part 4 oncology and hematology from harrisons section 1 neoplastic disorders from chapter 73 to 100 teach me every thing i need to know from harrisons and add some images and mneumonics if u can so i can become the best doctor

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Here is your complete, high-yield study guide for Harrison's Part 4: Oncology and Hematology, Section 1: Neoplastic Disorders, Chapters 73-100 (22nd Edition, 2025).

🏥 HARRISON'S ONCOLOGY & HEMATOLOGY: CHAPTERS 73–100

Your Complete Study Guide — Become the Best Doctor

CHAPTER 73 — Approach to the Patient with Cancer

The Big Picture

Cancer causes 1 in 4 deaths in the USA
2024: ~2 million new cases; ~612,000 deaths
~2/3 of patients are now cured with modern treatment

Top Cancers by Incidence

Males	Females
Prostate (29%)	Breast (32%)
Lung (11%)	Lung (12%)
Colorectal (8%)	Colorectal (7%)

Mnemonic for top causes of cancer DEATH in males: "Lung Prostate Colon Pancreas" (LPCP)

The Physician's Role

Take cancer diagnosis as seriously as end-stage heart failure — the median survival of pancreatic cancer (~8 months) equals symptomatic aortic stenosis with CHF, but the psychological impact is categorically different
The patient feels the whole self is diseased, not just an organ
Psychosocial, functional, and existential dimensions must be addressed

Performance Status (ECOG Scale)

Grade	Description
0	Fully active
1	Restricted in strenuous activity, ambulatory
2	Ambulatory, capable of self-care, up >50% of day
3	Limited self-care, confined to bed >50% of day
4	Completely disabled

Mnemonic: "0-Okay, 1-Limited, 2-Some help, 3-Mostly bed, 4-Fully bed"

CHAPTER 74 — Cancer Epidemiology and Prevention

Key Concepts

Carcinogenesis is a multistep process over years: initiation → promotion → progression
Both environmental and genetic factors interact
The leading preventable cause of cancer is tobacco (responsible for ~30% of all cancer deaths)

Attributable Risks

Factor	% of Cancer Deaths
Tobacco	~30%
Diet/Obesity	~30%
Infections	~5-10%
Alcohol	~3-4%

CHAPTER 75 — Prevention and Early Detection of Cancer

Chemoprevention Highlights

Agent	Cancer Prevented	Notes
Tamoxifen/Raloxifene	Breast (ER+)	50% risk reduction in high-risk women
Finasteride	Prostate	Reduces incidence but may shift grade
NSAIDs/COX-2 inhibitors	Colorectal	Polyp regression, not yet standard
HPV vaccine	Cervical, anal, oropharyngeal	Girls AND boys
HBV vaccine	Hepatocellular carcinoma

Screening Tests: The 4 Numbers

Sensitivity = TP/(TP+FN) — "How good at catching disease" Specificity = TN/(TN+FP) — "How good at ruling out disease" PPV depends on prevalence — low prevalence → low PPV even with good test

⚠️ For rare cancers in general population, even high-sensitivity tests have poor PPV!

Key Screening Recommendations (Harrison 22e)

Cancer	Test	Who/When
Colorectal	Colonoscopy/FIT	Age 45-75
Breast	Mammogram	Age 40-74 annually
Cervical	Pap + HPV	Age 21-65 every 3-5 yrs
Lung	Low-dose CT	Age 50-80, 20+ pack-yr history
Prostate	PSA (shared decision)	Age 50+ (45 high-risk)

Biases in Screening Studies

Lead-time bias — detecting early but not changing death date
Length bias — screening catches slow-growing, less lethal tumors
Overdiagnosis — finding tumors that would never cause symptoms
Selection bias — healthier people get screened

Mnemonic: "LLOS" = Lead-time, Length, Overdiagnosis, Selection

CHAPTER 76 — Cancer Genetics

Two Hit Hypothesis (Knudson)

Two mutations needed to inactivate a tumor suppressor gene
Hereditary cancers: first hit in germline (inherited), second hit somatic
Sporadic cancers: both hits somatic

Oncogenes vs Tumor Suppressors

	Oncogenes	Tumor Suppressors
Mutation type	Gain-of-function	Loss-of-function
Inheritance	Dominant	Recessive (2 hits)
Examples	RAS, MYC, HER2, BCR-ABL	TP53, RB1, APC, BRCA1/2
Analogy	Stuck "accelerator"	Broken "brake"

Mnemonic: "Oncogenes = ON stuck = Dominant; Suppressors = need both OFF = Recessive"

Key Hereditary Cancer Syndromes

Syndrome	Gene	Cancers
Hereditary Breast/Ovarian	BRCA1/2	Breast, ovary, prostate, pancreas
Lynch syndrome (HNPCC)	MLH1, MSH2, MSH6, PMS2	Colorectal, endometrial, ovarian, gastric
FAP	APC	Colorectal (near 100% by age 40)
MEN1	MEN1	Parathyroid, pituitary, pancreas
MEN2	RET gain-of-function	Medullary thyroid, pheo, parathyroid
Li-Fraumeni	TP53	Sarcoma, breast, brain, leukemia, adrenal
VHL	VHL	Clear cell RCC, hemangioblastoma, pheo
PTEN/Cowden	PTEN	Breast, thyroid, endometrial
Gorlin syndrome	PTCH1	Basal cell carcinomas (hundreds)

