Renal Path 3a Flashcards
Congenital disorders of the kidney
Agenesis (r/o unilateral prior to renal biopsy or nephrectomy; bilateral incompatible with life)
Hypoplasia —often unilateral
Ectopic kidney
Horseshoe kidney — usually fused at lower pole; often asymptomatic
In cases of unilateral agenesis of the kidney, the existing kidney commonly exhibits hypertrophy, increasing the risk of _____
HTN
Most common anatomic site for ectopic kidney
Just above pelvic brim or within the pelvis
Cystic diseases of the kidney
Multicystic renal dysplasia
Polycystic kidney disease (AD in adults, AR in kids)
Medullary cystic disease (includes medullary sponge kidney and nephronophthisis)
Acquired (dialysis-associated) cystic disease
Localized (simple) renal cysts
Renal cysts in hereditary malformation syndromes
Glomerulocystic disease
Extraparenchymal renal cysts (pyelocalyceal, hilar lymphangitic)
Inheritance, morphology, clinical features, and outcomes associated with adult polycystic kidney disease
Autosomal dominant
Large multicystic kidneys, liver cysts, berry aneurysms
Hematuria, flank pain, UTI, renal stones, HTN
Chronic renal failure beginning at age 40-60 years
Inheritance, morphology, clinical features, and outcomes associated with infant/childhood polycystic kidney
Autosomal recessive
Enlarged, cystic kidneys at birth
Hepatic fibrosis
Variable outcome, death in infancy or childhood
Inheritance, morphology, clinical features, and outcomes associated with medullary sponge kidney
No inheritance pattern
Medullary cysts on excretory urography
Hematuria, UTI, recurrent renal stones
Benign outcome
Inheritance, morphology, clinical features, and outcomes associated with familial juvenile nephronophthisis
Autosomal recessive
Corticomedullary cysts, shrunken kidneys
Salt wasting, polyuria, growth retardation
Outcome: progressive renal failure in childhood
Inheritance, morphology, clinical features, and outcomes associated with adult-onset nephronophthisis
Autosomal dominant
Corticomedullary cysts, shrunken kidneys
Salt wasting, polyuria
Results in chronic renal failure in adulthood
Inheritance, morphology, clinical features, and outcomes associated with simple kidney cysts
No inheritance pattern
Single or several cysts with normal-sized kidneys
Clinically: rare microscopic hematuria
Benign outcome
Inheritance, morphology, clinical features, and outcomes associated with acquired renal cystic disease
No inheritance pattern
Cystic degeneration in end-stage kidney disease
Clinically: hemorrhage, erythrocytosis, neoplasia
Outcome depends on dialysis
Inheritance, morphology, clinical features, and outcomes associated with multicystic renal dysplasia
No inheritance pattern
Irregular kidneys with cysts of various size, cartilage
Clinically associated with abdominal mass; other renal anomalies
Outcome: renal failure if bilateral; surgically curable if unilateral (normal life expectancy)
T/F: autosomal dominant polycystic kidney disease is universally unilateral
False — it is universally bilateral!
Specific genetics of autosomal dominant (adult) polycystic kidney disease
Occurs in individuals of Northern European descent. Manifestation requires mutation of both alleles of either PKD gene
85% ADPKD: defective PKD1 gene, chromosome 16 (codes for polycystin 1)
15% ADPKD: defective PKD2 gene, chromosome 4 (codes for polycystin 2)
Note that defective PKD2 gene has slightly better prognosis; PKD1 has higher likelihood of developing ESRF
Possible mechanism for cyst formation in ADPKD and their potential complications
Mutations in polycystin 1, 2, or fibrocystin of nephrocystins
Altered mechanosensation by tubular cilia or altered calcium flux
Altered tubular epithelial growth and differentiation
Abnormal ECM, cell proliferation, and fluid secretion
Cyst formation
Cysts may lead to glomerular or vascular damage as well as interstitial inflammation/fibrosis
Major clinical characteristics of ADPKD
5-10% of pts evolve to chronic renal failure
Insidious onset in 4th, 5th, or 6th decade with renal insufficiency (HTN, azotemia)
May exhibit abdominal pain, hemorrhage, hematuria
What patient populations with ADPKD may have a more aggressive clinical course?
