Clinical Approach: 60F with CKD, Epigastric Pain, Back Pain + Retro-pancreatic/Left Para-aortic/Para-iliac Conglomerate Lymph Nodes on CT

Step 1: Establish the Differential Diagnosis

Step 2: Immediate Investigations (Parallel Workup)

• Complete blood count (CBC) with differential - leukocytosis, lymphocytosis, anemia suggest lymphoma or infection
• ESR, CRP - inflammatory markers
• LDH and uric acid - elevated in lymphoma (tumor burden markers)
• Serum protein electrophoresis (SPEP) - for myeloma
• HIV serology - reactivation TB, lymphoma risk
• Renal function (baseline CKD assessment), electrolytes, eGFR
• Serum calcium - elevated in sarcoidosis and some lymphomas
• Serum beta-2 microglobulin - prognostic in lymphoma
• Tumor markers: CA-125 (ovarian), CEA, CA 19-9 (pancreatic/GI), AFP, beta-hCG
• Serum IgG4 level
• Mantoux/TST or IGRA (QuantiFERON-TB Gold) for TB screening

• Urinalysis and culture
• Urine cytology (if renal/urothelial malignancy suspected)

Step 3: Additional Imaging

• This is the investigation of choice for staging lymphoma and has superseded CT alone
• FDG PET/CT can detect disease in normal-sized lymph nodes, differentiate lymphomatous from reactive hyperplasia, and provides functional + morphological assessment simultaneously
• It results in clinically significant upstaging in up to 30% of patients compared with CT alone
• It achieves 94% sensitivity and 96% specificity for malignant lymphadenopathy vs 90%/94% for CT and 86%/94% for MRI
• Caveat: Low-grade lymphomas (CLL/SLL, mycosis fungoides, marginal zone NHL) may be FDG-negative; contrast-enhanced CT remains standard for these subtypes

• Upper GI endoscopy (EGD) - given epigastric pain, to rule out gastric lymphoma or primary gastric/pancreatic malignancy
• Pelvic ultrasound - to evaluate ovaries (primary ovarian malignancy metastasizing to para-aortic nodes)
• Dedicated pancreatic protocol CT/MRI if pancreatic tumor suspected (retro-pancreatic nodes may indicate pancreatic or periampullary cancer)

Step 4: Tissue Diagnosis (Biopsy - Central Step)

1. CT-guided percutaneous core needle biopsy (PREFERRED)
   • Patient placed prone in the CT scanner
   • Left-sided approach is preferred anatomically - because the inferior vena cava lies on the right and a right-sided approach would require the needle to pass between the IVC and aorta, which is technically hazardous
   • Skin anesthetized at the lateral border of quadratus lumborum muscle
   • Needle angled at ~45 degrees through quadratus lumborum into the retroperitoneum to access left para-aortic nodes
   • Core needle biopsy (vs FNA) is strongly preferred when lymphoma is suspected - FNA cannot assess nodal architecture, has a high false-negative rate (5.4%), and is often inadequate for lymphoma subtyping and immunophenotyping
   • Core needle biopsy enables immunohistochemistry, next-generation sequencing, flow cytometry
2. Endoscopic ultrasound (EUS)-guided FNA/biopsy - useful for retro-pancreatic and perigastric nodes accessible via the stomach wall
3. Surgical (laparoscopic/robotic/open) biopsy - if image-guided approaches are inconclusive or technically not feasible

Step 5: Histopathological Analysis of Biopsy

• H&E histomorphology - architecture, cell type
• Immunohistochemistry (IHC) - CD20, CD3, CD30, CD10, BCL-2, BCL-6, Ki-67 (for lymphoma subtyping)
• Flow cytometry - immunophenotyping
• FISH/cytogenetics - chromosomal translocations (e.g., t(14;18) in follicular lymphoma, c-MYC in DLBCL)
• Microbiology - ZN staining, TB culture, CBNAAT/Gene Xpert (if TB suspected)
• EBER in-situ hybridization - for EBV-associated lymphoma
• If metastatic carcinoma: CK7, CK20, PAX-8 (renal/ovarian), CDX2 (colorectal), TTF-1 (lung) markers

