RCC syndrome

FH

Cutaneous/uterine leiomyomas; aggressive RCC

Hereditary papillary RCC

MET

Multiple bilateral papillary tumors

Birt–Hogg–Dubé

BHD / folliculin

Skin fibrofolliculomas; lung cysts; varied renal tumors

Slide 12 · VHL syndrome: Renal manifestations

Autosomal dominant tumor predisposition associated with loss of VHL function.

Renal cysts and often multiple bilateral RCCs can develop.

Renal involvement in one-half to two-thirds of affected people; Penetrance rises with age.

The VHL pathway is also commonly inactivated in sporadic clear cell RCC.

Slide 13 · VHL provides a mechanistic bridge

Inherited VHL lesion

Loss of remaining VHL activity

HIF dysregulation

Clear cell RCC

Inherited VHL disease illustrates how loss of tumor suppressor function alters HIF-dependent gene expression.

Slide 14 · FH-deficient renal cell carcinoma

Hereditary leiomyomatosis and RCC syndrome is autosomal dominant.

Loss-of-function alterations affect FH, encoding fumarate hydratase.

Associated tumors may be high-grade and aggressive with metastatic propensity.

The descriptive entity FH-deficient RCC also includes cases without a family history.

Slide 15 · Fumarate hydratase connects metabolism and cancer

FH loss of function

Krebs-cycle enzyme deficit

Altered cellular metabolism

Renal carcinogenesis

FH encodes fumarate hydratase, illustrating metabolic alterations in oncogenesis.

Slide 16 · Hereditary papillary renal carcinoma

Autosomal dominant disorder associated with activating MET alterations.

Characteristically multifocal and bilateral papillary tumors.

Tumors often have low nuclear grade in the described hereditary form.

Familial MET alterations identify a central receptor tyrosine kinase pathway.

Slide 17 · Birt–Hogg–Dubé syndrome

Autosomal dominant syndrome caused by BHD gene loss of function.

BHD encodes folliculin, a tumor-suppressor protein.

Skin findings include fibrofolliculomas, trichodiscomas, and acrochordons.

Pulmonary cysts or blebs coexist with renal tumors of varied morphologic types.

Slide 18 · Hereditary phenotype: Which gene fits?

Presentation clue

Mechanistic association

Renal cysts + bilateral clear cell tumors

VHL pathway

Leiomyomas + aggressive RCC

FH loss

Multiple papillary RCCs, often low-grade

MET activation

Fibrofolliculomas + lung cysts + renal tumors

BHD / folliculin loss

Slide 19 · Classification uses three complementary dimensions

Histologic pattern

Cytogenetic alterations

Driver gene changes

No single growth pattern alone defines every renal carcinoma subtype.

Slide 20 · Major RCC histologic types

Clear cell

70–80%

VHL/3p-associated

Papillary

10–15%

Chromosomes 7, 17; MET

Chromophobe

~5%

Multiple chromosome losses

Collecting duct

≤1%

Medullary, desmoplastic

Approximate proportions given by Robbins; Minor categories are not all included.

Slide 21 · Clear cell RCC: Molecular hallmark

Clear cell carcinoma is the most prevalent RCC histologic subtype.

The VHL locus resides at chromosome 3p25.3.

Most cases have loss of chromosome 3p material involving one VHL allele.

Inactivation of the second VHL copy frequently occurs by mutation or promoter hypermethylation.

Slide 22 · The VHL two-hit model

3p deletion: One VHL copy lost

Mutation or silencing: Other copy

VHL function lost

HIF pathway activation

The source reports 3p deletion in 98% and second-copy inactivation in up to 80% of clear cell carcinomas; These are source-specific estimates.

Slide 23 · In normal oxygenation, VHL limits HIF

Oxygen-dependent HIF recognition

VHL ubiquitin ligase complex

HIF degradation

VHL complex promotes HIF-1 turnover in an oxygen-dependent manner.

Slide 24 · When VHL is inactive, HIF escapes degradation

VHL inactivation

HIF persists under normoxia

Hypoxia-response genes expressed

Tumor growth advantage

Even when oxygen is available, failure of HIF degradation allows inappropriate expression of target genes.