APC gene mutations: somatic mutations cluster at codon 1309 and 1450 (MCR); germline mutations at codons 1061 and 1309 — hotspots accounting for 1/3 of FAP families

Mnemonic for MEN syndromes:

MEN 1 = 3P's: Parathyroid, Pituitary, Pancreas
MEN 2A = 3M's: Medullary thyroid, pheochroMocytoma, Munching (hyperparathyroid)
MEN 2B = 2M + Mucosal neuroma + Marfanoid

CHAPTER 77 — Principles of Cancer Treatment

Hallmarks of Cancer (Hanahan & Weinberg)

Self-sufficiency in growth signals
Insensitivity to anti-growth signals
Evasion of apoptosis
Limitless replicative potential (telomerase)
Sustained angiogenesis (VEGF)
Tissue invasion and metastasis
Reprogrammed energy metabolism (Warburg effect)
Evasion of immune destruction
Tumor-promoting inflammation
Genome instability

Cancer Treatments Overview

Surgery

Best for localized disease
Principles: adequate margins, lymph node sampling
Sentinel node biopsy: inject radiotracer/dye → find first draining node

Radiation Therapy

Ionizing radiation → DNA double-strand breaks
Normal tissue tolerance limits dose
Types: External beam (EBRT), Brachytherapy (implanted sources), Stereotactic (SBRT/SRS)
Most sensitive: Rapidly dividing cells (marrow, GI mucosa, gonads)

Chemotherapy Cell Cycle Specificity

Phase-specific	Non-phase-specific
Methotrexate (S phase)	Alkylating agents
5-FU (S phase)	Platinum compounds
Vincristine/Vinblastine (M phase)	Anthracyclines
Taxanes (M phase)
Etoposide (G2/M)

Mnemonic for alkylating agents: "BCNU Can Make Cancer Worse"

Busulfan, CCNU (lomustine), Nitrogen mustard, Cyclophosphamide, Melphalan, Chlorambucil, Carmustine

Targeted Therapies (Key Table)

Drug	Target	Disease
Imatinib	BCR-ABL, c-Kit, PDGFR	CML, GIST
Erlotinib/Gefitinib	EGFR	NSCLC
Osimertinib	EGFR T790M	NSCLC (resistance mutation)
Trastuzumab	HER2	Breast, gastric
Bevacizumab	VEGF-A	Colorectal, lung, ovarian, GBM
Rituximab	CD20	B-cell lymphomas
Cetuximab	EGFR	Colorectal (RAS wild-type only!), H&N
Vemurafenib	BRAF V600E	Melanoma
Sorafenib	VEGFR, BRAF, PDGFR	RCC, HCC, thyroid
Sunitinib	VEGFR, c-Kit, PDGFR	RCC, GIST, PNET
ATRA	PML-RARα	APL (M3 AML)
Asciminib	BCR-ABL (allosteric)	CML (resistant/intolerant)

Immune Checkpoint Inhibitors

Target	Drugs	Key Tumors
PD-1	Pembrolizumab, Nivolumab	NSCLC, melanoma, many others
PD-L1	Atezolizumab, Durvalumab	Bladder, NSCLC, HCC
CTLA-4	Ipilimumab	Melanoma (with nivolumab)

Key immune-related adverse events (irAEs):

Colitis (most common with CTLA-4)
Pneumonitis (most common with PD-1)
Hepatitis, hypophysitis, thyroiditis, nephritis, dermatitis
Treatment: Corticosteroids; severe cases → infliximab (colitis), mycophenolate (hepatitis)

CAR-T Cell Therapy

T cells engineered to express chimeric antigen receptors (CARs)
FDA approved for B-cell ALL (tisagenlecleucel), DLBCL, myeloma, follicular lymphoma
Key toxicities:
- Cytokine Release Syndrome (CRS): fever, hypotension, hypoxia → treat with tocilizumab (IL-6 receptor blocker)
- Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): confusion, aphasia, seizures → corticosteroids

CHAPTER 78 — Principles of Cancer Treatment (Endocrine)

Covered in Ch 77; cancer immunotherapy-associated endocrinopathies:

CTLA-4 inhibitors → hypophysitis most common
PD-1 inhibitors → thyroid dysfunction most common
Both → type 1 DM (rare but irreversible)

CHAPTER 79 — Infections in Patients with Cancer

Neutropenic Fever (NF)

Definition: Fever ≥38.3°C (or ≥38°C x 1h) + ANC <500/µL (or expected to fall <500)

First Episode Management

Blood cultures → start antibiotics within 1 hour
Monotherapy with anti-pseudomonal coverage:
- Cefepime, ceftazidime, piperacillin-tazobactam, meropenem, imipenem
Add vancomycin only if: sepsis, soft tissue infection, catheter site infection, pneumonia, severe mucositis (with ceftazidime), MRSA carrier, penicillin-resistant pneumococcus carrier
Do NOT routinely add vancomycin (increases nephrotoxicity, no mortality benefit)

When to Add Antifungals

Add if fever persists 4-7 days on broad antibiotics + persistent neutropenia
Empirical antifungals: Liposomal amphotericin B, caspofungin, voriconazole
Prevention: Fluconazole prophylaxis in high-risk (AML induction, stem cell transplant)

