Cancer Pathology | Bone Wizardry

01 · Foundation

Lineage and Spread

Two fundamentally different tumor families with opposite default spread routes.

Epithelial

Carcinoma

Arises from solid organs. Default spread route is lymphatics. Subtypes named by cell type of origin.

Adenocarcinoma Squamous (SCC) Transitional (TCC)

Mesenchymal

Sarcoma

Arises from connective tissue, muscle, or bone. Default spread route is hematogenous (blood). IHC stains vimentin+.

Osteosarcoma Leiomyosarcoma Liposarcoma Ewing Sarcoma

The Hematogenous Carcinoma Exceptions (carcinomas that skip the lymph node rule and spread via blood first)

Primary Tumor	Hematogenous Pattern
Renal Cell Carcinoma	Invades renal vein then IVC. Secretes EPO and PTHrP.
Hepatocellular (HCC)	Arises in cirrhosis. Portal and hepatic vein invasion.
Follicular Thyroid CA	Blood spread to bone. FNA cannot diagnose it.
Choriocarcinoma	Beta-hCG+. Cannonball lung metastasis pattern.

Tumor marker strategy: Use trend, not absolute value. High before treatment, falls after, rises again at recurrence.

Before tx (high) → After tx falls → Rises again = recurrence

02 · Head and Neck

Thyroid Zoo

Four distinct cancers with four distinct profiles. Know the nucleus.

Most Common

Papillary

Ground-glass nuclei, nuclear grooves, intranuclear inclusions. Psammoma bodies in ~50%. RET/PTC mutation. Radiation exposure risk. Lymphatic spread. Best prognosis.

FNA Cannot Diagnose

Follicular

Uniform follicles. Requires capsular invasion to distinguish from adenoma. FNA is inadequate. Hematogenous spread to bone.

C-Cell Origin

Medullary

Parafollicular C-cells. Secretes calcitonin. Amyloid stroma (Congo red+). Linked to MEN 2A and MEN 2B. RET mutation.

Elderly, Worst Prognosis

Anaplastic

Rapidly fatal. Spindle and giant cells. Tracheal invasion causes dysphagia and stridor. Dedifferentiated from papillary or follicular.

Virchow's Node: Left supraclavicular node enlarged = GI primary (stomach, colon, pancreas). Hard, fixed, non-tender.

Sister Mary Joseph Node: Periumbilical nodule = intra-abdominal malignancy (stomach, colon, ovary).

03 · Brain and Pediatric

CNS Tumors and Pediatric Oncology

Location plus histology pins the diagnosis.

Adult · Grade IV

Glioblastoma Multiforme

Butterfly lesion crossing corpus callosum. Pseudopalisading necrosis around central necrosis. GFAP+. Worst prognosis.

Child · Cerebellum

Medulloblastoma

Homer-Wright rosettes. Small round blue cells. Highly radiosensitive. Can seed CSF (drop mets).

Adult · Parasagittal

Meningioma

Whorled pattern with psammoma bodies. Extra-axial. NF2 association. Usually benign, surgical resection curative.

Child · Cerebellum

Pilocytic Astrocytoma

Rosenthal fibers. Mural nodule with cystic component. GFAP+. Best prognosis of all gliomas.

Child · Suprasellar

Craniopharyngioma

Calcified suprasellar mass. Derived from Rathke's pouch remnant. Bitemporal hemianopia and hypopituitarism. Machine-oil fluid.

Bone · Diaphysis

Ewing Sarcoma

Small round blue cells. Onion-skin periosteal reaction. Diaphysis of long bones. t(11;22), EWS-FLI1 fusion.

CLICK TO REVEAL:

N-myc

Neuroblastoma

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Amplification = worse prognosis. Bombesin+ neuroendocrine marker. Adrenal medulla origin.

Rb gene

Retinoblastoma

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Two-hit hypothesis. Leukocoria (white pupillary reflex). High lifetime risk for osteosarcoma.

t(11;22)

Ewing Sarcoma

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EWS-FLI1 fusion. Diaphysis. Onion-skin periosteum. VACA chemotherapy regimen.

Desmin

Rhabdomyosarcoma

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IHC stain for muscle-origin tumors. Most common soft tissue sarcoma in children.

Vimentin

All Sarcomas

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Mesenchymal intermediate filament. Present in all sarcomas, endothelial cells, and fibroblasts.

