Humoral hypercalcaemia of malignancy associated with a gigantic cutaneous squamous cell carcinoma

Abstract

Humoral hypercalcaemia of malignancy is rarely associated with cutaneous squamous cell carcinoma (SCC), and only a few cases have been reported in the medical literature. We present an interesting case of a gigantic cutaneous SCC associated with severe hypercalcaemia.

A man in his mid 80s presented with a rapidly enlarging fungating mass of his scalp for 5 months. Laboratory studies logged severe hypercalcaemia, low intact parathyroid hormone, elevated parathyroid hormone related-peptide and normal 1,25 dihydroxy vitamin D. Skin biopsy revealed moderately differentiated invasive SCC. Further workup was negative for distant skeletal metastases. Severe hypercalcaemia was managed by intravenous fluids, bisphosphonates and calcitonin. A multidisciplinary approach was then made; the patient received radiotherapy and then underwent a successful surgical resection. By presenting this case, we aim to raise physicians’ awareness of the association between cutaneous SCC and hypercalcaemia. Severe hypercalcaemia should be detected early and promptly managed as it could be fatal.

Background

Humoral hypercalcaemia of malignancy (HHM) is a parathyroid hormone (PTH)-independent hypercalcaemia that is classically due to the excess secretion of PTH-related peptide (PTHrP) by the tumour cells. It accounts for 80% of cancer-associated hypercalcaemia.¹ HHM has been described with different malignancies, most commonly squamous cell carcinoma (SCC) of the head, neck and lungs, however, for unclear reasons, it is an infrequent association with cutaneous SCC (cSCC) with only a handful of cases reported in the medical literature to date.² We herein report a case of a patient presenting with a gigantic fungating SCC of the scalp complicated by severe hypercalcaemia due to elevated PTHrP. We aim to raise awareness of the association between cSCC and hypercalcaemia as severe hypercalcaemia could be life-threatening.

Case presentation

A man in his mid 80s with a past medical history of hypertension and coronary artery disease presented to the hospital with a painless, large fungating scalp mass. The mass appeared insidiously around 5 months prior to presentation, had gradually increased in size and drained serosanguinous fluid. The patient also endorsed unintentional weight loss of 40 pounds during that same period. Family history was significant for melanoma and basal cell carcinoma. The patient has never smoked tobacco, occasionally drinks alcohol and never used illicit drugs.

On physical examination, the patient was alert and oriented with stable vital signs. There was a large fungating, ulcerating mass, measuring (8.1×8 cm), over the left parietal region of the scalp with a raised everted edge, and extensive areas of haemorrhage and necrosis (figure 1A).

Figure 1.

(A) A large fungating ulcerating mass (8.1×8 cm) over the left parietal region of the scalp with extensive haemorrhage and necrosis. (B) Postsurgical resection with wide local excision of the tumour, craniotomy with dural excision, free flap latissimus skull reconstruction and split-thickness skin graft.

Investigations

Initial laboratory studies were notable for normocytic normochromic anaemia with haemoglobin of 93 g/L (normal range 139-163 g/dL), acute kidney injury with creatinine of 1.8 mg/dL(normal range 0.8–1.3 mg/dL), and hypercalcaemia with calcium of 15.8 mg/dL (normal range 8.4–10.4 mg/dL), and ionised calcium of 1.38 mmol/L (normal range 1.12–1.32 mmol/L), and hypoalbuminaemia with albumin of 2.2 g/dL (normal range 3.5–5.0 g/dL). Phosphorus and alkaline phosphatase were within the normal range; 2.7 mg/dL (normal range 2.3–4.2 mg/dL) and 67 IU/L (normal ranges 40–200 UL/L), respectively. Additional tests showed low intact PTH 2.7 pg/mL (normal range 12–67 pg/mL), normal levels of 1,25- dihydroxy vitamin D (20 pg/mL; normal range 18–72 pg/mL), and low 25 hydroxyvitamin D (16 ng/mL; normal range 30–100 ng/mL), and elevated PTHrP at 35 pg/mL (normal range, 14–27 pg/mL). Serum protein electrophoresis was obtained and revealed polyclonal gammopathy without paraproteins. Aerobic and anaerobic wound cultures isolated normal skin flora.

A surgical skin biopsy revealed cords and discrete nests of tumour cells with foci of keratinisation, numerous atypical mitoses, foci of tumour necrosis and multiple epithelioid cells exhibiting expansile eosinophilic cytoplasm with prominent nucleoli (figure 2A). Immunohistochemical stains showed strongly positive pan-cytokeratin and cytokeratin 5/6 stains (figure 2B). Cytokeratin 8/18 antibody (5D3) was focally positive, while cytokeratin 7 and SOX 10 stains were negative. Based on the clinicopathological findings, a diagnosis of moderately differentiated invasive cSCC was made.