MASCC Score (Low-Risk NF — Safe for Outpatient Tx)

Score ≥21 = low risk → can use oral ciprofloxacin + amoxicillin-clavulanate

Factor	Points
Burden of symptoms: no/mild	5
No hypotension	5
No COPD	4
Solid tumor or no fungal infection	4
No dehydration	3
Outpatient status at onset	3
Age <60	2

Mnemonic: "MASCC = Mild, Afebrile outpatient, Solid tumor, Compensated pressure, Can walk"

CHAPTER 80 — Oncologic Emergencies

Three categories:

Structural/Obstructive
Metabolic/Hormonal (Paraneoplastic)
Treatment-related

SUPERIOR VENA CAVA SYNDROME (SVCS)

Causes:

Lung cancer (~85% of malignant causes) — especially small cell and squamous cell
Lymphoma (young adults — most commonly NHL)
Benign causes now ~40% (intravascular devices, pacemakers)

Clinical Features:

Facial/arm swelling, dyspnea, headache (worse bending forward)
Distended neck/chest veins, plethora, Pemberton's sign

Treatment:

Endovascular stenting = fastest symptom relief
Radiation for radiosensitive tumors (lymphoma, SCLC)
Chemotherapy for SCLC, lymphoma (both radiation and chemo)

SPINAL CORD COMPRESSION

Most common tumors: Lung > Breast > Prostate > Lymphoma > Myeloma

Symptoms: Back pain (earliest!) → weakness → sensory loss → bowel/bladder dysfunction

Treatment: Dexamethasone 10mg IV immediately → MRI whole spine → XRT or surgery (decompression laminectomy preferred if single level, good prognosis, neurologically intact or rapidly progressive)

⚠️ Back pain in cancer patient = MRI spine until proven otherwise

INCREASED INTRACRANIAL PRESSURE (Brain Mets)

Most common: Lung, breast, melanoma, colon, RCC
Treatment: Dexamethasone + whole brain XRT ± resection ± stereotactic radiosurgery

PERICARDIAL EFFUSION/TAMPONADE

Breast, lung, lymphoma, leukemia
Treatment: Pericardiocentesis (diagnostic + therapeutic)

METABOLIC ONCOLOGIC EMERGENCIES

Hypercalcemia of Malignancy

Most common metabolic emergency in cancer!

Mechanisms:

PTHrP secretion (most common) — squamous (lung, H&N, esophagus), renal, breast
Osteolytic mets — breast, myeloma
1,25-OH vitamin D excess — lymphoma (granulomatous activation of 1-alpha-hydroxylase)
True ectopic PTH — rare

Symptoms (BONES, GROANS, MOANS, PSYCHIC OVERTONES):

Bones: pain
Groans: nausea, vomiting, constipation
Moans: fatigue, weakness
Psychic: confusion, coma

Treatment:

IV fluids (0.9% NS)
Bisphosphonates — pamidronate or zoledronate (onset 2-4 days, lasts weeks)
Denosumab — anti-RANKL (for bisphosphonate-refractory or renal failure)
Calcitonin — fastest onset (hours) but tachyphylaxis in 48h
Corticosteroids — for lymphoma and vitamin D-mediated

Tumor Lysis Syndrome (TLS)

Most common in: Burkitt lymphoma, ALL, AML (especially high WBC)

Lab findings (Cairo-Bishop criteria):

Hyperuricemia
Hyperkalemia
Hyperphosphatemia
Hypocalcemia
Elevated creatinine (AKI)

Prevention: Allopurinol (blocks uric acid synthesis) or Rasburicase (enzymatic degradation — preferred in high risk; contraindicated in G6PD deficiency)

Treatment: Aggressive IV hydration, rasburicase, dialysis if needed

Mnemonic: "TLS = Tumor Lysis Syndrome → Potassium Up, Phosphate Up, Uric Acid Up, Calcium Down"

SIADH in Cancer

Most common cause in cancer: Small Cell Lung Cancer
Also: brain mets, vincristine, cyclophosphamide
Treatment: fluid restriction; demeclocycline; conivaptan/tolvaptan

Lactic Acidosis

Leukemia, lymphoma, solid tumors with massive liver involvement
Treatment: Treat underlying cancer; bicarbonate for severe acidosis; hemodialysis

Hypoglycemia

Non-islet cell tumors: retroperitoneal sarcomas, hepatomas, adrenocortical tumors
Mechanism: IGF-II secretion (big IGF-II — incompletely processed)
Distinguish from insulinoma: suppressed C-peptide and insulin, elevated IGF-II/IGF-I ratio

CHAPTER 81 — Lung Cancer

Epidemiology

#1 cancer killer in both sexes worldwide
~85% are non-small cell lung cancer (NSCLC); ~15% small cell (SCLC)

NSCLC Types

Type	Location	Key Mutation	Association
Adenocarcinoma	Peripheral	EGFR (Asian women), KRAS, ALK, ROS1	Never/light smokers
Squamous	Central	SOX2, FGFR1	Heavy smokers
Large cell	Peripheral	—	Smokers