Step 6: Bone Marrow Examination

• Bilateral bone marrow biopsy and aspirate for staging (extranodal disease assessment)
• This is particularly important in NHL

Step 7: Multidisciplinary Team (MDT) Referral

• Oncology/Hematology referral if lymphoma or metastatic malignancy confirmed
• Pulmonology/ID if TB is confirmed (especially important given CKD - anti-TB drug dose adjustments required: rifampicin, isoniazid, pyrazinamide, ethambutol all need renal dose modification)
• Nephrology involvement for CKD management throughout workup and treatment

Summary Algorithm

CT showing conglomerate retro-pancreatic + left para-aortic + left para-iliac nodes
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Labs: CBC, LDH, ESR/CRP, IGRA, tumor markers, IgG4, protein electrophoresis
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FDG PET/CT (staging + identify highest SUV node for targeted biopsy)
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EGD (given epigastric pain) + Pelvic USG
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CT-guided core needle biopsy (left para-aortic, posterior approach via quadratus lumborum)
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Histopathology: H&E + IHC + flow cytometry + FISH + ZN stain/culture
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Bone marrow biopsy (if lymphoma/hematological malignancy)
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MDT: Oncology/Hematology vs ID/Pulmonology vs Surgical Oncology

• Gray's Anatomy for Students, p. 457-478
• Sabiston Textbook of Surgery, 11th Ed, p. 1462
• Grainger & Allison's Diagnostic Radiology, p. 1671

Clinical Approach: 15-Year-Old Obese Boy with Peripheral Nerve Sheath Tumor (Ulnar Nerve, Left Hand) + Intraoperative/Postoperative Hypertension (BP 160/90)

Step 1: Recognize the Clinical Syndrome - This Points to NF1

• Peripheral nerve sheath neoplasm (ulnar nerve)
• Obesity (a recognized feature of NF1)
• Hypertension in a 15-year-old

• Cutaneous/subcutaneous neurofibromas
• Café-au-lait macules (≥6, >5 mm prepubertal / >15 mm postpubertal)
• Axillary/inguinal freckling (Crowe sign)
• Lisch nodules (iris hamartomas)
• Optic pathway gliomas
• Skeletal defects
• Pheochromocytoma
• Renal artery stenosis - both are established causes of hypertension in NF1
• Malignant peripheral nerve sheath tumors (MPNSTs) - arising from malignant transformation of neurofibromas

Step 2: Immediate Clinical Assessment

1. ≥6 café-au-lait macules
2. ≥2 neurofibromas of any type, or 1 plexiform neurofibroma
3. Axillary or inguinal freckling
4. Optic glioma
5. ≥2 Lisch nodules (slit-lamp exam)
6. Distinctive osseous lesion (sphenoid wing dysplasia, tibial pseudarthrosis)
7. First-degree relative with NF1

• BP 160/90 in a 15-year-old is Stage 2 hypertension (≥95th percentile + 12 mmHg for age 15 is ≥139 SBP; 160 mmHg is significantly above this threshold)
• This is NOT primary/essential hypertension in a 15-year-old - a secondary cause must be found
• The 50th percentile for BP in a 15-year-old boy is 113/65 mmHg; 95th percentile is ~132/83 mmHg (Harriet Lane Handbook, 23rd Ed)

Step 3: Differential Diagnosis for Hypertension in NF1

Step 4: Investigations - Parallel Workup

• Plasma fractionated metanephrines - sensitivity 96-100% (screening test of choice); specificity 85-89%
• If plasma metanephrines are elevated: confirm with 24-hour urine fractionated catecholamines and metanephrines (sensitivity 98%, specificity 98%)
• Normal reference values (Goldman-Cecil Medicine):
  • Plasma normetanephrine: <0.9 nmol/L
  • Plasma metanephrine: <0.5 nmol/L
  • 24h urine norepinephrine: <170 µg; epinephrine: <35 µg; normetanephrine: <900 µg

• Renal Doppler ultrasound - first-line, non-invasive
• If Doppler abnormal or high clinical suspicion: CT renal angiography or MR renal angiography
• Compare bilateral renal sizes (asymmetry suggests unilateral renal artery stenosis)
• Measure plasma renin activity (PRA) and aldosterone - elevated renin supports renovascular hypertension