Figure 2.

(A) Cords and discrete nests of tumour cells with foci of keratinisation, numerous atypical mitoses, foci of tumour necrosis and multiple epithelioid cells exhibiting expansile eosinophilic cytoplasm with prominent nucleoli (Hx&E stain, original magnification ×200) (B) Immunohistochemistry with a strongly positive cytokeratin 5/6 stain (original magnification ×200).

MRI of the brain revealed a fungating scalp mass, measuring 9.4×8.1×2.2 cm in its greatest dimension, at the high left parietal region with diffuse heterogeneous enhancement and focal invasion of the calvarium, extending through the inner table and contacting the dura (figure 3). CT scan venogram of the head showed a patent intracranial venous system without invasion. Further imaging for staging included a normal CT scan of the neck without pathologically enlarged cervical lymph nodes. CT scan of the chest, abdomen and pelvis showed no evidence of distant organ or skeletal metastases, however, it showed incidental acute pulmonary emboli, and therapeutic anticoagulation was initiated. Positron emission tomography (PET) scan after radiotherapy showed fluorodeoxyglucose (FDG) avid left scalp lesion eroding into the adjacent bone with maximum standard uptake value of 20.5. There was no evidence of regional lymph node or distant metastases. Clinical stage was cT4a, cN0 and cM0.³

Figure 3.

MRI head: Fungating scalp mass 9.4×8.1×2.2 cm in greatest dimension at the high left parietal region with diffuse heterogeneous enhancement and focal invasion of the calvarium at the high left parasagittal posterior parietal region, extending through the inner table and contacting the dura with mild dural thickening and enhancement as evidence for dural involvement. It nearly abuts the superior sagittal sinus but does not invade it.

Differential diagnosis

The differential diagnosis of this case includes different aetiopathogenesis of hypercalcaemia associated with malignancy. Bone invasion and hypercalcaemia from local effects of malignancy on bone was excluded by Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan. PTH-related hypercalcaemia, and 1,25- dihydroxycholecalciferol induced hypercalcaemia, were excluded by respective biochemical tests. So, the present case was solely due to PTHrP-induced HHM.

Treatment

Hypercalcaemia was initially managed by continuous infusion of 0.9% saline and intravenous pamidronate 90 mg. Persistent hypercalcaemia for 14 days was managed by repeat treatment with bisphosphonates; intravenous zoledronic acid 4 mg, and a total of two doses of subcutaneous calcitonin 200 units each on two consecutive days, which resulted in a decrease in serum calcium to 9.2 mg/dL, and serum creatinine normalised 1.09 mg/dL. Given the local extent of the tumour and the underlying comorbidities, a multidisciplinary approach was made by dermatology, plastic surgery, neurosurgery, medical and radiation oncology. The patient initially received neoadjuvant radiation therapy of 3000 cGY via external beam radiation therapy. He was then referred for surgical evaluation. No chemotherapy was used at any stage. Surgical management was pursued and included a wide local excision of the tumour, craniotomy with dural excision, free flap latissimus skull reconstruction and split-thickness skin graft (figure 1B).

Outcome and follow-up

Frozen section biopsies showed free margins, negative dura mater for carcinoma, left and right parietal bones with invasive SCC, and acute and chronic osteomyelitis. WHO histological type was keratinising SCC, the histological grade was well differentiated with a depth of invasion of 0.8 cm, without lymphovascular or perineural invasion, and with no positive lymph nodes or extranodal extension. Based on these findings, the pTNM classification—according to AJCC cancer staging, eighth edition and guidelines of College of American Pathologists—was pT4aNx.³

A postoperative head CT scan was negative for intracranial haemorrhage, mass effect or territorial infarct. The postoperative course was complicated by temporary hypotension requiring vasopressors and admission to the neurocritical care unit. The patient eventually improved, with excellent healing of his surgical wound (figure 1B). He was discharged, with further follow-up with radiation and medical oncology.