African-Americans (correlation with sickle cell trait)
M > F
Those with concomitant HTN
[overall increased incidence of nephrolithiasis and UTI in these pts]
Clinically significant extra-renal manifestations of ADPKD
40% have hepatic cysts
4-10% die of subarachnoid hemorrhage secondary to ruptured berry aneurysms in circle of willis
25% have mitral valve prolapse
82% have diverticular dz of the colon
Specific genetics with autosomal recessive polycystic kidney disease (ARPKD)
In most cases, the defective gene is PKHD 1 on chromosome 6, which encodes the large novel protein fibrocystin
Numerous mutations occur which probably account for the spectrum/diversity of clinical presentations
Characteristic gross appearance of kidneys with ARPKD
Characteristically slightly enlarged, exhibiting numerous small (1-2mm) LINEAR/radial-arrayed cysts derived from dilated collecting ducts
4 major clinical subtypes of ARPKD including most common types
Perinatal (MOST common): >90% of ducts are cystic, minimal hepatic fibrosis, survival only a few hours; death associated with concomitant hypoplastic lungs
Neonatal: ~60% renal CDs are cystic; mild hepatic fibrosis. Generally survive several months but die from renal failure
Infantile: ~20% CDs are cystic; hepatic fibrosis/hepatic failure, portal HTN, and systemic HTN common; 90% survive neonatal period but nearly all die in childhood
Juvenile: <10% CDs are cystic; hepatic fibrosis is PROGRESSIVE; most salient clinical problem is portal HTN with esophageal varices. Most do not survive to adolescence
As a group, now considered to be the most common GENETIC cause of ESRD in adolescents and young adults
Nephronophthisis-Medullary cystic disease
Clinical features of nephronophthisis-medullary cystic disease
3 forms recognized: sporadic, familial/juvenile (MOST COMMON), and renal-retinal dysplasia
Generally affect distal tubules — associated with inability to concentrate urine; present initially with polyuria and polydipsia
Renal failure occurs secondary to progressive cortical/tubulointerstitial damage
Mutations in ____ and _____ have been identified as causing medullary cystic disease
MCKD1; MCKD2
What are some anomalies often noted with multicystic renal dysplasia?
Most cases have an absent ureter (agenesis), ureteropelvic obstruction or other lower GU anomalies
[these are rather common masses to find in perinatal period]
Pathologic morphology features of multicystic renal dysplasia
Extensive multiple, variably sized cysts with intervening rather poorly-differentiated mesenchyme, often with cartilage formations and immature collecting ducts
Note on histology: markedly disorganized architecture, dilated tubules with cuffs of primitive stroma, no glomeruli and an island of cartilage (H&E stain)
5-10% of americans experience kidney stone formation (80% are unilateral). What populations are most at risk?
Men > women
Familial predisposition
Peak age of onset = 3rd decade (age 20-30)
Other predisposing factors: increased concentration of stone constituents, changes in urine pH, decreased urine volume, presence of bacteria
Complications of nephrolithiasis
Intense pain/renal colic
Ulceration and bleeding or ureter (or calyceal) mucosa
Obstruction of urinary flow
Small stones are hazardous because they can ente the ureter; these small jagged stones cause severe pain as they may elicit spasms of the ureteral smooth muscle (this is what causes renal colic)
Types of renal stones (note most common)
70% are calcium oxalate or phosphate (most common)
15-20% are magnesium ammonium phosphate (struvite)
5-10% are uric acid
1-2% are cystine
Benign forms of renal neoplasia (note most common)
Renal papillary adenoma (MOST common)
Angiomyolipoma
Oncocytoma
Renal fibroma or hamartoma (renomedullary interstitial cell tumor in adults, mesoblastic nephroma in children)
Juxtaglomerular cell tumor (renin-producing)
Other stromal or mesenchymal tumors — lipoma, leiomyoma, angioma, etc
The majority of benign renal neoplasms rarely cause clinical problems and are usually discovered as incidental findings on imaging studies or at autopsy. The majority are also small (many less than a cm). However, occasionally _____ or ______ can measure 10cm or more
Oncocytomas; angiomyolipomas
What does it mean to say that renal papillary adenomas are defined by size?
Considered benign when < 1cm
Neoplasms > 1cm in diameter with adenoma histomorphology now usually classified as low grade RCC (aka potentially malignant)
Gross and histological appearance of renal papillary adenoma
What is a cytogenic association?
