Cutaneous Squamous Cell Carcinoma with Hypercalcemia of Malignancy and Skeletal Metastasis: Perioperative Case Report of Above-Knee Amputation

Summary

Here, we present a protocol to optimize perioperative management in patients with cutaneous squamous cell carcinoma complicated by malignancy-associated hypercalcemia.

Abstract

Malignancy-associated hypercalcemia (MAH) is one of the most frequent and life-threatening metabolic emergencies in oncology; however, it is rarely observed in cutaneous squamous cell carcinoma (cSCC). We report the perioperative management of a 48-year-old man with a left long-standing anterior knee scar complicated by recurrent ulceration. In August 2024, pathology confirmed well-differentiated cSCC; however, the patient was lost to follow-up. One year later, he presented with a progressive ulcer, fatigue, severe hypercalcemia, and renal impairment. Laboratory evaluation revealed suppressed parathyroid hormone (PTH) levels consistent with MAH. Computed tomography angiography showed extensive ulceration with bone destruction and vascular involvement, and FAPI-PET/CT confirmed local recurrence and skeletal metastases in the contralateral tibia.

Preoperative optimization consisted of isotonic crystalloid resuscitation, calcitonin, antiresorptive therapy with intravenous bisphosphonates or denosumab, and short-course continuous renal replacement therapy as indicated, allowing the patient to meet the physiologic criteria required for anesthesia induction. An above-knee amputation was performed using staged vascular control with continuous hemodynamic monitoring, followed by intensive care unit admission for targeted calcium-lowering therapy and organ support. The postoperative course was notable for the absence of fatal arrhythmias or deep surgical infection.

This case highlights that, in cSCC complicated by MAH, skeletal metastases, and chronic infection, adherence to explicit physiologic thresholds for anesthesia induction within a standardized perioperative pathway -- combined with advanced imaging for metabolic and anatomic stratification -- can create a safe operative window of time, mitigate acute risks, and improve the feasibility and safety of definitive oncologic surgery in a high-risk setting.

Introduction

Malignancy-associated hypercalcemia is one of the most common and life-threatening electrolyte emergencies among hospitalized patients with cancer^1,2. Evidence-based treatment centers on the use of isotonic crystalloid resuscitation, calcitonin, and antiresorptive therapy^1,2. In the perioperative setting, prevention of fatal arrhythmia and hemodynamic instability is paramount³. Pathophysiologically, humoral mechanisms mediated by parathyroid hormone-related peptide are most common; osteolytic hypercalcemia from skeletal metastases and 1,25-dihydroxyvitamin D-mediated hypercalcemia may occur alone or in combination^1,2. The typical laboratory phenotype features suppressed parathyroid hormone (PTH) levels with elevated parathyroid hormone-related peptide (PTHrP) levels². In many cases, malignancy-associated hypercalcemia is characterized by elevated parathyroid hormone-related peptide (PTHrP), which stimulates renal calcium reabsorption and bone resorption, leading to marked hypercalcemia. Cutaneous or chronic-wound-derived squamous cell carcinoma (Marjolin's ulcer) complicated by malignancy-associated hypercalcemia is rare. Reported cases generally demonstrate parathyroid hormone-related peptide positivity and require simultaneous control of hypercalcemia and definitive removal of the causative lesion^4,5,6,7. Denosumab is an effective option for patients refractory to bisphosphonates or with renal impairment⁸. Denosumab is a fully human monoclonal antibody targeting RANKL, the key mediator of osteoclast differentiation and activity, thereby reducing osteoclastic bone resorption and effectively lowering serum calcium, particularly in bisphosphonate-refractory hypercalcemia of malignancy⁹. In critical or refractory scenarios, intermittent hemodialysis or continuous renal replacement therapy can rapidly reduce ionized calcium and correct acid-base and volume status within hours, creating a safety window of time for anesthesia and major surgery^10,11. Fibroblast activation protein inhibitor positron emission tomography/computed tomography (FAPI-PET/CT) offers higher tumor-to-background contrast than fluorodeoxyglucose imaging in multiple settings and can be leveraged to advance surgical choice, margin planning, and target delineation for adjuvant radiotherapy^12,13,14. Foundational perioperative measures -- including infection prevention, normothermia, and surgical safety check procedures -- ensure consistency and reproducibility of care^15,16,17. This syndrome is associated with adverse short-term outcomes¹⁸. Perioperative kidney assessment and acute kidney injury management were guided by the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines, which provide standardized recommendations for fluid management, electrolyte optimization, medication adjustment, and criteria for renal replacement therapy¹⁹. Institutional work further underscores oncologic vigilance for nonhealing lesions and pathway-based access for patients with chronic infected wounds to mitigate perioperative risk^20,21.