Discussion

Hypercalcaemia can occur in up to 30% of patients with malignancy. It is four times more common in advanced stages of cancer and is usually associated with a poor prognosis.⁴

The pathophysiology of cancer-related hypercalcaemia is attributed to several proposed mechanisms, the three main mechanisms include excess secretion of humoral factors that mimic PTH, bone osteolysis mediated by local tumour cell secretion of osteoclast-activating cytokines like IL-1, IL-3, IL-6, TNF-alpha and prostaglandins; or excess extrarenal secretion of 1,25 dihydroxy vitamin D by tumour cells.⁵ HHM is the most common mechanism of hypercalcaemia of malignancy accounting for 80% of the cases, and it is defined as hypercalcaemia due to the excess secretion of humoral factors—specifically PTHrP—without evidence of skeletal metastases.¹ PTHrP is a ubiquitous polypeptide hormone that is structurally similar to PTH and has a high affinity to PTH/PTHrP receptors on the bone and the kidneys, leading to increased phosphaturia, increased calcium reabsorption, and increased bone resorption.⁶ PTHrP is highly expressed in the skin, specifically in the pilous follicle, stratum basale, stratum granulosum and melanocytes. Moreover, the skin has a complex PTH/PTHrP receptor network, where PTHrP stimulates keratinocyte proliferation and pilous follicle development.⁷

HHM is usually seen in solid malignancies and rarely in haematological malignancies. It is most commonly associated with SCC of the head, neck, and lungs, genitourinary, and breast cancers.¹ Interestingly, HHM has been rarely described in association with cSCC. In a recent review compiling data on paraneoplastic syndromes (PNS) associated with keratinocyte skin cancers, hypercalcaemia of malignancy was the most common reported PNS and accounted for 78% of the cases, nearly half of the cases had metastatic disease and in 20 out of 21 patients, it was secondary to elevated PTHrP. This reflects the rarity of such association, and possibly the limited capacity of skin cancers to provoke overt PNS.² Underlying predisposing factors to cSCC reported in those cases included: genodermatoses (dystrophic epidermolysis bullosa,⁸ porokeratosis of mibelli,⁹ xeroderma pigmentosum¹⁰) and acquired factors, for example, burn scars,¹¹ hidradenitis suppurativa,¹² chronic arsenic intoxication¹³ and lymphoedema.¹⁴

The clinical presentation of HHM varies widely from asymptomatic to severe, associated with volume depletion, acute renal insufficiency, altered mental status and coma, depending on the serum calcium level.⁴ Diagnostic laboratory tests include elevated serum calcium and PTHrP, with low or normal PTH and 1,25 dihydroxy vitamin D.

HHM usually resolves by treatment of the underlying malignancy. In invasive cSCC, tumour excision or radiotherapy can improve hypercalcaemia and PTHrP levels.¹⁵ However, moderate to severe hypercalcaemia (calcium >12 mg/dL) can be life-threatening and require prompt management, especially when complicated by renal or neurological complications. Initial medical therapy includes fluid replacement, with isotonic saline. Patients should be closely monitored for signs of fluid overload, and urine output should be monitored, especially in patients with renal or cardiac impairment.⁴ Bisphosphonates are the first line and also the mainstay of long-term therapy, they induce osteoclast apoptosis, prevent osteoblast apoptosis, neutralise the RANKL-mediated stimulation of osteoclasts and reduce osteoclastic bone resorption.¹⁶ Pamidronate and zoledronic acid are the two U.S. Food and Drug Administration (FDA)-approved drugs in the treatment of hypercalcaemic crises. Both drugs should be used with caution in renal insufficiency.⁶ They should be administered within 48 hours of the diagnosis, however, they can take 2–4 days to show an effect.¹⁷ Due to its immediate effect, calcitonin is usually considered an adjunctive treatment that serves as a bridge to acutely manage severe hypercalcaemia while other treatment modalities are reaching therapeutic effects. The expected maximum drop in serum calcium is 2 mg/dL within 4 hours, and it is usually given no longer than 48 hours as tachyphylaxis can occur.¹⁷ Denosumab is a monoclonal antibody against RANKL; that is effective in refractory PTHrP-induced malignant hypercalcaemia and was more efficacious than zoledronic acid in delaying and preventing hypercalcaemia in patients with advanced cancers.^{18 19}

In conclusion, despite the high incidence of cSCC, PNSs, including hypercalcaemia, are rare associations. This could be a true rarity or simply underdiagnosing and under-reporting. Physicians should be wary of this possible association and adequately monitor susceptible patients to prevent and early manage severe hypercalcaemia which is a medical emergency associated with poor prognosis and increased mortality.

Learning points.

• Humoral hypercalcaemia of malignancy (HHM) accounts for 80% of cancer-related hypercalcaemia, and it is most commonly due to the release of parathyroid hormone-related peptide (PTHrP) by tumour cells.

• HHM associated with cutaneous squamous cell carcinoma is extremely rare, nonetheless should be considered and treated in patients presenting with skin mass and hypercalcaemia.

• Main laboratory findings of HHM include elevated serum calcium, elevated PTHrP and low to normal PTH-intact.

• HHM usually resolves after resection or radiation of the tumour, however, acute treatment of moderate to severe hypercalcaemia is essential.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).