Wilms Tumor (Nephroblastoma) — Complete Study Guide

1. Overview

2. Associated Syndromes & Genetics

• WT1 (11p13): transcription factor critical for renal and gonadal development. In WAGR → deletion; in DDS → dominant-negative point mutation
• WT2/IGF2 (11p15.5): IGF-2 is normally expressed from paternal allele; loss of maternal imprinting → overexpression → tumorigenesis (BWS)
• Sporadic tumors (90% of cases): mutations in β-catenin (~10%), or genes encoding microRNA processing proteins (15–20%) — leads to failure of mesenchymal-to-epithelial transformation and persistent blastemal rests
• TP53 mutations → anaplastic histology → especially poor prognosis

3. Gross Pathology

• Large, solitary, well-circumscribed mass replacing renal parenchyma
• Soft, homogeneous, tan to gray on cut section
• Foci of hemorrhage, cystic degeneration, and necrosis common
• 10% are bilateral or multicentric at diagnosis
• 13% bilateral in some series

4. Histology — Classic Triphasic Pattern

• Favorable histology (FH): classic triphasic OR epithelial-predominant (less aggressive, often stage I)
• Unfavorable histology (UFH): anaplasia (focal or diffuse), clear cell sarcoma, rhabdoid tumor
  • Anaplastic WT: TP53 mutated, chemoresistant, high recurrence risk
  • Blastemal-predominant: clinically aggressive, associated with advanced stage

5. Clinical Presentation

• Asymptomatic abdominal/flank mass — usually noticed by parents while bathing/dressing (most common presentation)
• Hypertension in ~25% (secondary to renin-angiotensin axis disruption)
• Hematuria (gross or microscopic)
• Vague abdominal discomfort
• Rarely: varicocele, hepatomegaly (hepatic vein obstruction), ascites, heart failure, obstipation, weight loss
• Sometimes discovered after blunt abdominal trauma

6. Imaging & Workup

7. Staging — NWTSG System

8. Treatment

• Bilateral disease (Stage V)
• IVC involvement above the hepatic veins
• Involvement of a solitary kidney

Surgery

• Radical nephrectomy is standard
• Explore contralateral kidney
• Lymph node sampling mandatory for staging

Chemotherapy

• Stage I/II FH: Vincristine + Actinomycin D (2-drug)
• Stage III/IV FH: Vincristine + Actinomycin D + Doxorubicin (3-drug)
• Anaplastic/UFH: Vincristine + Actinomycin D + Doxorubicin ± Cyclophosphamide + Etoposide

Radiation

• Stage III and IV with FH → whole abdomen/flank radiation
• All diffuse anaplastic stages → radiation
• Pulmonary mets: whole-lung radiation if present

9. Prognosis

10. High-Yield Summary for Exams

• Most common renal tumor in children (peak 2–5 years)
• Always think WT1 (11p13) with aniridia → WAGR
• BWS → IGF-2 overexpression → WT2 locus (11p15)
• Triphasic histology: blastemal + epithelial + stromal
• Anaplasia = unfavorable, TP53, chemoresistant
• Presents as painless abdominal mass; BP ↑ in 25%
• Do NOT rupture the tumor during surgery — causes upstaging to III
• Bilateral = Stage V → preoperative chemo, nephron-sparing surgery goal
• Overall cure ~90% — paradigm for multimodal pediatric oncology

Recent Evidence

• PMID 41459843 (2025): Compared SIOP vs. NWTSG/COG protocols — confirms equivalent survival outcomes between the two approaches
• PMID 41219039 (2026): Minimally invasive vs. open nephrectomy under SIOP guidelines — MIS appears feasible in selected patients, though long-term data are still emerging

Mitral Stenosis — Complete Study Guide

1. Overview & Epidemiology

• Most common cause worldwide: Rheumatic fever (rheumatic heart disease)
• Occurs in 40% of all rheumatic heart disease patients
• 2:1 female predominance for isolated MS
• ~60% of pure MS patients recall a prior episode of rheumatic fever
• In developed countries, MS is now rare and mostly seen in elderly foreign-born women, often post-commissurotomy

2. Pathology & Pathophysiology

Structural Changes (Rheumatic)

• Leaflet thickening and nodularity
• Commissural fusion (anterior + posterior leaflets fuse at edges)
• Subvalvular involvement — chordal thickening, fusion, and shortening
• Calcification of leaflets
• Classic appearance: "fish-mouth" orifice (short axis); "hockey stick" deformity of anterior leaflet (long axis — doming due to restricted tip mobility with pliable body)

Hemodynamic Cascade

MVA↓ → LA pressure↑ → LA dilation → AF
                     ↓
           Pulmonary venous HTN → dyspnea, pulmonary edema, hemoptysis
                     ↓
           Pulmonary arterial HTN (chronic) → RV failure, TR