CASE PRESENTATION:
A 48-year-old man with a long-standing scar over the left anterior knee and distal thigh experienced recurrent ulceration over several years, accompanied by foul odor, anemia, and hypoalbuminemia. In August 2024, debridement and reconstruction were performed. Pathology revealed well-differentiated cutaneous squamous cell carcinoma with negative epidermal margins. He did not attend regular follow-up and was lost to follow-up for approximately one year. In June 2025, he presented with a progressively enlarging, painful ulcer and fatigue. Outpatient biochemical testing showed critically elevated serum calcium levels and mild-to-moderate renal dysfunction. Inpatient testing confirmed suppressed parathyroid hormone (PTH) levels in the setting of hypercalcemia, supporting the diagnosis of malignancy-associated hypercalcemia.

Computed tomography angiography demonstrated a left large anterior knee ulcer with destruction of the patella, distal femur, and proximal tibia, accompanied by arterial and venous involvement and arteriovenous communications (Figure 1). FAPI-PET/CT showed intense radiotracer uptake around the left distal thigh and knee, consistent with local recurrence, as well as a focal intensely tracer-avid (high-uptake) lesion in the right proximal tibia, which was subsequently confirmed as a skeletal metastasis; no metabolically active inguinal lymph nodes were identified (Figure 2).

A complete panel of laboratory markers was performed upon admission, including total calcium, PTH, 25-hydroxyvitamin D, and FT (Table 1). The patient demonstrated critically elevated calcium (total Ca 4.23 mmol/L) with appropriately suppressed PTH (3.2 pg/mL), confirming malignancy-associated hypercalcemia rather than primary hyperparathyroidism. During treatment with isotonic crystalloid infusion, calcitonin, bisphosphonates, and continuous renal replacement therapy, calcium levels progressively normalized, achieving the physiologic criteria required for anesthesia induction. After optimization with isotonic crystalloid resuscitation, calcitonin, antiresorptive therapy (intravenous bisphosphonates or denosumab), and short-course continuous renal replacement therapy when indicated, surgery proceeded only after all physiologic criteria for anesthesia induction were met. These criteria included corrected total calcium ≤2.75 mmol/L or ionized calcium ≤1.32 mmol/L, potassium 3.5-5.0 mmol/L, magnesium ≥0.8 mmol/L, arterial pH 7.35-7.45, lactate <2 mmol/L, mean arterial pressure ≥65 mmHg, core temperature ≥36.0 °C, hemoglobin ≥80-90 g/L, urine output of drainage ≥0.5 ml·kg^-¹·h^-¹, and establishment of at least two 18-gauge peripheral intravenous lines with arterial access as needed. Emergency medications and calcium-free infusions were prepared prior to induction.

A left above-knee amputation was performed. In the operating room, continuous electrocardiographic monitoring, invasive arterial pressure measurement, core temperature monitoring, and urine output and drainage assessment were instituted. When feasible, combined femoral and sciatic nerve blocks were utilized to reduce opioid requirements. Staged vascular control was implemented, beginning with proximal vessel control and initial occlusion, followed by stepwise re-control coordinated with key phases of the procedure, including bone transection and stump shaping. The postoperative pathological examination demonstrated keratinizing squamous cell carcinoma with keratin microspicules infiltrating the deep dermis; margin biopsies showed downward proliferation of atypical epithelium (Figure 3). Team pause-checks, rewarming, and intravascular volume reassessment were integrated before all critical procedural steps. The planned operative sequence consisted of proximal vascular control, bone transection and stump shaping, instrument table change, and placement of negative-pressure drainage and assessment of skin-edge tension (Figure 4).

Following surgery, the patient was transferred directly to the intensive care unit. Ionized calcium, electrolytes, arterial blood gases, and hemoglobin levels were reassessed within one hour, at 6-12 h, at 24 h, and at 48-72 h postoperatively. If ionized calcium (Figure 5) exceeded 1.35 mmol/L or if ventricular arrhythmias occurred, therapeutic escalation and repeat testing were initiated. Negative-pressure wound drainage was maintained until the 24-h output of drainage was <30-50 mL with clear fluid and well-perfused flaps. Multimodal analgesia and early rehabilitation were administered according to standardized pain assessment protocols.