Slide 25 · HIF transcriptional targets reshape the tumor

HIF stabilization

VEGF: Angiogenesis

IGF-1: Growth stimulation

HIF-dependent VEGF and IGF-1 exemplify proangiogenic and proliferative outputs.

Slide 26 · Metabolism and epigenetics in clear cell RCC

HIF collaborates with MYC in complex changes to cellular metabolism.

Reprogrammed metabolic pathways can support tumor cell growth.

Genome sequencing reveals recurrent defects in histone-modifying genes.

Thus genetic, epigenetic, and metabolic disturbances reinforce RCC development.

Slide 27 · Clear cell appearance follows cellular biochemistry

Lipid and glycogen accumulate

Cytoplasm appears optically clear

Nests or solid tumor architecture

Clear and granular cells may coexist.

Slide 28 · Clear cell RCC: Characteristic gross appearance

Usually a unilateral, solitary, rounded cortical mass, often in a renal pole.

Bright yellow areas reflect abundant lipid in tumor cells.

Hemorrhage, necrosis, and cystic degeneration may create variegation.

The mass is often sharply demarcated, although it can invade adjacent structures.

Slide 29 · Clear cell RCC: Nested architecture

Schematic — not a histologic specimen

Clear or granular cytoplasm; Nests separated by delicate branching vascular channels.

Slide 30 · Clear cell RCC: Histologic variations

Growth can be nested, tubular, solid, or pseudopapillary.

Cells may have abundant clear or granular cytoplasm.

Delicate branching microvasculature is a recurring feature.

Larger lesions may show cysts or hyalinized areas; High-grade tumors may show bizarre nuclei and giant cells.

Slide 31 · Renal vein invasion: A defining local spread pattern

Renal parenchyma

RCC

Renal vein → inferior vena cava

Intraluminal tumor extension

Schematic — not gross pathology or imaging

Slide 32 · Papillary RCC: Major genetic distinctions

Papillary RCC contributes approximately 10%–15% of RCC in the source.

It is not characterized by the 3p loss typical of clear cell RCC.

Trisomies of chromosomes 7 and 17 occur in sporadic tumors.

Activation of MET is causal in hereditary papillary carcinoma and occurs in a subset of sporadic cases.

Slide 33 · Papillary RCC: Sporadic versus familial

Feature

Sporadic papillary RCC

Hereditary papillary RCC

Cytogenetics

Gains of chromosomes 7 and 17; Y loss in men

Trisomy 7

MET

Activated in a small subset

Activating MET mutation is characteristic

Multiplicity

Often multifocal

Often multiple and bilateral

Slide 34 · MET signaling and papillary carcinogenesis

MET receptor tyrosine kinase

Hepatocyte growth factor signaling

Growth, migration and invasion

MET is encoded on chromosome 7 and is the hepatocyte growth factor receptor.

Slide 35 · Papillary RCC: Gross and distribution pattern

Unlike clear cell tumors, papillary RCC is frequently multifocal.

Papillary neoplasms may also affect both kidneys.

Large tumors are often hemorrhagic and cystic.

Papillary, tubulopapillary, and solid configurations may coexist.

Slide 36 · Papillary RCC: Papillary architecture

Schematic — not a histologic specimen

Fibrovascular core

Papillary frond with cuboidal/columnar epithelial lining and foam histiocytes enclosed within the stalk; Psammoma bodies may occur.

Slide 37 · Papillary RCC: Microscopy details

Papillae are lined by cuboidal to low columnar epithelial cells.

Foamy macrophages commonly occur in papillary cores.

Lamellated psammoma bodies may be present.

The full architectural spectrum includes papillary, tubulopapillary, and solid regions.

Slide 38 · Chromophobe RCC: Genotype and origin

Chromophobe RCC accounts for approximately 5% of RCC.

Chromosomal losses across multiple chromosomes are typical.

Extreme hypodiploidy may result.

The source describes a likely origin from intercalated cells of collecting ducts.

Slide 39 · Chromophobe RCC: Cell morphology

Schematic — not a histologic specimen

Pale eosinophilic cells with prominent membranes and perinuclear halos; Usually solid sheets.

Slide 40 · Chromophobe carcinoma versus oncocytoma

Chromophobe RCC

Oncocytoma (differential)

Malignant renal epithelial neoplasm.

Pale eosinophilic cells with perinuclear halos.

Strong cell borders; Multiple chromosome losses.