Cortical, discrete, yellow-gray, small, may be multiple
Histology: acidophilic cytoplasm, papillae (may see psammoma bodies), thin fibrovascular cores
Cytogenetics: trisomy 7 and 17
Type of renal tumor arising from [type A] intercalated cells of renal cortical collecting ducts (involved in acid-base homeostasis)
Renal oncocytoma
Renal oncocytomas represent 5-15% of primary renal epithelial neoplasms (oncocytes are enlarged cells with pink cytoplasm with glassy appearance). Most are sporadic, but familial cases do exist. What are features of a familial form of renal oncocytoma?
Multicentricity, bilaterality, or oncocytosis (increased cytoplasmic change)
What type of benign renal tumor is highly clinically significant because it may appear similar to renal cell carcinoma, especially clear cell or chromophobe variant?
Renal oncocytoma
Gross and histologic appearance of renal oncocytoma
Typically mahogany brown and well-circumscribed, often with central stellate scar; may be quite large (>10-15cm)
Histo: abundant acidophilic, granular cytoplasm (mitochondria); may show alveolar, nesting, tubular or solid pattern
What type of renal tumor has strong association with tuberous sclerosis?
Renal angiomyolipoma
What patient population tends to get renal angiomyolipoma? What are some genetic associations?
Present in adults, typically middle-aged, Females more likely
Associated with loss of TSC1 or TSC2 tumor suppressor genes
Clinical significance of renal angiomyolipoma
DDx with RCC; on occasion may spontaneously rupture with massive retroperitoneal and/or intraabdominal hemorrhage, so initial presentation may be shock
Renal angiomyolipoma is associated with loss of TSC1 or 2 tumor suppressor genes
TSC = tuberous sclerosis complex
What is the inheritance pattern for this, and what tumor lesions are associated?
Autosomal dominant inheritance
Tumors or lesions of brain, skin, kidney, heart, lungs, eyes
Brain: intraventricular hamartomas Skin: angiofibromas Kidneys: angiomyolipomas Heart: rhabdomyomas Lungs: leiomyomas Eyes: leisch nodules
Demographics of RCC
Unusual but nevertheless MOST COMMON of adult kidney cancers (85%)
Affects adults in 6th-8th decade, Males more common
Risk factors and inheritance patterns for RCC
Risk factors: cigarette smoking, HTN, obesity, estrogens, asbestos, chronic renal disease, tuberous sclerosis, acquired cystic disease
Most are sporadic, but 4% are hereditary (autosomal dominant, affect younger pts)
Other genetic associations: VHL syndrome, hereditary clear cell carcinoma, hereditary papillary carcinoma
Classifications of renal cell carcinoma include clear cell, papillary carcinoma, chromophobe renal carcinoma, Xp11 translocation carcinoma, collecting [Bellini] duct carcinoma, and medullary carcinoma
Describe clear cell type
MOST COMMON — 70-80%
Non-papillary
Clear cytoplasm (some granular)
Sporadic in 95% of cases
Of the familial ~98% have Chr 3 short arm deletions/translocations (**VHL tumor suppressor gene)
Classifications of renal cell carcinoma include clear cell, papillary carcinoma, chromophobe renal carcinoma, Xp11 translocation carcinoma, collecting [Bellini] duct carcinoma, and medullary carcinoma
Describe papillary carcinoma in terms of incidence, general prognosis and genetics associated
10-15% of RCC cases; Has papillary growth pattern
Relatively better prognosis
Genetics: trisomy 7, 16, 17; lost Y (MET proto-oncogene)
Classifications of renal cell carcinoma include clear cell, papillary carcinoma, chromophobe renal carcinoma, Xp11 translocation carcinoma, collecting [Bellini] duct carcinoma, and medullary carcinoma
Describe chromophobe type in terms of incidence, histology, general prognosis, and cells from which it arises from
5% of RCC cases
Pale eosinophilic cytoplasm, nuclear halos
Relatively better prognosis
Arises from [type B] intercalated cells of renal cortex collecting ducts (compare to type A in oncocytoma)
Classifications of renal cell carcinoma include clear cell, papillary carcinoma, chromophobe renal carcinoma, Xp11 translocation carcinoma, collecting [Bellini] duct carcinoma, and medullary carcinoma
Describe collecting [bellini] duct carcinoma in terms of location and general prognosis
Medullary location
Poor prognosis
Sporadic clear cell RCC often involves deletions on chromosome ____ —> loss of ______ which codes for proteins that degrade many growth factors (i.e., tumor suppressor)
3; VHL
RCC classic triad of most common presenting signs/symptoms
Hematuria
Costovertebral pain
Palpable flank mass
Note that all 3 are present in only 10% of RCC pts
Clinical course of RCC
Tends to reach large size and widespread metastases before local signs/symptoms
Then generalized non-specific symptoms like weight loss, malaise, weakness, FEVER
RCC is considered one of the great “mimics” in medicine d/t propensity to cause numerous symptoms unrelated to kidney — including hormonal effects causing many paraneoplastic and other unusual manifestations
2 most important factors in prognosis of RCC
Stage
Histologic type:
Chromophobe has better prognosis
Papillary and clear cell have avg prognosis
CD, sarcomatoid, and medullary have worse prognosis
Typical mode of spread of RCC
Typically hematogenous, not lymphatic (d/t early invasion of renal vein)
What type of RCC may mimic adrenal gland on histology?