The standardized perioperative pathway (Figure 6) began with comprehensive imaging and metabolic stratification to delineate tumor extent and correct physiologic derangements. After the predefined induction criteria were achieved, the surgical team assessed the feasibility of an R0 resection. Based on these evaluations, a left above-knee amputation was selected as the definitive procedure. The patient was then transferred directly to the intensive care unit for continued monitoring and supportive management, ensuring a seamless transition from operative intervention to postoperative stabilization.

Diagnosis, Assessment, and Plan:
The patient initially presented with progressive ulceration of a left chronic anterior knee scar, accompanied by fatigue, foul odor, anemia, and hypoalbuminemia. Laboratory evaluation revealed critically elevated serum calcium levels, suppressed parathyroid hormone (PTH) levels, and mild-to-moderate renal dysfunction, findings consistent with malignancy-associated hypercalcemia (MAH). Initial diagnostic tests -- including serum calcium (total and ionized), renal function, and PTH levels -- were performed to differentiate primary hyperparathyroidism from tumor-mediated hypercalcemia, and the biochemical profile supported the latter.

Computed tomography angiography was subsequently obtained to evaluate the extent of local tumor invasion, vascular involvement, and operative feasibility. FAPI-PET/CT imaging further provided metabolic and anatomic stratification, confirming local recurrence of cutaneous squamous cell carcinoma and identifying skeletal metastasis in the right tibia. Differential diagnoses at presentation included infection-related hypercalcemia, other paraneoplastic syndromes, and metabolic bone disease; however, these were excluded based on laboratory and imaging correlations.

The treatment plan prioritized rapid correction of metabolic derangements and physiologic stabilization to meet predefined criteria for anesthesia induction. Management included isotonic crystalloid resuscitation, calcitonin for rapid calcium reduction, antiresorptive therapy with intravenous bisphosphonates or denosumab for sustained calcium control, and short-course continuous renal replacement therapy when indicated. After achieving the physiologic thresholds required for safe anesthesia, an above-knee amputation was performed using staged vascular control and standardized perioperative monitoring.

The rationale for amputation was to achieve definitive oncologic control while reducing the risks of ongoing sepsis, persistent metabolic instability, and further systemic progression. Anticipated perioperative complications included arrhythmias, hemodynamic instability, surgical-site infection, and delayed wound healing; these were addressed through intensive care monitoring, stringent electrolyte surveillance, infection prophylaxis, and multimodal analgesia. The overall management strategy emphasized integration of biochemical correction, advanced imaging, and structured perioperative pathways to optimize the safety and outcomes of major oncologic surgery in a high-risk patient.

Protocol

This protocol was reviewed and approved by the Human Research Ethics Committee of the First Affiliated Hospital of Zhejiang University (IIT20240869A). All procedures performed in this study complied with institutional guidelines and adhered to the principles of the Declaration of Helsinki. Written informed consent was obtained from the patient for participation and publication of clinical data and images.

1. Initial assessment and stabilization

1. Upon admission, a baseline laboratory evaluation is performed, including total and ionized serum calcium, phosphate, magnesium, sodium, potassium, creatinine, liver function tests, and arterial blood gas analysis.
2. Blood samples are collected from a peripheral vein using a standard 21-G butterfly needle and processed with routine automated biochemical analysis. Parathyroid hormone (PTH), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D levels are measured to confirm malignancy-associated hypercalcemia.
3. Continuous cardiac monitoring is established using a standard three-lead ECG configuration with alarm limits set for heart rate <40 or >120 beats per minute and a prolonged QTc interval > 500 ms. Intravenous infusion of 0.9% normal saline is initiated at 200-300 mL/h using an infusion pump through an 18-G peripheral catheter.
4. Urine output of drainage is monitored hourly, aiming to maintain ≥0.5 mL·kg^-1·h^-1. Once adequate hydration is achieved, intravenous furosemide 20 mg every 12 h is administered to enhance renal calcium clearance, while withholding diuretics if the mean arterial pressure falls below 65 mmHg or oliguria is present.