• Urinalysis (renal parenchymal disease)
• Serum electrolytes, creatinine, BUN (renal function)
• Fasting glucose, HbA1c (obesity-related metabolic syndrome)
• Fasting lipid panel
• TSH (thyroid)
• Echocardiography - assess for left ventricular hypertrophy (target organ damage)
• 24-hour ambulatory blood pressure monitoring (ABPM) to confirm true hypertension
• Four-limb BP measurement to exclude coarctation of aorta

• CT abdomen/pelvis with contrast - adrenal masses (most common site)
• MIBG scintigraphy (I-123 MIBG) or FDG-PET/CT or 18F-DOPA PET/CT - functional localization, especially for extra-adrenal paragangliomas and multifocal disease

• Send for full histological workup to determine if this is a benign neurofibroma, schwannoma, or MPNST
• If MPNST: this is a high-grade malignancy requiring oncologic referral
• Genetic testing for NF1 germline mutation to confirm diagnosis

Step 5: Immediate BP Management

• Do NOT give beta-blockers first - this causes unopposed alpha-adrenergic stimulation and worsens hypertension
• Use intravenous phentolamine (short-acting alpha-blocker) for acute hypertensive crises intraoperatively
• Once biochemical diagnosis is confirmed preoperatively: start phenoxybenzamine (nonselective, irreversible alpha-blocker) 10 mg twice daily, titrate upward every 2-3 days (max 40 mg TID) for 10-14 days before any further surgery
• Only add beta-blocker (propranolol/atenolol) AFTER adequate alpha-blockade has been established, to control tachycardia
• Calcium channel blockers (nifedipine, nicardipine) may be added for inadequate BP control

• Start ACE inhibitor or ARB (monitor renal function closely)
• Definitive treatment: percutaneous transluminal renal angioplasty (PTRA) or surgical revascularization

• Lifestyle: aerobic exercise, sodium restriction, weight loss (obesity management)
• First-line pharmacologic agents: ACE inhibitors, ARBs, thiazide diuretics, long-acting calcium channel blockers
• Target BP: <90th percentile or <130/80 mmHg in adolescents ≥13 years

Step 6: Surgical/Oncologic Follow-up

• Histopathology result of ulnar nerve sheath tumor is pending: if MPNST confirmed, this requires wide surgical re-excision, adjuvant radiotherapy, and oncology referral (MPNST carries a poor prognosis and is the leading cause of cancer-related death in NF1 patients)
• If pheo is confirmed: laparoscopic adrenalectomy after adequate preoperative alpha-blockade (minimum 10-14 days)
• Genetic counseling for the patient and family (NF1 is autosomal dominant; offspring have 50% risk)
• Ophthalmology referral for slit-lamp (Lisch nodules) and optic glioma screen
• Multidisciplinary NF1 clinic - neurology, surgery, oncology, endocrinology, ophthalmology, genetics

Summary Algorithm

15F obese boy + ulnar nerve sheath tumor + intraoperative/postoperative HTN (160/90)
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Recognize NF1 syndrome - examine for café-au-lait spots, axillary freckling, Lisch nodules
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URGENT: Plasma fractionated metanephrines → if elevated → 24h urine catecholamines
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Renal Doppler ultrasound + four-limb BP → exclude renal artery stenosis & coarctation
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Echocardiography (LVH assessment) + ABPM
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If pheo biochemically confirmed → CT/MRI abdomen → adrenal/paraganglioma localization
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Start alpha-blockade (phenoxybenzamine 10 mg BD) for 10-14 days BEFORE any further surgery
Then add beta-blocker only after alpha-blockade established
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Histopathology of nerve sheath tumor → if MPNST → wide re-excision + oncology referral
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NF1 genetic confirmation + multidisciplinary NF1 clinic referral

• Adams & Victor's Principles of Neurology, 12th Ed, p. 1029
• Robbins & Cotran Pathologic Basis of Disease, p. 3015
• Sabiston Textbook of Surgery, p. 1576
• Goldman-Cecil Medicine, p. 355
• Harriet Lane Handbook, 23rd Ed, p. 694