A 74-year-old man presents to the physician with a painful lesion over his right lower limb which began 2 days ago. He says that the lesion began with pain and severe tenderness in the area. The next day, the size of the lesion increased and it became erythematous. He also mentions that a similar lesion had appeared over his left lower limb 3 weeks earlier, but it disappeared after a few days of taking over the counter analgesics. There is no history of trauma, and the man does not have any known medical conditions. On physical examination, the physician notes a cordlike tender area with erythema and edema. There are no signs suggestive of deep vein thrombosis or varicose veins. Which of the following malignancies is most commonly associated with the lesion described in the patient?

Squamous cell carcinoma of head and neck

A 39-year-old female presents with confusion. Her husband reports that she doesn't know where she is and cannot remember the date. She was recently diagnosed with small cell lung cancer. Vital signs are T 37C, HR 80, BP 120/80 mmHg, RR 14, and O2 sat 99% on room air. She is not orthostatic. Physical examination reveals moist mucous membranes and normal capillary refill. A basic metabolic profile reveals that serum sodium is 129. Regarding this patient's illness, which of the following is true?

Urinary osmolarity will be > 100, and this illness will not correct with normal saline infusion

Urinary osmolarity will be < 100, and another potential cause of this disorder is excessive water drinking

Urinary sodium will be > 20 and another potential cause of this disorder is renal failure

Urinary sodium will be > 20 and fractional excretion of sodium will be >1%

Urinary sodium will be < 10, and fractional excretion of sodium will be <1%

A 31-year-old man comes to the physician because of worsening abdominal pain, an inability to concentrate at work, and a general lack of motivation over the past several months. He has a history of spontaneous passage of two kidney stones. His father and uncle underwent thyroidectomy before the age of 35 for thyroid cancer. Physical examination shows diffuse tenderness over the abdomen. Serum studies show: Na+ 142 mEq/L K+ 3.7 mEq/L Glucose 131 mg/dL Ca2+ 12.3 mg/dL Albumin 4.1 g/dL Parathyroid hormone 850 pg/mL Further evaluation is most likely to show elevated levels of which of the following?

Serum aldosterone to renin ratio

Urine 5-hydroxyindoleacetic acid

A lung mass of a 50 pack-year smoker is biopsied. If ADH levels were grossly increased, what would most likely be the histologic appearance of this mass?

Sheets of small round cells with hyperchromatic nuclei

Layered squamous cells with keratin pearls

Pleomorphic giant cells with leukocyte fragments in cytoplasm

Hyperplasia of mucin producing glandular tissue

Tall columnar cells bordering the alveolar septum

A 54-year-old man comes to the emergency department for nausea and vomiting for the past 2 days. The patient reports that he felt tired and weak for the past week without any obvious precipitating factors. Past medical history is significant for hypertension controlled with hydrochlorothiazide. He denies diarrhea, changes in diet, recent surgery, vision changes, or skin pigmentation but endorses a 10-lb weight loss, headaches, fatigue, and a chronic cough for 2 years. He smokes 2 packs per day for the past 20 years but denies alcohol use. Physical examination demonstrates generalized weakness with no peripheral edema. Laboratory tests are shown below: Serum: Na+: 120 mEq/L Cl-: 97 mEq/L K+: 3.4 mEq/L HCO3-: 24 mEq/L Ca2+: 10 mg/dL Osmolality: 260 mOsm/L Urine: Na+: 25 mEq/L Osmolality: 285 mOsm/L Specific gravity: 1.007 What is the most likely finding in this patient?

Chromogranin positive mass in the lung

Antibodies against presynaptic calcium channels

Orphan Annie eyes and psammoma bodies in the thyroid

An obese 63-year-old man comes to the physician because of 3 episodes of red urine over the past week. He has also had recurrent headaches and intermittent blurry vision during the past month. He has benign prostatic hyperplasia. He works as an attendant at a gas station. The patient has smoked one pack of cigarettes daily for the last 40 years. He does not drink alcohol. Current medications include tamsulosin. His temperature is 37.4°C (99.4°F), pulse is 90/min, and blood pressure is 152/95 mm Hg. Examination shows a flushed face. Cardiopulmonary examination shows no abnormalities. The abdomen is soft and non-tender. Digital rectal examination shows an enlarged prostate with no nodules. Urinalysis shows: Blood 3+ Glucose negative Protein negative WBC 1-2/hpf RBC 40-45/hpf RBC casts none Which of the following is the most likely diagnosis?