Clear cell RCC aka hypernephroma
Characteristic morphology of papillary RCC
Papillae and foamy macrophages in stalk
Characteristic histology of chromophobe RCC
Pale, eosinophilic cells arranged in solid sheets; well-defined cell membranes and faintly granular cytoplasm with perinuclear clear halos; tend to concentrate around blood vessels
What rare type of RCC is composed of spindle cells simulating a mesenchymal neoplasm?
Sarcomatoid RCC — note that a sarcomatoid component may arise in any RCC, implying a poor prognosis
What rare type of RCC shows branching tubules lined by highly atypical cuboidal cells?
Collecting duct carcinoma
Urothelial carcinoma of the kidney may be multiple and 50% of pts have concomitant tumors in the ____
Bladder
Clinical presentation and prognosis of urothelial (transitional cell) carcinoma of kidney
Painless hematuria
Usually small when discovered; location related to degree and persistence of hematuria
May block urinary outflow and lead to palpable hydronephrosis and flank pain
Frequently infiltrates wall of pelvis/calyces
Generally poor prognosis
4th most common childhood malignancy behind acute leukemia (1), neuroblastoma (2), and retinoblastoma (3)
Wilms tumor (used to be called nephroblastoma)
Population affected by wilms tumor
Asians > Whites > Blacks
Generally childhood tumor, peak cases at age 2-5
Clinical presentation of wilms tumor
Typically discovered as large abdominal mass by parent or medical practitioner and may exhibit pain, microscopic hematuria, HTN
5-10% of Wilms tumors are bilateral, indicating familial inheritance. What are some associated genetic changes and syndromes?
Group 1: WAGR syndrome (Wilms-Aniridia-Genital-Retardation)
Group 2: Denys-Drash Syndrome
Group 3: Beckwith-Wiedemann syndrome
Groups 1 and 2 associated with Chr11, WT1 mutations, or loss and 2nd hit
Group 3 is non-WT1, possibly WT2; IGF2
NOTE THAT THE VAST MAJORITY (90%) OF WILMS TUMOR PTS ARE SPORADIC CASES
In terms of WAGR syndrome wilms tumors, the most commonly observed GU malformation in affected males is ________, whereas females may be affected by ______
Undescended testes; streak gonads or uterine malformation
Denys Drash syndrome pts with Wilms tumor also often have what other type of tumor?
Gonadal tumors
Beckwith Wiedemann pts with Wilms tumor also often have what 2 other syndromic associations?
Hemihypertrophy
Macroglossia
Histopathology of Wilms tumor
Many associated with nephrogenic rests (precursor lesion) — note that when these are present, additional tumors or bilaterality are distinct possibilities
Typical triphasic (favorable) histomorphology: mimics germinal development of normal kidney with 3 cell types — blastemal, epithelial (tubules), and stromal; no significant anaplasia
Anaplastic (unfavorable) histomorphology: may be focal or diffuse (extreme cellular pleomorphism and atypia); note that focal anaplasia does not always confer poor prognosis but diffuse does! Anaplasia tends to be associated with p53 mutations and resistance to chemotherapy
Gross appearance of wilms tumor
Well-circumscribed margins
Tan-to-gray color
Large, expansile tumor in lower pole of kidney
Most critical prognostic element in wilms tumor
Presence or absence of DIFFUSE ANAPLASIA
[note that today, wilms tumor is curable in majority of children; other prognostic factors include histologic elements and stage at dx as well as p53, 11q, and 16q deletions, 1q gain; older age tends to have better prognosis]
Metastatic disease TO the kidney is uncommon but often a terminal event. It is frequently multifocal and bilateral. Cancers of what organs tend to metastasize to the kidneys?
Lung Melanoma Breast GI Pancreas
