Pathology · Year 2 · from Pathology
Case 1: Breast Cancer with Paraneoplastic Hypercalcemia
Patient Demographics
- Age: 62 years old
- Sex: Female
- Occupation: Retired teacher
Chief Complaint
"Confusion, fatigue, and excessive thirst for 2 weeks"
History of Present Illness
A 62-year-old female is brought to the emergency department by her daughter due to progressive confusion and lethargy over the past 2 weeks. The daughter reports that her mother has been complaining of increased thirst, frequent urination, constipation, and nausea. She has also noted significant fatigue and weakness. The patient has a history of breast cancer diagnosed 3 years ago, treated with mastectomy followed by chemotherapy. She was in remission but has not had imaging in 6 months. She reports increasing back pain over the past month.
Physical Examination
- Vital Signs: BP 110/68 mmHg, HR 92 bpm, RR 18/min, Temp 37.2C
- General: Appears lethargic, oriented to person only, dry mucous membranes
- Cardiovascular: Regular rhythm, normal S1/S2, no murmurs
- Respiratory: Clear to auscultation bilaterally
- Abdomen: Soft, mild tenderness throughout, decreased bowel sounds
- Musculoskeletal: Point tenderness over thoracic and lumbar spine
- Neurologic: Altered mental status, decreased concentration, proximal muscle weakness
Diagnostic Workup
Laboratory Studies:
| Test | Result | Reference Range |
|---|---|---|
| Calcium (total) | 14.8 mg/dL | 8.5-10.5 mg/dL |
| Ionized calcium | 1.85 mmol/L | 1.12-1.32 mmol/L |
| PTH | 8 pg/mL | 10-65 pg/mL |
| PTHrP | 85 pmol/L | <2 pmol/L |
| Creatinine | 1.8 mg/dL | 0.7-1.3 mg/dL |
| CA 15-3 | 285 U/mL | <30 U/mL |
| Alkaline phosphatase | 320 U/L | 44-147 U/L |
Imaging:
- CT Chest/Abdomen/Pelvis: Multiple pulmonary nodules, hepatic lesions, and suspicious lymphadenopathy
- Bone Scan: Widespread skeletal metastases involving spine, ribs, pelvis, and proximal femurs
- MRI Spine: Multiple lytic lesions throughout thoracic and lumbar spine
Tumor Markers:
| Marker | Result | Clinical Significance |
|---|---|---|
| CA 15-3 | 285 U/mL | Elevated; monitoring breast cancer |
| CEA | 12.5 ng/mL | Mildly elevated |
Pathology Correlation
This case demonstrates paraneoplastic syndrome and tumor marker utility:
Hypercalcemia of Malignancy: Two main mechanisms:
- Humoral hypercalcemia of malignancy (HHM):
- Tumor produces PTHrP (parathyroid hormone-related peptide)
- PTHrP mimics PTH effects: increases bone resorption, renal calcium reabsorption
- Common in squamous cell carcinomas, breast cancer, renal cell carcinoma
- PTH is suppressed (distinguishing from primary hyperparathyroidism)
- Local osteolytic hypercalcemia:
- Direct bone destruction by metastases
- Tumor cells produce factors (IL-1, TNF, RANK-L) stimulating osteoclasts
- Common with breast cancer, multiple myeloma
Clinical Features of Hypercalcemia ("Stones, Bones, Moans, Groans, Psychiatric Overtones"):
- Stones: Nephrolithiasis, nephrocalcinosis
- Bones: Bone pain, pathologic fractures
- Moans: Abdominal pain, constipation
- Groans: Nausea, vomiting
- Psychiatric overtones: Confusion, lethargy, depression
Tumor Markers:
- CA 15-3: Monitoring breast cancer (not for screening)
- Rising levels suggest disease progression/recurrence
- Useful for treatment response assessment
Clinical Image
Gross pathology of invasive breast carcinoma showing a stellate, firm, white mass with irregular borders characteristic of infiltrating ductal carcinoma. The spiculated margins represent tumor invasion into surrounding breast tissue.
Image Source: Wikimedia Commons - "Breast cancer" License: CC BY-SA 3.0 URL: https://commons.wikimedia.org/wiki/File:CA_Breast_Macro.jpg
Diagnosis
Metastatic Breast Cancer with Paraneoplastic Hypercalcemia of Malignancy
- TNM Stage: Stage IV (M1 - distant metastases)
Treatment
Immediate (Hypercalcemia):
- Aggressive IV fluid resuscitation (normal saline)
- IV bisphosphonate (zoledronic acid or pamidronate)
- Consider denosumab if bisphosphonate-refractory
- Calcitonin for rapid initial effect
- Treat underlying malignancy
Oncologic:
- Restage disease with tissue confirmation if possible
- Tumor profiling (ER/PR, HER2 status)
- Systemic therapy based on receptor status
- Bone-modifying agents (ongoing bisphosphonate or denosumab)
- Radiation therapy for painful bone metastases
Teaching Points
- Paraneoplastic syndromes are clinical manifestations not caused by direct tumor invasion
- Hypercalcemia is the most common paraneoplastic syndrome; PTHrP-mediated (humoral) vs. local osteolytic
- Suppressed PTH with elevated calcium suggests malignancy-related hypercalcemia
- Tumor markers are most valuable for monitoring disease, not screening
- TNM staging is the most important prognostic factor for solid tumors
- Stage IV disease indicates distant metastasis regardless of T and N status