SCLC

Central, aggressive, neuroendocrine
Paraneoplastic syndromes: SIADH, Cushing's (ectopic ACTH), Lambert-Eaton
Very chemo/radiation-sensitive but almost always recurs
Limited stage: cisplatin + etoposide + thoracic XRT ± prophylactic cranial irradiation (PCI)
Extensive stage: cisplatin/carboplatin + etoposide ± atezolizumab

NSCLC Treatment by Stage

Stage I-II: Surgery (lobectomy preferred)
Stage III: Concurrent chemoradiation + durvalumab maintenance
Stage IV: Biomarker-driven:
- EGFR mutation → Osimertinib
- ALK/ROS1 rearrangement → Alectinib (ALK), Entrectinib (ROS1)
- BRAF V600E → Dabrafenib + Trametinib
- MET exon 14 skipping → Capmatinib
- KRAS G12C → Sotorasib/Adagrasib
- PD-L1 ≥50% → Pembrolizumab monotherapy
- PD-L1 any → Chemo + pembrolizumab

CHAPTER 82 — Head and Neck Cancers

Squamous cell carcinoma in >90% of cases
Risk: tobacco + alcohol (synergistic), HPV (oropharyngeal — especially HPV-16)
HPV-positive oropharyngeal cancer: better prognosis, younger, non-smokers
Treatment: Surgery and/or radiation ± cisplatin; cetuximab if cisplatin-ineligible
Recurrent/metastatic: pembrolizumab ± chemo (KEYNOTE-048)

CHAPTER 83 — Esophageal Cancer

Feature	Squamous Cell (SCC)	Adenocarcinoma
Location	Upper/mid	Lower/GEJ
Risk factors	Tobacco, alcohol, achalasia	GERD, Barrett's, obesity
Trend	Declining	Increasing

Localized: Surgery + neoadjuvant chemoradiation (CROSS trial: carboplatin-paclitaxel + XRT)
Metastatic: Nivolumab + chemo (first line, PD-L1 CPS ≥5)

CHAPTER 84 — Gastric Cancer

Helicobacter pylori is the #1 risk factor for intestinal type
Lauren classification: Intestinal (better prognosis) vs. Diffuse (signet ring, worse prognosis)
Diffuse = CDH1 mutation in hereditary cases
HER2 overexpression in ~20% → trastuzumab + chemo (first line, metastatic)
Nivolumab + FOLFOX now standard for HER2-negative advanced disease

CHAPTER 85 — Pancreatic Cancer

5th leading cause of cancer death; only ~10% resectable at diagnosis
Risk: smoking, DM, chronic pancreatitis, familial (BRCA2, PALB2, ATM)
Whipple procedure (pancreaticoduodenectomy) for resectable head tumors
Adjuvant: mFOLFIRINOX (fit patients) or gemcitabine + capecitabine
Metastatic: FOLFIRINOX (fit) or gemcitabine + nab-paclitaxel
BRCA1/2 mutant: maintenance olaparib (POLO trial)

CHAPTER 86 — Colorectal Cancer (CRC)

Risk Factors

Mnemonic: "DISH + Fat"

Diet (animal fat, red/processed meat)
Inflammatory bowel disease
Streptococcus bovis bacteremia
Hereditary syndromes
Fat (Obesity), tobacco

Hereditary CRC Syndromes

Syndrome	Gene	Key Features
FAP	APC (AD)	Thousands of polyps, 100% cancer by 40s, duodenal ampullary cancer
Gardner's	APC	FAP + osteomas + desmoid + epidermoid cysts + retinal pigment hypertrophy
Turcot's	APC or mismatch repair	FAP + brain tumors
Lynch (HNPCC)	MLH1/MSH2/MSH6/PMS2	~80% lifetime CRC risk, proximal colon predominant, endometrial/ovarian cancer
Peutz-Jeghers	STK11/LKB1	Hamartomas + mucocutaneous pigmentation + GI/ovarian/breast/pancreas
MUTYH-polyposis	MUTYH (AR)	Adenomas, CRC

Molecular Pathways in CRC

Chromosomal instability (CIN) — APC → K-RAS → SMAD4 → TP53 (85%)
Microsatellite instability (MSI/MMR-deficient) — Lynch syndrome and sporadic (15%)
CIMP/serrated pathway — BRAF V600E + MLH1 methylation (serrated polyps)

Staging and Treatment

Stage	5-yr Survival	Treatment
I	90%	Surgery alone
II	70-80%	Surgery ± adjuvant (high-risk features)
III	40-65%	Surgery + FOLFOX or CAPOX x 6 months
IV	~15-25%	Systemic therapy; resect if resectable

Metastatic CRC Key Drugs: 5-FU/capecitabine, oxaliplatin, irinotecan, bevacizumab

MSI-High (dMMR): Pembrolizumab first-line (long-term responses possible!)
RAS wild-type, left-sided: Add cetuximab or panitumumab to chemo
BRAF V600E: Encorafenib + cetuximab in 2nd line

⚠️ Always check RAS (KRAS/NRAS) and BRAF status before starting biologics!

