Malignancy Hypercalcemia Workup

---
name: malignancy-hypercalcemia-workup
description: Work up Malignancy-Associated Hypercalcemia (MAH) — distinguish humoral hypercalcemia of malignancy (HHM, PTHrP-driven), local osteolytic hypercalcemia, 1,25(OH)2D-mediated lymphoma hypercalcemia, ectopic PTH secretion, and multiple myeloma — and pick the right confirmatory tests and therapy direction. Trigger when a clinician asks "is this hypercalcemia from cancer", "PTHrP positive what now", "hypercalcemia in lung cancer / breast cancer / lymphoma / myeloma", "humoral hypercalcemia of malignancy", "MAH workup", or any hypercalcemia case with suppressed PTH and a known or suspected malignancy.
---

# Malignancy-Associated Hypercalcemia (MAH) — Workup

Use this skill when hypercalcemia is **PTH-suppressed** and malignancy is on the differential. MAH is usually acute, severe, and a marker of advanced disease.

---

## STEP 1 — Confirm MAH vs. other PTH-independent causes

You should already have:
- Suppressed intact PTH
- Hypercalcemia (often >12 mg/dL with rapid onset)
- Suggestive setting (known cancer, weight loss, advanced disease, pathological fracture)

Order if not yet done:
- **PTHrP**
- **1,25(OH)2D and 25(OH)D**
- **SPEP + UPEP + serum free light chains**
- **CBC, peripheral smear, LDH**
- **Skeletal imaging** — whole-body low-dose CT or PET-CT (more sensitive than bone scan, especially in myeloma)
- **TSH, cortisol** to exclude endocrine mimics

---

## STEP 2 — Sub-classify MAH

### Pattern A — **Humoral Hypercalcemia of Malignancy (HHM)** — PTHrP elevated, 1,25(OH)2D low/normal, often few or no bone metastases

Typical tumours:
- **Squamous cell carcinoma**: lung (most common), head & neck, oesophagus, cervix, vulva, skin
- **Renal cell carcinoma**
- **Bladder, ovarian carcinoma**
- Less commonly: colon, gastric, prostate, thyroid, non-squamous lung

Biochemistry: hypophosphatemia, low TmP/GFR, increased nephrogenous cAMP — mimics PTH action.

Action: **search for the primary** with imaging guided by symptoms (CT chest/abdomen/pelvis, ENT review for head & neck SCC, dermatologic exam, urine cytology). PTHrP can be tracked as a tumour marker once the diagnosis is established.

---

### Pattern B — **Solid tumour with skeletal metastases + elevated PTHrP** (mixed mechanism)

Typical: **breast cancer**, prostate (rarely), other osteolytic mets.

Mechanism: PTHrP from tumour both raises systemic calcium and drives local osteolysis (RANKL ↑, OPG ↓, TGF-β feedback loop).

Action: confirm bone metastases (CT, bone scan, MRI as needed). Treat as MAH plus bone-targeted therapy.

---

### Pattern C — **Hematologic malignancy with elevated 1,25(OH)2D** — lymphoma pattern

Typical: **non-Hodgkin lymphoma, Hodgkin lymphoma**.

Mechanism: extrarenal 1α-hydroxylase in tumour tissue. PTHrP may also be elevated in some cases.

Action: confirm lymphoma — LDH, lymph node biopsy, PET-CT, bone marrow if suspected. Glucocorticoids are particularly effective here (suppress 1α-hydroxylase + tumour activity).

---

### Pattern D — **Ectopic PTH secretion** — PTH itself elevated (not PTHrP) in a non-parathyroid tumour

Rare. Documented tumours: **ovarian, lung, thyroid, thymus, gastric**.

Suspicion arises when imaging fails to identify a parathyroid adenoma despite biochemically PTH-dependent hypercalcemia. Confirm with tumour-tissue PTH immunostaining or molecular studies in selected cases.

Action: surgical removal of the primary if feasible.

---

### Pattern E — **Multiple myeloma** — SPEP/UPEP positive, light chains elevated

Mechanism: bone-resorbing factors (MIP-1α, IL-6, RANKL ↑, OPG ↓, DKK-1, sclerostin). PTHrP rarely elevated.

Key clinical features:
- Hypercalcemia in **~30%** of myeloma patients
- Often coexists with **renal failure** (Bence-Jones nephropathy, light-chain cast nephropathy) → so unlike other MAH, expect **hyperphosphatemia**, not hypophosphatemia
- ALP usually normal (no osteoblastic activity); bone scans frequently negative
- Bone pain in 80%, pathological fractures common

Action:
- Confirm: bone marrow biopsy, FISH (del17p, t(4;14), t(14;16), 1q gain, t(11;14)), whole-body low-dose CT or PET-CT.
- Bisphosphonates have a **dual benefit** — control hypercalcemia AND reduce skeletal events / tumour burden.
- See the **mm-diagnostic-workup** skill for the full myeloma workup.

---

## STEP 3 — Decide treatment direction

Two parallel tracks:

**Track 1 — Treat the hypercalcemia** (use **acute-hypercalcemia-management** skill if Ca >12 with symptoms or >14):
- Hydration (NS), then antiresorptive (denosumab 120 mg SC, or zoledronic acid 4 mg IV, or pamidronate 60–90 mg IV).
- **Glucocorticoids** are particularly effective in lymphoma, myeloma, and granulomatous-pattern (1,25(OH)2D-driven) MAH.
- **Calcitonin** (4–8 IU/kg SC/IM q6–12h) for first 48–72 h while waiting for antiresorptive to take effect.

**Track 2 — Treat the underlying cancer** — definitive control of MAH requires reducing tumour burden. Without this, hypercalcemia recurs rapidly.

Track PTHrP after treatment:
- PTHrP **does not fall** with hypercalcemia treatment.
- PTHrP **does fall** with successful tumour reduction → useful as a tumour marker on follow-up.

---

## CLINICAL GUARDRAILS

- **MAH = advanced disease.** Patients with new-onset MAH have a poor prognosis; involve oncology and palliative care early.
- **Bone scan misses myeloma.** Use whole-body low-dose CT or PET-CT.
- **Hyperphosphatemia + hypercalcemia + suppressed PTH** → think myeloma with renal failure, not HHM.
- **Glucocorticoids are not first-line for HHM** (they don't work) but ARE effective for lymphoma, myeloma, and granulomatous causes.
- **Bisphosphonates need dose adjustment in renal impairment** — denosumab is preferred when CrCl <30 mL/min (no renal clearance).
- **Watch for hypocalcemia after antiresorptive** in vitamin D-deficient patients — correct 25(OH)D first if low.
- **PTHrP can be elevated in normocalcemic cancer patients** — significance unclear; do not use in isolation to diagnose MAH.

---

## SOURCE

Bilezikian JP, Endotext. *Approach to Hypercalcemia*. NCBI Bookshelf NBK279129. Section: Malignancy-Associated Hypercalcemia (HHM, MAH with skeletal metastases, hematologic malignancies, ectopic hyperparathyroidism, multiple myeloma).