2. Imaging and diagnostic evaluation

1. Imaging studies are performed to determine the extent of tumor invasion, evaluate vascular involvement, and identify metastatic disease.
2. Prior to imaging, the patient is positioned supine on the CT table with the affected limb fully extended and secured using Velcro straps to minimize movement. An 18-G intravenous catheter is placed in the contralateral upper extremity for contrast injection, and baseline vital signs are documented.
3. For computed tomography angiography (CTA), 100 mL of iodinated contrast is injected through an automated dual-syringe contrast injector at a rate of 4 mL/s, followed by a 30-mL saline flush.
4. Arterial-phase acquisition is initiated using bolus-tracking with the region of interest placed within the femoral artery, and scanning is automatically triggered once enhancement reaches 120 Hounsfield units.
5. Image acquisition proceeds from the pelvis to the ankle with a slice thickness of 1.0 mm, and multiplanar reconstructions are generated in the sagittal and coronal planes to evaluate osseous destruction and arterial and venous involvement.
6. The radiologist reviews the images immediately, focusing on the presence of arteriovenous malformations, involvement of major vessels, and extent of bone erosion to guide operative planning.
7. Following CTA, fibroblast activation protein inhibitor positron emission tomography/computed tomography (FAPI-PET/CT) is performed to evaluate metabolic activity and assess systemic tumor burden. The patient rests comfortably in a quiet room for 50-60 min following intravenous administration of 68Ga-FAPI tracer to allow adequate uptake.
8. Immediately prior to imaging, the patient voids to reduce pelvic artifact and is positioned supine with both arms raised above the head, secured to prevent motion. Whole-body PET acquisition begins from the skull base to the mid-thigh using standard 2-3 min per bed position, followed by low-dose CT correction for attenuation measurement, reconstructed at 1.25-mm slice thickness.
9. SUVmax is recorded for the primary lesion and metastatic foci using a standardized spherical region-of-interest tool. If focal uptake is identified at a suspected metastatic site, targeted region-of-interest measurements are repeated on fused PET/CT images for confirmation.
10. Metabolic maps are compared with CTA anatomy to ensure correlation of perfusion abnormalities with tumor distribution.
11. Histologic confirmation is obtained when imaging findings indicate recurrence. A 6-mm punch biopsy is performed under sterile conditions with local anesthesia using 1% lidocaine injected in a circumferential field block around the lesion.
12. The sample is collected from the edge of the ulcerated lesion, where viable tissue and tumor interface are most representative. The punch tool is rotated through the dermis and subcutaneous layer using steady downward pressure, and the specimen is lifted with forceps and sharply separated at the base using scissors.
13. The sample is immediately placed in formalin for fixation. Hemostasis at the biopsy site is achieved by direct pressure, and a sterile dressing is applied. Histopathologic results are reviewed to confirm squamous cell carcinoma, margin pattern, and differentiation grade.

3. Preoperative optimization

1. Calcitonin is administered subcutaneously at 4 IU/kg every 12 h, rotating injection sites to prevent local irritation.
2. Calcium-lowering antiresorptive therapy is selected based on renal function; intravenous bisphosphonate infusion over approximately 30 min is used when renal function is adequate, while denosumab 120 mg subcutaneously is considered for impaired renal function or insufficient response.
3. Continuous renal replacement therapy (CRRT) is initiated when ionized calcium exceeds 1.6 mmol/L or remains refractory to pharmacologic therapy. Typical settings include a blood flow of 180-220 mL/min with calcium-free dialysate at approximately 1,500 mL/h and regional citrate anticoagulation titrated based on laboratory monitoring.
4. Surgery proceeds only after meeting predefined physiologic induction criteria: corrected total calcium ≤2.75 mmol/L or ionized calcium ≤1.32 mmol/L, potassium 3.5-5.0 mmol/L, magnesium ≥0.8 mmol/L, arterial pH 7.35-7.45, lactate <2 mmol/L, mean arterial pressure ≥65 mmHg, hemoglobin ≥80-90 g/L, core temperature ≥36.0°C, and stable urine output of drainage ≥0.5 mL·kg^-1·h^-1.
5. Laboratory results must be obtained within 2 h of entering the operating room.