CHAPTER 87 — Hepatocellular Carcinoma (HCC)

Epidemiology

Most common primary liver cancer globally (5th most common overall)
Risk factors: Cirrhosis (any cause), HBV, HCV, aflatoxin B1, alcohol, NASH/NAFLD, hemochromatosis

Mnemonic for HCC risk factors: "CIA + HABN"

Cirrhosis, Infection (HBV/HCV), Aflatoxin
Hemochromatosis, Alcohol, NAFLD, Birth weight/genetics

Screening

All cirrhotic patients: ultrasound + AFP every 6 months
AFP >200 in right context is diagnostic; AFP >400 essentially diagnostic

Diagnosis (Barcelona Criteria)

Can diagnose without biopsy in cirrhotic patients:
- Lesion >1 cm with arterial enhancement + portal venous washout on CT/MRI

Staging (Barcelona BCLC)

Stage	Characteristics	Treatment
0/A (Very early/Early)	Single ≤2cm or ≤3 nodules ≤3cm, good PS, no portal HTN	Resection, ablation, transplant
B (Intermediate)	Multinodular, compensated	TACE
C (Advanced)	Vascular invasion or extrahepatic spread	Sorafenib → Lenvatinib; Atezolizumab + bevacizumab (preferred first-line)
D (Terminal)	Poor PS, decompensated	Best supportive care

Transplant criteria (Milan): Single ≤5 cm or ≤3 nodules ≤3 cm, no vascular invasion, no extrahepatic spread

Current First-Line Systemic Therapy

Atezolizumab + bevacizumab (IMbrave150) — improved OS vs sorafenib Second line: Regorafenib, cabozantinib, ramucirumab (AFP >400)

CHAPTER 88 — Cholangiocarcinoma (CCA) and Biliary Cancers

Types: Intrahepatic (iCCA), Perihilar (Klatskin tumor), Distal
Risk: PSC (especially perihilar), liver flukes (Clonorchis/Opisthorchis), IBD, bile duct cysts

Treatment

Resectable: Surgery → adjuvant capecitabine x 6 months (BILCAP trial)
Unresectable: Gemcitabine + cisplatin + durvalumab (TOPAZ-1) — now standard of care
2nd line: mFOLFOX; IDH1 inhibitor (ivosidenib) for IDH1-mutant; FGFR inhibitors (pemigatinib, infigratinib) for FGFR2-fused iCCA

CHAPTER 89 — Gastrointestinal Neuroendocrine Tumors (NETs)

Classification

Graded by Ki-67 proliferation index:
- G1: Ki-67 <3%, well-differentiated
- G2: Ki-67 3-20%, well-differentiated
- G3: Ki-67 >20% (includes both well-diff NETs and poorly-diff NECs)

Carcinoid Syndrome

Requires liver mets (bypasses hepatic first-pass metabolism) or non-hepatic source
Symptoms: flushing + diarrhea + bronchospasm + right heart disease (tricuspid/pulmonic)
Marker: 24-hour urinary 5-HIAA, serum chromogranin A
Treatment: Octreotide (somatostatin analog) — symptom control and antiproliferative
Carcinoid crisis (during surgery) → IV octreotide infusion

Mnemonic for Carcinoid: "FDBR" = Flushing, Diarrhea, Bronchospasm, Right heart disease

Pancreatic NETs (Functioning)

Tumor	Hormone	Syndrome
Insulinoma	Insulin	Whipple's triad (symptoms, low glucose, relief with glucose)
Gastrinoma	Gastrin	Zollinger-Ellison (peptic ulcers, diarrhea)
VIPoma	VIP	WDHA (watery diarrhea, hypokalemia, achlorhydria)
Glucagonoma	Glucagon	Necrolytic migratory erythema, DM, weight loss
Somatostatinoma	Somatostatin	Diabetes, cholelithiasis, steatorrhea

Mnemonic: "I Get Very Good Somatostatin" = Insulinoma, Gastrinoma, VIPoma, Glucagonoma, Somatostatinoma

Treatment

Resectable: Surgery
Unresectable G1/G2: Octreotide/Lanreotide (PROMID, CLARINET trials) → Everolimus (mTOR) → Sunitinib (VEGFR) → PRRT (177Lu-DOTATATE for somatostatin receptor-positive)

CHAPTER 90 — Thyroid Cancer

Type	Frequency	Genetics	10-yr Survival
Papillary	80-85%	BRAF V600E, RET/PTC rearrangement	>95%
Follicular	10-15%	RAS, PAX8-PPARγ	85-90%
Medullary	3-5%	RET mutation (25% familial → MEN2)	75%
Anaplastic	1-2%	TP53, BRAF, TERT	<10% (months)

Medullary thyroid: Calcitonin is tumor marker; RET proto-oncogene testing for ALL patients (and family screening)
Anaplastic: BRAF V600E targeted therapy (dabrafenib + trametinib) for ~50%

CHAPTER 91 — Bladder and Urinary Tract Cancer

Epidemiology

4th most common cancer in men
Transitional cell carcinoma (urothelial) in >90%
Risk factors: Smoking (#1), aniline dyes, cyclophosphamide, schistosomiasis (squamous cell in endemic areas), pelvic radiation

Classification

NMIBC (non-muscle invasive, Ta/T1/CIS): ~75% at presentation
MIBC (T2+): Requires cystectomy