Transitional cell bladder carcinoma

Paraneoplastic syndromes — USMLE Lesson

Paraneoplastic Syndromes - Cancer's Covert Ops

Systemic symptoms not from local invasion or metastasis. Mediated by hormones (e.g., ACTH, ADH), peptides (PTHrP), or immune cross-reactivity (antibodies).
Key Syndromes & Cancers:
- Endocrine:
  - Cushing Syndrome (ectopic ACTH): Small Cell Lung Cancer (SCLC)
  - SIADH (ectopic ADH): SCLC
  - Hypercalcemia (PTHrP): Squamous Cell Lung Cancer
- Neurologic:
  - Lambert-Eaton Syndrome (anti-VGCC Abs): SCLC
  - Cerebellar Ataxia (anti-Yo/Hu Abs): SCLC, Ovarian

⭐ Lambert-Eaton Myasthenic Syndrome (LEMS) presents with proximal muscle weakness that improves with repetition, unlike Myasthenia Gravis. It's often the first sign of an underlying Small Cell Lung Cancer.

Paraneoplastic Syndromes by Cancer Type and Clinical Result

Endocrine Syndromes - Hormone Hijinks

Syndrome / Ectopic Hormone	Key Cancer Associations	Mechanism & High-Yield Points
SIADH (ADH)	Small Cell Lung Cancer (SCLC)	Ectopic ADH → ↑Free water retention → Euvolemic hyponatremia. Concentrated urine.
Cushing Syndrome (ACTH)	SCLC, Pancreatic, Neural tumors	Ectopic ACTH secretion → ↑Cortisol → Hypertension, hyperglycemia, hypokalemia.
Hypercalcemia (PTHrP)	Squamous Cell Lung Cancer, Renal, Bladder	PTH-related peptide (PTHrP) mimics PTH → ↑Ca²⁺. Serum PTH is ↓.
Hypercalcemia (Calcitriol)	Lymphoma, Myeloma	↑$1,25-(\text{OH})_2\text{D}_3$ (Calcitriol) by tumor cells or activated macrophages.
Hypoglycemia (IGF-2)	Mesenchymal tumors (e.g., fibrosarcoma)	Ectopic Insulin-like Growth Factor 2 (IGF-2) → ↑Glucose uptake → Hypoglycemia.
Polycythemia (EPO)	Renal Cell Carcinoma, Hepatocellular Carcinoma	Ectopic erythropoietin (EPO) → ↑RBC production → ↑Hematocrit.

Neurologic Syndromes - Brains Under Siege

Paraneoplastic Neurologic Syndromes: Immune Mechanisms

Syndromes caused by immune responses against tumor antigens that cross-react with neuronal proteins. The autoantibodies are often the pathogenic culprits.

Syndrome	Antibody	Associated Cancer(s)	Key Features
Lambert-Eaton Myasthenic Syndrome	Anti-VGCC	Small Cell Lung Cancer (SCLC)	Proximal weakness, autonomic dysfunction. Strength ↑ with repetition.
Paraneoplastic Cerebellar Degeneration	Anti-Yo, Anti-Hu	Ovary, Breast, SCLC	Progressive ataxia, dysarthria, nystagmus. Severe neuronal loss in cerebellum.
Limbic Encephalitis	Anti-Hu, Anti-NMDA-R	SCLC, Testicular teratoma	Seizures, psychosis, memory loss. Affects medial temporal lobes.
Opsoclonus-Myoclonus Syndrome	Anti-Ri	Neuroblastoma (kids), Breast/Lung (adults)	"Dancing eyes, dancing feet"; chaotic eye movements & myoclonus.

📌 Mnemonic: Lungs Eff-up Muscle Signals (LEMS) for the SCLC association.

Miscellaneous Syndromes - The Grab Bag

Trousseau syndrome: Migratory thrombophlebitis, often seen with visceral adenocarcinomas (pancreas, lung).
Nonbacterial thrombotic endocarditis (NBTE): Sterile vegetations on heart valves, associated with mucinous adenocarcinomas.
Hypertrophic osteoarthropathy: Digital clubbing, arthritis, periosteal new bone formation (esp. lung adenocarcinoma).

⭐ Trousseau syndrome (migratory thrombophlebitis) can be the first sign of a hidden malignancy, classically pancreatic cancer.

X-ray: Hypertrophic Osteoarthropathy with Periostitis

High‑Yield Points - ⚡ Biggest Takeaways

Paraneoplastic syndromes are remote effects of a tumor, not caused by direct invasion or metastasis.

Often mediated by ectopic hormone production (e.g., ACTH, ADH) or autoantibodies against shared antigens.

Small cell lung cancer is the most notorious culprit, linked to SIADH, Cushing's, and LEMS.

Squamous cell lung cancer is classically associated with hypercalcemia via PTHrP.

These syndromes may be the earliest manifestation of an occult neoplasm.

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