04 · Chest, GI, and Breast

Organ-Specific High Yield

Paraneoplastic syndromes, GI pearl rules, and breast cancer pharmacology.

Central Location

Small Cell Lung CA

Neuroendocrine. SIADH (hyponatremia). ACTH (Cushing). Lambert-Eaton (proximal muscle weakness, improves with use). L-myc oncogene. Chromogranin+.

Central Location

Squamous Cell Lung

PTHrP (hypercalcemia). Keratin pearls. Cavitates. Central, adjacent to bronchus. Smokers. Cavitation on CXR.

Peripheral Location

Adenocarcinoma Lung

Most common in non-smokers. KRAS/EGFR mutations. Peripheral nodule. Bronchoalveolar subtype shows pneumonia-like consolidation.

GI Pearl Rules

Colon CA Buzzwords

Bovis in blood = scope the colon. C. septicum bacteremia = hunt for occult colon CA. Signet ring cells = gastric linitis plastica.

Lambert-Eaton vs. Myasthenia Gravis: Lambert-Eaton = weakness that improves with repetition (presynaptic Ca channel Abs), linked to small cell lung CA. Myasthenia = weakness that worsens with repetition (postsynaptic AChR Abs), linked to thymoma.

HER2 (ERBB2) in Breast CA: HER2+ means aggressive, poor prognosis, but also targetable with trastuzumab. HER2- means safer prognosis, no trastuzumab benefit. BRCA1/2 = hereditary DNA repair defect, both breast and ovarian risk.

BREAST CANCER PREVENTION DRUGS:

Drug	Class	Key Point	Caution
Raloxifene	SERM	Antagonist on breast, agonist on bone (good for osteoporosis). Post-menopausal.	DVT risk
Tamoxifen	SERM	Pre-menopausal preferred. Blocks ER on breast tissue.	Endometrial CA + DVT risk
Anastrozole	Aromatase Inhibitor	Post-menopausal only. Letrozole also in class. Blocks estrogen synthesis.	Bone loss (osteoporosis)
Prophylactic mastectomy	Surgical	BRCA1/2 carriers with verified germline mutation. High-risk reduction.	Irreversible

05 · ~15-20% of World Cancers

Infection to Malignancy

Chronic inflammation drives DNA damage drives malignancy. Know the bug, know the cancer.

The Mechanism: Chronic infection creates persistent inflammation. Reactive oxygen species damage DNA. Over years, mutations accumulate and neoplastic transformation occurs.

Bacteria

Organism	Cancer Link	High-Yield Note
H. pylori	Gastric adenocarcinoma · MALT lymphoma	MALToma can fully regress with H. pylori eradication alone
Strep bovis (gallolyticus)	Colon CA	Endocarditis + colon CA. Scope them immediately.
Clostridium septicum	Colon CA	Bacteremia = hunt for occult colon malignancy.
Salmonella typhi	Gallbladder CA	Chronic carrier state. Gallstones + chronic typhoid = gallbladder risk.

Parasites

Organism	Cancer Link	Geography / Clue
Clonorchis sinensis	Cholangiocarcinoma (CBD)	Liver fluke. SE Asia, raw freshwater fish. Bile duct inflammation.
Schistosoma mansoni	Hepatocellular CA / portal HTN	Periportal pipe-stem fibrosis. Africa, Middle East.
Schistosoma haematobium	Bladder CA (SCC)	Egypt, sub-Saharan Africa. Painless hematuria. SCC (not TCC).

Viruses

Virus	Cancer Link	High-Yield Note
HPV 16, 18	Cervical · Vulvar · Vaginal · Anal · Oropharyngeal	E6 inactivates p53. E7 inactivates Rb. Pap smear screens.
EBV	Nasopharyngeal CA · Burkitt · Hodgkin (mixed) · CNS lymphoma	Nasopharyngeal CA in Asian adults. Burkitt jaw in Africa, abdomen sporadically.
HBV / HCV	Hepatocellular carcinoma	Cirrhosis is the main pathway. AFP elevated. Check AFP + ultrasound q6mo.
HHV-8	Kaposi Sarcoma	AIDS-defining. Purple vascular skin lesions. Also in Mediterranean elderly males.
HTLV-1	Adult T-cell leukemia/lymphoma	Japan and Caribbean. Hypercalcemia. CD4+ T-cells clonal.

Board Pearl: Bovis in the blood = scope the colon. Septicum bacteremia = same rule. Both have the same downstream action.