Treatment

NMIBC: TURBT → intravesical BCG (intermediate/high-risk) → repeat TURBT
- BCG failure → cystectomy (preferred) or pembrolizumab/nadofaragene
MIBC: Neoadjuvant cisplatin + chemo → radical cystectomy OR bladder-sparing (chemoradiation)
Metastatic: Cisplatin + gemcitabine → maintenance avelumab (after platinum response) OR pembrolizumab (cisplatin-ineligible)

CHAPTER 92 — Prostate Cancer

Key Facts

Most common cancer in men
PSA — screening controversial, shared decision-making
Gleason score → Grade Groups 1-5 (GG1 = most favorable)

Staging and Treatment Overview

Stage	Treatment Options
Localized (low-risk GG1)	Active surveillance
Localized (intermediate/high-risk)	Radical prostatectomy or definitive XRT ± ADT
Locally advanced (T3/N1)	XRT + long-term ADT
Metastatic hormone-sensitive	ADT + docetaxel or ADT + abiraterone/enzalutamide/apalutamide
Castration-resistant (mCRPC)	Abiraterone, enzalutamide, docetaxel, cabazitaxel, radium-223 (bone mets), PARP inhibitors (BRCA1/2)

Mnemonic for hormonal agents: "Abi-En-Apa" block androgen axis at 3 levels:

Abiraterone → CYP17 (blocks testosterone synthesis, adrenal + gonadal)
Enzalutamide → AR (blocks receptor)
Leuprolide/Degarelix → GnRH (castrate testosterone)

CHAPTER 93 — Testicular Cancer

Most common solid tumor in men age 15-35
Highly curable, even with metastasis (paradigm of curable solid tumor cancer)
Arise from primordial germ cells

Classification

Type	Markers	Features
Seminoma	hCG (rarely), ALP	Pure, radiosensitive, NEVER makes AFP
Nonseminoma (NSGCT)	AFP, hCG, LDH	Includes embryonal, choriocarcinoma, yolk sac, teratoma

⚠️ Elevated AFP = NSGCT by definition, even if pathology shows pure seminoma

Staging & Treatment

Stage	Treatment
I Seminoma	Orchiectomy ± surveillance (preferred)/para-aortic XRT/carboplatin x1
I NSGCT	Orchiectomy + RPLND or surveillance (low-risk)
IIA/B Seminoma	XRT
IIA/B NSGCT	BEP x3 cycles
III (any)	BEP x3-4 cycles

BEP = Bleomycin + Etoposide + Cisplatin

Mnemonic: "SEMinoma = Sensitive Every time (radiotherapy works), NSGCT = Need Surgery/Chemo"

CHAPTER 94 — Gynecologic Malignancies

Ovarian Cancer

#1 cause of gynecologic cancer death (because diagnosed late)
Serous high-grade = most common and aggressive (TP53, BRCA1/2 somatic)
Hereditary: BRCA1 (40% lifetime risk), BRCA2 (15-25% risk), Lynch syndrome (endometrial > ovarian)
Tumor marker: CA-125 (monitoring, not screening)
Treatment: Surgical cytoreduction ("debulking") + carboplatin + paclitaxel ± bevacizumab
Maintenance: PARP inhibitors (olaparib, niraparib, rucaparib) — especially in BRCA1/2 mutant or HRD positive → dramatic PFS improvement

Mnemonic: "PARP inhibitors = Platinum-Responsive homologous-recombination Affected tumors respond Permanently"

Endometrial Cancer

Most common gynecologic cancer in the USA
Risk: unopposed estrogen (obesity, PCOS, nulliparity, estrogen therapy without progesterone, Lynch syndrome)
Type I: Endometrioid (low-grade, estrogen-driven, good prognosis)
Type II: Serous/Clear cell (high-grade, non-estrogen, worse prognosis)
Molecular classification (TCGA): POLE ultramutated (best) > MMR-deficient > copy-number low > copy-number high/serous-like (worst)
Metastatic: Pembrolizumab + lenvatinib (regardless of MSI status) — [KEYNOTE-775/Study 309]

Cervical Cancer

HPV types 16 and 18 → 70% of cervical cancers
Screening: Pap + HPV co-test every 5 years (age 25-65)
Treatment: IA1 → conization; IA2-IIA → surgery; IIB+ → chemoradiation (cisplatin + XRT)
Metastatic: Pembrolizumab + bevacizumab + chemo → improved OS

CHAPTER 95 — Breast Cancer

Risk Factors

ABCDEFG: Age, BRCA/genes, Contraceptives, Density, Estrogen exposure, Family history, Glandular tissue prior bx

Subtypes by Receptor Status

Subtype	ER	PR	HER2	Treatment
Luminal A	+	+	-	Endocrine therapy ± CDK4/6 inhibitors
Luminal B	+	+/-	-	Endocrine + chemo
HER2-enriched	-	-	+	Anti-HER2 (trastuzumab, pertuzumab, T-DM1)
Triple negative (TNBC)	-	-	-	Chemo ± immunotherapy; PARP if BRCA

Key Drugs

Tamoxifen (ER+, premenopausal); Aromatase inhibitors (letrozole, anastrozole — postmenopausal)
CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) + AI → standard 1st-line metastatic ER+ HER2-
Trastuzumab + pertuzumab + docetaxel → metastatic HER2+
Olaparib/talazoparib → BRCA1/2 mutant HER2-negative advanced