Benign renal epithelial tumor.

Can resemble eosinophilic chromophobe cells.

Histologic separation may be difficult.

Slide 41 · TFE3-rearranged RCC

Defined by a rearrangement involving TFE3 at chromosome Xp11.2.

Different fusion partners lead to TFE3 overexpression.

Often occurs in younger patients.

Morphology varies with fusion partner: Nested, solid, and tubulopapillary patterns occur.

Slide 42 · Collecting duct carcinoma

Rare subtype, accounting for approximately 1% or less of renal epithelial tumors.

Typically arises in the renal medulla from collecting duct epithelium.

Irregular malignant glands are embedded in a prominent desmoplastic stroma.

Cells can line gland-like channels with highly atypical, hobnail architecture.

Slide 43 · Renal medullary carcinoma: Clinical association

Patient with sickle cell trait

Medullary renal malignancy

Morphologic overlap with collecting duct carcinoma

Robbins provides an association and morphologic comparison but no detailed treatment algorithm.

Slide 44 · Sarcomatoid change signals aggressive disease

Sarcomatoid morphology can occur in multiple RCC histologic types.

It is a pattern of high-grade transformation, not one exclusive molecular subtype.

Sarcomatoid change is associated with particularly poor prognosis.

Reporting should recognize both underlying type and aggressive component when possible.

Slide 45 · Major renal carcinoma subtypes compared

Subtype

Core finding

Molecular / context clue

Clear cell

Lipid-rich clear cells; fine vascular nests

3p/VHL loss; HIF signaling

Papillary

Papillae; foam macrophages; possible psammoma

Trisomy 7/17; subset MET activation

Chromophobe

Strong membranes; perinuclear halos

Multiple chromosome losses

TFE3-rearranged

Variable nested or papillary growth

TFE3 fusion; often younger

Collecting duct

Medullary infiltrating glands; desmoplasia

Rare; medullary origin

Slide 46 · Why incidental detection is increasingly common

Cross-sectional imaging

Asymptomatic renal mass found

RCC enters diagnostic pathway

Textbook notes rising incidental detection on CT and MRI; No quantified current prevalence.

Slide 47 · The classic RCC clinical triad is uncommon

Flank or costovertebral pain.

Palpable renal mass.

Hematuria.

All three together occur in only about 10% of cases, according to the text.

Slide 48 · Hematuria: An important but imperfect clue

Hematuria is the most reliable of the classic symptoms.

Bleeding may be intermittent or only microscopic.

A large primary tumor may develop before local symptoms become evident.

Absence of visible blood does not exclude a clinically significant RCC.

Slide 49 · Systemic symptoms may dominate presentation

Fever, malaise, weakness, and weight loss can occur.

These complaints may accompany large tumors.

RCC can act as a systemic disease long before kidney-specific symptoms appear.

This broad clinical profile underlies its reputation as a medical “great mimic.”

Slide 50 · Paraneoplastic phenomena in RCC

Category

Examples reported by Robbins

Hematologic

Polycythemia; eosinophilia; leukemoid reactions

Mineral/endocrine

Hypercalcemia; hypertension; Cushing syndrome

Hormonal phenotype

Feminization or masculinization

Other systemic

Hepatic dysfunction; amyloidosis

Slide 51 · Paraneoplastic syndromes: Diagnostic logic

Renal epithelial malignancy

Abnormal production of biologic mediators

Systemic manifestations beyond kidney

Clinical manifestations may reflect ectopic or excessive mediator production rather than local invasion.

Slide 52 · Local progression can obstruct the collecting system

Enlarging parenchymal mass

Calyceal / pelvic extension

Possible ureteral involvement

Source documents progressive tumor bulging/fungation into the collecting system.

Slide 53 · RCC can spread through the venous system

Renal vein invasion

Inferior vena cava extension

Potential right-heart involvement

The primary tumor can form a solid column of cells into major veins.

Slide 54 · RCC may metastasize before it is symptomatic

A major diagnostic difficulty is early distant spread without local signs.

Radiologic metastasis at initial presentation in approximately 15% of new patients.

Lung and bone are frequent sites of distant spread.

Lymph nodes, liver, adrenal glands, and brain are additional common locations.