06 · Diagnostic Codes

Tumor Markers and IHC Stains

Tap each marker to reveal what it monitors and the board trap.

PSA

Prostate CA

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Trend matters, not absolute value. Use for monitoring recurrence post-treatment. BPH also elevates.

CEA

Colon · GI

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Carcinoembryonic antigen. Recurrence monitor for colon CA. Also elevated in pancreas, gastric, lung, breast. Non-specific.

AFP

HCC · Yolk Sac

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Hepatocellular carcinoma (cirrhosis) or testicular yolk sac tumor. Also elevated in neural tube defects in pregnancy.

β-hCG

Choriocarcinoma

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Embryonal carcinoma, choriocarcinoma, hydatidiform mole. Testicular germ cell tumors. Cannonball lung mets.

CA-125

Ovarian CA

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Surface epithelial ovarian tumors (serous subtype). Monitoring after resection. Not diagnostic alone.

CA 19-9

Pancreatic CA

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Pancreatic adenocarcinoma marker. Also elevated in colon and biliary CA. Poor early-stage sensitivity.

IHC STAIN SHEET:

Stain	Positive In	Memory Hook
Desmin	Rhabdomyosarcoma	Muscle intermediate filament. Desmin = muscle-destined.
Vimentin	All sarcomas (mesenchymal)	Connective tissue marker. All sarcomas express it.
GFAP	Astrocytomas (GBM, pilocytic)	Glial fibrillary acidic protein. Brain glial tumors.
S-100	Melanoma, Schwannoma, Langerhans	Neural crest origin tumors.
CK (Cytokeratin)	Carcinomas (epithelial origin)	Confirms epithelial lineage vs. sarcoma.

07 · Molecular Oncology

Oncogenes, Suppressors, and Translocations

Know the fusion protein, not just the numbers.

Chromosomal Translocations

t(?;?)	Disease	Fusion / Result
t(9;22)	CML (Philadelphia Chromosome)	BCR-ABL tyrosine kinase. Treat with imatinib.
t(8;14)	Burkitt Lymphoma	c-MYC overexpression. Starry-sky histology. EBV link.
t(14;18)	Follicular Lymphoma	BCL-2 anti-apoptosis gene switched ON. Indolent course.
t(11;22)	Ewing Sarcoma	EWS-FLI1 fusion protein. Onion-skin periosteum.
t(15;17)	APL (AML M3)	PML-RARA. Auer rods. DIC risk. Treat with ATRA.

Oncogenes

L-myc

Small Cell Lung

L for Lung. Amplification drives neuroendocrine small cell carcinoma.

N-myc

Neuroblastoma

N for Neuro. Amplification = worse prognosis. Adrenal medulla origin. Bombesin+ marker.

c-MYC

Burkitt Lymphoma

t(8;14). Jaw mass in Africa (EBV), abdominal mass sporadically. Starry-sky histology.

RET oncogene

MEN 2A / 2B

Medullary thyroid CA + pheo + (2A: parathyroid, 2B: marfanoid + mucosal neuromas). Also in Hirschsprung disease.

ERBB2 / HER2

Breast CA

Overexpression = aggressive. Target with trastuzumab. Also found in gastric CA.

BCL-2

Follicular Lymphoma

Anti-apoptotic protein. t(14;18) juxtaposes BCL-2 to Ig heavy chain promoter. Cells refuse to die.

Tumor Suppressors

Gene	Cancer / Syndrome	Trace It
Rb	Retinoblastoma · Osteosarcoma	G1/S checkpoint guardian. Two-hit hypothesis. Loss releases E2F, driving S-phase.
p53 (TP53)	Li-Fraumeni Syndrome	Sarcoma, breast, brain, adrenal cancers in families. Most common tumor suppressor mutated. HPV E6 targets p53.
BRCA1 / BRCA2	Breast + Ovarian CA	DNA double-strand break repair. Germline mutation = hereditary risk. BRCA1 also linked to triple-negative breast CA.
APC	Familial Adenomatous Polyposis	5q deletion. 100% colon CA risk without colectomy. Gardner syndrome: osteomas + desmoid tumors.

Myc mnemonic: L-myc = Lung. N-myc = Neuro. c-MYC = Burkitt. Three different Myc family members, three different cancers.

08 · Knowledge Check

The Oncology Final

Apply everything. One question at a time.