• Symptoms begin when MVA ≤1.5 cm² (mean gradient 5–10 mmHg)
• Severe MS = MVA <1.0 cm², gradient >10 mmHg
• AF develops from LA dilation → loss of atrial kick → acute symptom worsening + thromboembolic risk
• LA thrombus (especially LAA) → systemic embolism, stroke
• Death primarily from heart failure or systemic embolism

3. Clinical Presentation

Symptoms

• Dyspnea on exertion (most common) → orthopnea, PND, pulmonary edema
• Hemoptysis (pulmonary venous hypertension → rupture of bronchopulmonary anastomoses)
• Palpitations (atrial fibrillation)
• Systemic embolism / stroke
• Fatigue, exercise intolerance
• Hoarseness — Ortner's syndrome (LA compression of left recurrent laryngeal nerve)
• Right heart failure symptoms in advanced disease (edema, ascites)

Physical Examination

In elderly patients with calcified valves: S1 may be soft, OS may be absent, murmur may be inaudible — echocardiography is essential.

4. Investigations

ECG

• P mitrale (bifid P wave in II, negative component in V1) — LA enlargement
• Atrial fibrillation — common in advanced disease
• RV hypertrophy pattern if pulmonary hypertension develops

Chest X-Ray

• LA enlargement — double density at right heart border, elevation of left main bronchus, splaying of carina
• Pulmonary venous congestion — upper lobe diversion, Kerley B lines
• Mitral valve calcification (lateral CXR)
• Straightening of left heart border (LAA prominence)

Echocardiography — Gold Standard

• Leaflet thickening, calcification, restricted mobility
• Commissural fusion
• "Hockey stick" / "doming" AMVL on parasternal long axis
• "Fish-mouth" orifice on short axis
• LA enlargement, LA thrombus assessment

1. Planimetry — direct tracing of orifice in PSAX (most reliable; 3D echo = highest accuracy)
2. Pressure Half-Time (PHT): MVA = 220 ÷ T½ (T½ = DT × 0.29)
3. Continuity equation: MVA = (LVOT TVI × LVOT area) ÷ MV TVI — used when PHT is unreliable (e.g., after valvuloplasty, significant AR, abnormal LV compliance)

5. Wilkins Echocardiographic Score

• Score ≤8: Favorable for PMBV — excellent outcomes
• Score >8: Increasing risk of suboptimal result, restenosis, and complications
• Score >12: Generally unsuitable for PMBV; consider surgery

• Group 1: Pliable, noncalcified AMVL + mild subvalvular disease
• Group 2: Pliable AMVL + severe subvalvular disease
• Group 3: Any calcification (fluoroscopy) — worst outcomes with PMBV

6. Treatment

Medical Management

Note: DOACs are not approved for rheumatic MS — warfarin remains standard.

Percutaneous Mitral Balloon Valvuloplasty (PMBV) — Inoue Technique

• Symptomatic MS with MVA ≤1.5 cm², favorable morphology (Wilkins ≤8), no LA thrombus, MR <moderate (Class I)
• Asymptomatic severe MS + new-onset AF (Class IIb, after excluding LA thrombus)
• Symptoms with mild MS (MVA >1.5 cm²) if exercise testing shows significant obstruction (Class IIb)
• High surgical risk patients with calcified valves — PMBV as palliation

Surgical Options

• Mechanical valves: Better durability; require lifelong anticoagulation
• Bioprosthetic valves: Avoid anticoagulation (if sinus rhythm); wear out in 10–15 years

7. MS in Special Populations

MS in Pregnancy

• Hemodynamic stress of pregnancy (↑HR, ↑CO, ↑blood volume) → acute decompensation
• Symptoms may worsen precipitously in 2nd trimester
• Management: beta-blockers for rate control; diuretics cautiously; PMBV in 2nd trimester if refractory; avoid MVR if possible (fetal risks of cardiopulmonary bypass + anticoagulation)

MS in the Elderly

• Often calcific rather than rheumatic; loud S1 and OS may be absent
• Higher procedural risk with both PMBV and MVR (periop mortality ≥10% for MVR)
• AF + superimposed age-related LA changes → higher embolic risk

8. Complications

9. High-Yield Summary

• Cause: Rheumatic fever → commissural fusion → "fish-mouth" valve
• Symptoms begin at MVA ≤1.5 cm²; severe at <1.0 cm²
• Key auscultation: Loud S1 → A2 → OS → rumbling diastolic murmur at apex; short S2–OS = severe; pre-systolic accentuation lost in AF
• Echo: Hockey-stick AMVL, fish-mouth orifice, MVA by planimetry or PHT (220/T½)
• Wilkins score ≤8 = favorable for PMBV; >8 = worse outcomes
• Rate control in AF is critical — tachycardia reduces diastolic filling time, precipitates pulmonary edema
• Anticoagulation = warfarin (not DOACs) for AF or prior embolism
• PMBV is first-line intervention for favorable-anatomy symptomatic severe MS
• Avoid vasodilators — can cause catastrophic CO drop
• Pregnancy + MS = high-risk combination requiring close monitoring