A 55-year-old man with squamous cell carcinoma of the lung presents with hypercalcemia (serum calcium 12.5 mg/dL), elevated parathyroid hormone-related peptide (PTHrP), and normal parathyroid hormone (PTH) level. Regarding humoral hypercalcemia of malignancy (HHM), all of the following are correct EXCEPT:

Question

Accepted Answer

B. PTHrP increases renal phosphate reabsorption, leading to hyperphosphatemia. ## Humoral Hypercalcemia of Malignancy (HHM)

### Mechanisms of Malignancy-Induced Hypercalcemia

| Mechanism | Hormone/Mediator | Cancers | Effect on Phosphate |
|-----------|------------------|---------|--------------------|
| **PTHrP secretion (HHM)** | PTHrP | SCC lung, kidney, breast | **Phosphate wasting** (↓ reabsorption) |
| **Calcitriol production** | 1,25-(OH)~2~D~3~ | Lymphomas (Hodgkin, NHL) | Phosphate reabsorption variable |
| **Osteolytic metastases** | IL-6, TNF-α, RANKL | Breast, myeloma | Local bone destruction |

### PTHrP Mechanism in HHM

**Key Point:** PTHrP mimics PTH by binding to the **PTH1 receptor** on osteoblasts and kidney tubules, but the renal phosphate handling differs:

1. **Bone:** Increases osteoclast activation → bone resorption → ↑ serum calcium
2. **Kidney (Proximal Tubule):** Decreases phosphate reabsorption → **phosphate wasting** → ↓ serum phosphate
3. **Kidney (Distal Tubule):** Increases calcium reabsorption → ↑ serum calcium
4. **Kidney (1α-hydroxylase):** PTHrP does NOT reliably stimulate 1,25-(OH)~2~D~3~ production (unlike PTH)

### Why the Distractor is Wrong

**High-Yield:** PTHrP causes **hyperphosphaturia** (phosphate wasting), NOT hyperphosphatemia. The serum phosphate is typically **low or normal** in HHM, not elevated.

- PTHrP ↓ proximal tubular phosphate reabsorption
- Result: ↓ serum phosphate, ↑ urinary phosphate
- This contrasts with primary hyperparathyroidism (PTH also causes phosphate wasting, so phosphate is low there too)

### Cancer Associations with PTHrP

**Clinical Pearl:** The most common PTHrP-secreting malignancies are:
1. **Squamous cell carcinoma** (lung, skin, esophagus)
2. **Renal cell carcinoma**
3. Breast cancer (especially with bone metastases)
4. Ovarian cancer

### Calcitriol-Mediated Hypercalcemia (Lymphomas)

**Mnemonic: CAL-L** — Calcitriol production, Associated with Lymphomas (Hodgkin and non-Hodgkin)
- Tumor-associated macrophages express 1α-hydroxylase
- Produce 1,25-(OH)~2~D~3~ → ↑ intestinal calcium absorption
- Serum phosphate is typically **normal or elevated** (due to calcitriol's phosphate-reabsorbing effect)

### Laboratory Differentiation

| Feature | PTHrP-HHM | Calcitriol-Lymphoma | Primary HPT |
|---------|-----------|-------------------|-------------|
| PTH | ↓ (suppressed) | ↓ (suppressed) | ↑ |
| PTHrP | ↑ | Normal | Normal |
| 1,25-(OH)~2~D~3~ | Normal/↓ | ↑↑ | Normal/↑ |
| Phosphate | ↓ (wasting) | Normal/↑ | ↓ (wasting) |
| Urine cAMP | ↑ | Normal | ↑ |

Answer

A. PTHrP acts on PTH1 receptors in bone and kidney, mimicking PTH action

Answer

C. Squamous cell carcinoma and renal cell carcinoma are the most common PTHrP-secreting malignancies

Answer

D. 1,25-dihydroxyvitamin D production by tumor-associated macrophages causes calcitriol-mediated hypercalcemia in lymphomas

Explanation

Humoral Hypercalcemia of Malignancy (HHM)

Mechanisms of Malignancy-Induced Hypercalcemia

PTHrP Mechanism in HHM

Why the Distractor is Wrong

Cancer Associations with PTHrP

Calcitriol-Mediated Hypercalcemia (Lymphomas)

Laboratory Differentiation

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Mechanism	Hormone/Mediator	Cancers	Effect on Phosphate
PTHrP secretion (HHM)	PTHrP	SCC lung, kidney, breast	Phosphate wasting (↓ reabsorption)
Calcitriol production	1,25-(OH)₂D₃	Lymphomas (Hodgkin, NHL)	Phosphate reabsorption variable
Osteolytic metastases	IL-6, TNF-α, RANKL	Breast, myeloma	Local bone destruction

Feature	PTHrP-HHM	Calcitriol-Lymphoma	Primary HPT
PTH	↓ (suppressed)	↓ (suppressed)	↑
PTHrP	↑	Normal	Normal
1,25-(OH)₂D₃	Normal/↓	↑↑	Normal/↑
Phosphate	↓ (wasting)	Normal/↑	↓ (wasting)
Urine cAMP	↑	Normal	↑