4. Operative management

1. Following anesthesia induction and placement of an arterial line, the patient is positioned supine with the affected limb slightly abducted for improved surgical access. The operative field is prepared using a standard chlorhexidine-alcohol scrub.
2. A fish-mouth flap incision is outlined at the mid-thigh to ensure well-vascularized closure. Skin and subcutaneous tissue are incised sequentially while preserving flap thickness.
3. The femoral artery and vein are dissected and clamped, employing staged vascular control with intermittent reassessment of hemodynamic stability, including mean arterial pressure and heart rhythm.
4. Bone transection is performed at the mid-thigh using an oscillating surgical saw, beveling the cut surface at approximately 45 degrees and sealing exposed bone with wax.
5. Muscle groups are mobilized and sutured using a myoplasty technique to provide a cushioned stump. The femoral and sciatic nerves are placed under gentle tension, sharply transected, and allowed to retract into soft tissue to reduce neuroma formation.
6. Hemostasis is completed, and a 14-Fr closed-suction drain is positioned and connected to continuous negative pressure.
7. Fascial closure is performed with interrupted absorbable sutures, and skin flaps are closed with interrupted non-absorbable sutures, ensuring tension-free approximation. A final confirmation on hemostasis, drain function, and flap perfusion is performed before sterile dressings are applied.

5. Postoperative care

1. The patient is transferred directly to the intensive care unit for continuous cardiovascular and electrolyte monitoring. Ionized calcium, electrolytes, arterial blood gas, lactate, and hemoglobin levels are reassessed at one hour postoperatively, then at 6-12 h, 24 h, and again at 48-72 h.
2. If ionized calcium rises above 1.35 mmol/L or arrhythmias occur, targeted therapy is resumed. The surgical drain remains in place until the output of drainage decreases to less than 30-50 mL over 24 h with clear drainage fluid.
3. Multimodal analgesia is initiated, including scheduled non-opioid therapy supplemented with patient-controlled opioid analgesia if required.
4. Venous thromboembolism prophylaxis is administered according to risk stratification. Rehabilitation begins on postoperative day three with bed-based exercises and progressive stump strengthening.

Results

Following correction of metabolic derangements and achievement of all predefined physiologic criteria, the patient underwent a left above-knee amputation with successful staged vascular control and stable intraoperative hemodynamics. No episodes of fatal arrhythmia, circulatory collapse, or severe electrolyte disturbances occurred during the operation. Postoperatively, the patient was transferred directly to the intensive care unit, where ionized calcium, electrolytes, and arterial blood gases were closely monitored at 1...

Discussion

FAPI-PET/CT visualizes cancer-associated fibroblast activity and, compared with fluorodeoxyglucose imaging, often provides higher tumor-to-background contrast across multiple sites; It can therefore be used for preoperative stratification at three levels: (i) anatomic extent, delineating skin, fascia, muscle, and bone involvement and proximity to neurovascular structures; (ii) disease burden, detecting occult skeletal and soft-tissue metastases and estimating lesion activity; and (iii) treatment strategy, informing feasi...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
0.9% Normal Saline
14-Fr closed-suction drain	Ethicon	VAC14
18-G peripheral IV catheter	BD	381412
21-G butterfly needle	BD	367281
68Ga-FAPI Tracer	ITM Isotopen Technologien München AG	FAPI-46
Calcitonin (subcutaneous, 4 IU/kg)	Novartis	HUM/CT/4IU
Chlorhexidine-alcohol surgical scrub	3M	CHG-0150
Citrasate 4%	Fresenius	https://freseniusmedicalcare.com/en-us/products/disposables/concentrates/citrasate-liquid-acid/	Regional citrate anticoagulation solution
Denosumab 120 mg (subcutaneous)	Amgen	55513-710-01
Formalin (for biopsy fixation)	Sigma-Aldrich	HT501128
Furosemide injection (20 mg)	Sanofi	FRS20
IntelliVue MX450	Philips	https://www.philips.co.in/healthcare/product/HC866062/intellivue-mx450-patient-monitor	Standard 3-lead ECG monitor
Intravenous bisphosphonate	Roche	BNP-50
MEDRAD Stellant D	Bayer	https://radiology.bayer.com.au/products/medrad-stellant	Dual-syringe contrast injector (for CTA)
Myoplasty sutures (absorbable for fascia, non-absorbable skin)	Ethicon	VCP778H / MFS-29
Omnipaque 350	GE Healthcare	https://www.gehealthcare.com/products/contrast-media/omnipaque	CTA contrast: Iodinated contrast media (100 mL)
Perfusor Space	B. Braun	https://catalogs.bbraun.com/en-01/p/PRID00001226/perfusor-space	Patient-controlled analgesia pump
Prismaflex M100	Baxter	https://ecatalog.baxter.com/ecatalog/loadproduct.html?cid=20016&lid=10001&pid=822776	CRRT machine + calcium-free dialysate
Punch biopsy tool (6 mm)	Kai Medical	BP-60F
Surgical saw (oscillating)	Stryker	6208 System 6