CHAPTER 96 — Soft Tissue and Bone Sarcomas

Soft Tissue Sarcomas

Liposarcoma (most common overall), leiomyosarcoma, synovial sarcoma, rhabdomyosarcoma (children)
Grading is the most important prognostic factor (FNCLCC system: G1/G2/G3)
Treatment: Wide surgical excision ± radiation; Doxorubicin ± ifosfamide (metastatic)
Special targetable sarcomas:
- GIST: Imatinib → sunitinib → regorafenib
- Synovial sarcoma: EZH2 inhibitor (tazemetostat)
- Alveolar soft part sarcoma: Atezolizumab

Bone Sarcomas

Tumor	Age	Location	Features
Osteosarcoma	Teens	Distal femur/proximal tibia/proximal humerus	Sunburst pattern, Codman triangle (XR)
Ewing's sarcoma	Teens	Diaphysis long bones, flat bones	"Onion skin" periosteal reaction, t(11;22) EWS-FLI1
Chondrosarcoma	Adults 40-70	Pelvis, long bones, ribs	Central calcifications, chemotherapy-resistant

Osteosarcoma treatment: Limb-sparing surgery + neoadjuvant MAP (methotrexate, adriamycin, cisplatin) Ewing's treatment: Chemotherapy (VDC-IE) + local control (surgery or radiation)

⚠️ Chondrosarcoma = chemotherapy resistant → surgery is mainstay

CHAPTER 97 — Carcinoma of Unknown Primary (CUP)

Definition

Metastatic cancer found without identifiable primary site despite workup

Initial Workup

CT chest/abdomen/pelvis
PET-CT (increases primary detection ~20-30%)
Immunohistochemistry panel (cytokeratins, TTF-1, CDX2, PSA, ER/PR, etc.)
Next-generation sequencing (NGS)/Molecular profiling — 85% have ≥1 actionable mutation

Favorable Subsets (Treatable Like Known Primary)

Subset	Presumed Site	Treatment
Women with axillary nodes	Breast	Treat as breast cancer
Women with peritoneal carcinomatosis	Ovary	Treat as ovarian cancer
Squamous cell in cervical nodes	H&N	XRT ± surgery
Squamous cell in inguinal nodes	Anal/vulva/cervix	XRT + chemo
Young men midline mass, AFP/hCG elevated	Germ cell	BEP chemotherapy
PSA positive, blastic bone mets	Prostate	ADT
Single metastasis	—	Aggressive local therapy

General CUP Prognosis

Median survival: 6-10 months
Chemotherapy: Carboplatin + paclitaxel (most common empiric)
Tumor-agnostic therapies: Pembrolizumab (MSI-H/TMB-H), NTRK inhibitors (NTRK fusion)

CHAPTER 98 — Paraneoplastic Syndromes

Endocrine Paraneoplastic Syndromes

Syndrome	Mechanism	Tumor
SIADH	Ectopic ADH	SCLC (most common)
Cushing's	Ectopic ACTH	SCLC, carcinoid, thymoma
Hypercalcemia	PTHrP	Squamous (lung, H&N), renal, breast
Hypoglycemia	IGF-II	Sarcoma, hepatoma
Carcinoid syndrome	5-HT, substance P	Carcinoid (with liver mets)
Acromegaly	Ectopic GHRH	Carcinoid, PNET
Erythrocytosis	Ectopic EPO	RCC, HCC, cerebellar hemangioblastoma
Granulocytosis	G-CSF, GM-CSF, IL-6	Lung, GI, ovarian

Neurologic Paraneoplastic Syndromes

Syndrome	Antibody	Tumor
Paraneoplastic cerebellar degeneration	Anti-Yo (PCA-1)	Breast, ovary
Lambert-Eaton	Anti-VGCC	SCLC
Encephalomyelitis/sensory neuropathy	Anti-Hu (ANNA-1)	SCLC
Limbic encephalitis	Anti-LGI1, Anti-NMDAR	Thymoma, ovarian teratoma
Opsoclonus-myoclonus	Anti-Ri	Breast, SCLC
Stiff-person syndrome	Anti-amphiphysin	Breast, SCLC
Dermatomyositis	—	Lung, GI, ovary

Mnemonic for anti-Hu: "Hu = SCLC Sensory neuropathy, Encephalomyelitis" (Hu = Horrible Underlying = SCLC)

VGCC = Voltage-Gated Calcium Channel antibody → Lambert-Eaton myasthenic syndrome

Proximal weakness improving with repetition (contrast with myasthenia which worsens)
Diminished reflexes, autonomic dysfunction
Treatment: 3,4-diaminopyridine (DAP) → pyridostigmine; treat tumor (SCLC)

Caspr2 antibodies → Morvan syndrome (encephalitis + peripheral nerve hyperexcitability + autonomic + insomnia) — associated with thymoma

LGI1 antibodies → faciobrachial dystonic seizures + hyponatremia + limbic encephalitis

CHAPTER 99 — Paraneoplastic Neurologic Syndromes (see Ch 98)