Slide 55 · Sites of metastasis reported in RCC

Lung

>50%

Overall metastasis-site frequency

Bone

33%

Overall metastasis-site frequency

Other

—

Nodes, liver, adrenal, brain

Patients may have disease at more than one metastatic site; Do not add these percentages.

Slide 56 · Prognosis tracks anatomic disease extent

Localized tumor

Renal vein or perinephric extension

Distant metastasis

Increasing spread generally reduces survival.

Slide 57 · Textbook five-year survival estimates

No distant metastasis

Near 100%

Textbook estimate

Renal vein / fat invasion

~60%

Textbook estimate

Overall average

~70%

Textbook estimate

Survival depends on stage and clinical context; Estimates shown are approximate statements from the source.

Slide 58 · Treatment principles in the pathology context

Surgical management

Advanced or metastatic disease

Nephrectomy historically used for localized RCC.

Nephron-sparing surgery preserves renal function.

The source supports partial nephrectomy for T1a tumors and selected larger resectable tumors.

VEGF pathway inhibitors are used in systemic therapy.

Tyrosine kinase inhibitors target oncogenic signaling.

Immunotherapy is an important treatment class; Specific regimens require current guidance.

Slide 59 · RCC versus renal pelvic urothelial carcinoma

Feature

Parenchymal RCC

Renal pelvic urothelial carcinoma

Cell of origin

Renal tubular epithelial compartment

Urothelial lining of pelvis

Hallmark genetics in source

VHL/3p, MET, chromosomal losses

Not detailed in the kidney section

Typical gross position

Parenchyma; often renal pole

Pelvis / collecting system

Clinical clue

Often incidentally detected

Early hematuria with small lesion

Slide 60 · Case application: Yellow renal cortical mass

A patient is found to have a solitary golden-yellow renal cortical tumor.

CLUES

Microscopy shows cells with abundant clear cytoplasm.

Tumor cells form nests interspersed by delicate vascular channels.

Molecular analysis identifies loss affecting chromosome 3p.

Which subtype and tumor-suppressor pathway best explain these findings?

Slide 61 · Case interpretation: Clear cell carcinoma

Yellow cortex mass + clear cells

3p loss involving VHL

HIF / angiogenic signaling

Clear-cell phenotype reflects lipid/glycogen while 3p/VHL loss supports molecular classification.

Slide 62 · Case application: Multiple papillary tumors

A relatively young adult presents with bilateral renal masses.

CLUES

Histology demonstrates papillary architecture and foam histiocytes.

Several tumors are identified in both kidneys.

A germline activated receptor tyrosine kinase is suspected.

Which oncogene and growth-factor receptor are implicated?

Slide 63 · Case interpretation: MET-associated papillary RCC

Multifocal papillary tumors

Activating MET alteration

HGF receptor signaling

MET encodes hepatocyte growth factor receptor tyrosine kinase.

Slide 64 · Integration: Morphology and genotype are complementary

Observed pattern

Most useful next mechanistic inference

Clear cells + delicate vascular nest

VHL loss → persistent HIF target expression

Papillary fronds + foam histiocytes

Papillary RCC; chromosome 7/17 changes; subset MET

Strong cell borders + halos

Chromophobe RCC; multiple chromosome losses

Medullary glands + desmoplasia

Consider collecting duct carcinoma

Any RCC with sarcomatoid change

Aggressive behavior across different RCC types

Slide 65 · Core diagnostic and clinical principles

RCC is a molecularly heterogeneous group of renal epithelial cancers.

Clear cell RCC centers on VHL/HIF dysregulation; Hereditary papillary RCC centers on MET activation.

Gross appearance and microscopic architecture narrow the differential but can overlap.

Tumor extent, especially venous invasion and distant metastasis, is central to prognosis.

Hereditary syndromes provide mechanistic insights into sporadic renal carcinogenesis.

Slide 66 · Primary reading and source limitations

Primary source

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026). Chapter 20, The Kidney, pp. 863–865; “Malignant Neoplasms” and “Renal Cell Carcinoma.”

Scope and interpretation

Figures, subtype proportions, and survival estimates are textbook statements, not independently updated registry data.

Original source chapter PDF and copyrighted diagnostic figures were not available for direct image verification.

All mechanisms and illustrative diagrams are editable schematics; no clinical histopathology or gross specimen images are claimed.