Summary of Key Antibodies

Antibody	Syndrome	Cancer
Anti-Hu	Sensory neuropathy, encephalomyelitis	SCLC
Anti-Yo (PCA-1)	Cerebellar degeneration	Ovary, breast
Anti-Ri (ANNA-2)	Opsoclonus-myoclonus	Breast, SCLC
Anti-VGCC	Lambert-Eaton	SCLC
Anti-NMDAR	Limbic encephalitis	Ovarian teratoma
Anti-LGI1	Faciobrachial seizures, limbic enceph	Thymoma (rare)
Anti-Caspr2	Morvan syndrome, peripheral nerve hyperex	Thymoma
Anti-GABA-B	Limbic encephalitis, seizures	SCLC
Anti-amphiphysin	Stiff-person	Breast, SCLC

CHAPTER 100 — Cancer Survivorship and Late Effects

Growing Problem

18 million cancer survivors in USA (and growing)
Late effects can occur years to decades after treatment

Key Late Effects by Treatment

Chemotherapy:

Anthracyclines (doxorubicin) → Cardiomyopathy (dose-dependent; >550 mg/m² high risk)
Bleomycin → Pulmonary fibrosis (dose + oxygen exposure)
Cisplatin → Nephrotoxicity, ototoxicity, peripheral neuropathy
Alkylating agents → Secondary leukemia (AML), infertility, bladder cancer (cyclophosphamide)
Cyclophosphamide >9 g/m² → Long-term azoospermia

Radiation:

Head/neck XRT → Hypothyroidism, dental caries, xerostomia, cataracts, secondary cancers
Thoracic XRT → Cardiomyopathy, pericarditis, lung fibrosis
Pelvic XRT → Infertility, premature menopause, secondary malignancy (~1% at 10 yrs)
Cranial XRT → Cognitive decline, growth hormone deficiency, obesity (leptin biology)

Immunotherapy (ICIs):

CTLA-4 inhibitors → Hypophysitis > colitis > hepatitis
PD-1 inhibitors → Thyroiditis > pneumonitis > hepatitis
Autoimmune toxicities require lifelong hormone replacement if glands destroyed

Second Malignancies

Most feared late effect
Alkylating agents + topoisomerase inhibitors → therapy-related AML (t-AML)
- Alkylating → t-AML latency 5-7 years, complex karyotype
- Topoisomerase II → t-AML latency 2-3 years, 11q23 (MLL rearrangement), balanced translocations
Radiation → solid tumors (breast after Hodgkin's, sarcomas)

Fertility Preservation

All patients: Counsel before treatment
Males: Sperm cryopreservation
Females: Oocyte or embryo cryopreservation (preferred); ovarian tissue banking (experimental)
GnRH agonists concurrent with chemo → may preserve ovarian function (evidence modest)

Key counseling point: Spermatogenesis is more radiosensitive than Leydig cell function; fertility is lost at lower doses than endocrine function

MASTER MNEMONICS SUMMARY

Mnemonic	Topic
"LPCP"	Top cancer deaths in males: Lung, Prostate, Colon, Pancreas
"LLOS"	Screening biases: Lead-time, Length, Overdiagnosis, Selection
"3P's" for MEN1	Parathyroid, Pituitary, Pancreas
"BONES GROANS MOANS PSYCHIC"	Hypercalcemia symptoms
"TLS PPUC"	Tumor lysis: K+↑, Phos↑, Urate↑, Ca↓
"FDBR"	Carcinoid: Flushing, Diarrhea, Bronchospasm, Right heart
"I Get Very Good Somatostatin"	Pancreatic NET types
"DISH + Fat"	CRC risk factors
"MASCC"	Neutropenic fever low-risk criteria
"CIA + HABN"	HCC risk factors
"BEP"	Testicular cancer chemo: Bleomycin, Etoposide, Cisplatin
"Hu = SCLC"	Anti-Hu antibody → SCLC paraneoplastic
"On stuck = Oncogene"	Oncogenes are gain-of-function, dominant
"Two hits = tumor suppressor"	Knudson 2-hit hypothesis

HIGH-YIELD EXAM FACTS AT A GLANCE

#1 cancer killer in both sexes = Lung cancer
Most common cancer in men = Prostate; in women = Breast
Hypercalcemia mechanism in malignancy = PTHrP (most common)
SVCS most common malignant cause = Lung cancer (SCLC/SqCC)
Fastest acting agent for hypercalcemia = Calcitonin (hours); most durable = bisphosphonate
Tumor Lysis Syndrome highest risk = Burkitt lymphoma, ALL
AFP elevated = NSGCT (even if pathology says seminoma)
Carcinoid syndrome requires liver mets (or non-hepatic primary)
CRC + MSI-High = First-line pembrolizumab (not chemotherapy)
PARP inhibitors benefit BRCA-mutated: ovarian, breast, prostate, pancreatic cancers
BCR-ABL in CML → Imatinib/TKIs; ATRA for APL
Lambert-Eaton = VGCC antibody, SCLC, weakness improves with repetition
Anti-Yo = cerebellar degeneration, ovary/breast
Osimertinib = EGFR T790M resistance mutation in NSCLC
Milan criteria for liver transplant in HCC: single ≤5 cm or ≤3 nodules ≤3 cm

All content sourced from Harrison's Principles of Internal Medicine, 22nd Edition (2025), Chapters 73-100.

Harrison's Principles of Internal Medicine 22E (2025, McGraw Hill Medical)

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