Missed diagnosis of lymphoma presenting with humoral hypercalcemia of malignancy due to cessation of oncological workup after negative computed tomography scans

Malignancy is the most common cause of hypercalcemia among hospitalised patients and is frequently caused by elevations in parathyroid hormone-related peptide (PTHrP). The most common PTHrP-producing cancers are carcinomas of the head, neck and lung. Hypercalcemia can be the presenting sign of cancer and, in these cases, solid tumours are usually discovered on CT scan. In rare cases, lymphoma may also present with hypercalcemia. CT scan is less sensitive for lymphoma than for most solid tumours and the diagnosis may be missed. We present the case of a 69-year-old woman who presented with hypercalcemia in the setting of severe weight loss and elevated PTHrP. Oncological workup was stopped after unrevealing CT scans and an underlying lymphoma was missed. Our case emphasises the need for a comprehensive oncological workup for patients with unexplained hypercalcemia and elevated PTHrP, even when CT scans are unrevealing.

Development of a PTHrP Chemiluminescent Immunoassay to Assess Humoral Hypercalcemia of Malignancy

Background: Measurement of parathyroid hormone related peptide (PTHrP) is helpful in the diagnosis and clinical management of patients suspected of humoral hypercalcemia of malignancy (HHM). In these patients uncontrolled release of PTHrP by tumor cells is responsible for the hypercalcemia and PTH concentrations are typically suppressed. Objective: Develop a sensitive and specific assay for quantitation of PTHrP in plasma. Method: Calibrators (PTHrP 1-86) and samples (50uL) were incubated with an anti-PTHrP goat polyclonal acridinium ester labeled antibody. Complexes were transferred and incubated in a microplate coated with an anti-PTHrP polyclonal rabbit antibody. After washing, the acridinium ester generated signal, which is directly proportional to the amount of PTHrP in sample, was quantified. Results: In this assay PTHrp was stable for 24 hours ambient, 3 days refrigerated, 34 days frozen and through 3 freeze/thaws. Intra and inter-assay imprecision in EDTA plasma (~0.16-35.0 pmol/L) ranged from 2.2-8.6% and 5-15%, respectively. The limit of detection was 0.04 pmol/L and the limit of quantitation was 0.16 pmol/L (15% CV). The analytical measuring range was 0.39-50.5 pmol/L (slope of 1.07 and r2 of 0.99). Average spike recovery was 98% (range 85-108%). The assay was not affected by hemoglobin of ≤500 mg/dL, triglycerides of ≤2000 mg/dL, or bilirubin of ≤50mg/dL. No hook effect was noted up to 500 pmol/L. PTH (1-84) did not cross-react in the assay. C-terminal PTHrP(107-139), and N-terminal PTHrP(1-36) had no significant cross-reactivity (≤1.1%). Mid-PTHrP(38-94) had 8.3% cross-reactivity. Comparison with an in-house PTHrP assay (n=267) showed an r2 of 0.96, and slope of 2.25 by Passing-Bablok regression fit. The 97.5% reference interval for PTHrP (n=114) was ≤0.7 pmol/L, however a higher concentration (≤4.2 pmol/L) was identified as a more specific clinical cut-off. A retrospective clinical validation study showed that using ≤4.2 pmol/L resulted in a 91% clinical sensitivity and a 98% clinical specificity. Conclusion: We have developed an analytically and clinically sensitive and specific PTHrP immunoassay. A cutoff of ≤4.2 pmol/L is clinically useful in the evaluation of patients suspected of hypercalcemia of malignancy.

Hypercalcemia Associated with Extramammary Paget’s Disease

Hypercalcemia of malignancy occurs in up to one third of patients at some point during the course of their advanced stage. The majority of them is caused by humoral hypercalcemia of malignancy due to systemic secretion of parathyroid hormone–related protein (PTHrP) by tumor cells. Extramammary Paget’s disease is a slow-growing cutaneous malignancy commonly limited to the epidermis of the anogenital region, but rarely becomes invasive and metastatic to distant sites. Herein, we report a 70-year-old male patient with metastatic extramammary Paget’s disease. He consulted our hospital with altered consciousness and tumor in his genital area. Physical examination revealed erythematous plaque with a tumor on the scrotum and perineum. It was diagnosed as extramammary Paget’s disease (multiple liver metastases and multiple lymph node metastases by skin biopsy and image examination). Increases in serum-corrected calcium and PTHrP-intact levels (15.3 mg/dL and 66.1 pg/L, respectively) were confirmed. PTHrP immunohistochemistry showed positive staining in the tumor cells. We diagnosed humoral hypercalcemia of malignancy. We treated hypercalcemia with saline, furosemide, zoledronic acid, and elcatonin. Regarding the local control of the tumor, 30 Gy/10 Fr electron beam therapy was performed. However, treatment with zoledronic acid was only temporally effective to correct hypercalcemia, and an increased serum calcium level developed again. Concurrently, the liver metastases were rapidly enlarged, and his general condition gradually deteriorated. The patient died on day 55. When patients with extramammary Paget’s disease show unconsciousness, serum calcium level should be measured and PTHrP-producing tumor distinguished.

When CKD-MBD is not just CKD-MBD, a case of humoral hypercalcemia of malignancy in a dialysis patient

Patients on maintenance hemodialysis have dysregulations of calcium and phosphorus homeostasis which results in a plethora of mineral and bone pathologies. Management is typically focused on maintenance eucalcemia and limiting hyperphosphatemia while avoiding extremes of intact parathyroid hormone. Hypercalcemia in this setting is often iatrogenic. We present a case of humoral hypercalcemia of malignancy initially thought to be iatrogenic due to mineral bone management and discuss the overlap of management of hypercalcemia and management of mineral bone disease in end stage kidney disease. We highlight the relationship between malignancy and end stage kidney disease and the increased risk of hypercalcemia associated with malignancy.

SAT-120 Humoral Hypercalcemia of Malignancy Caused by Squamous Cell Carcinoma of the Penis

Background. Humoral hypercalcemia of malignancy (HHM) accounts for approximately 80% of hypercalcemia associated with cancer. We present an unusual case of HHM caused by recurrent squamous cell carcinoma of the penis. Case. A 45 year old male was brought to the emergency department (ED) due to worsening confusion over 48 hours. History was notable for squamous cell carcinoma of the penis initially diagnosed 12 years ago and managed by partial penectomy and ilioinguinal lymphadenectomy. Recurrence had been diagnosed approximately 30 days before presentation to the ED. The patient was somnolent, disoriented, and unable to follow commands. Admission laboratories were remarkable for new occurrence of hypercalcemia (serum calcium corrected for low albumin 17.0 mg/dL, 8.6–10.3) and acute renal failure (Cr 1.7 mg/dL, 0.6–1.3; BUN 44 mg/dL, 7–25). No masses or hemorrhages were observed on head imaging, though computed tomography of the chest, abdomen, and pelvis revealed multiple lung and liver masses and lytic bone lesions. Biopsy of a rib mass confirmed metastatic squamous cell carcinoma. Intact PTH level was suppressed at 1 pg/mL (12–88), but parathyroid hormone related protein (PTHrP) was significantly elevated at 120 pM (0.0–2.3). HHM due to PTHrP was diagnosed. Corrected calcium level reached a nadir of 9.5 mg/dL on hospital day seven after saline hydration, calcitonin, and zoledronic acid, but high dose denosumab (120 mg weekly) was started hospital day 10 after corrected calcium level increased to 11.7 mg/dL. Despite corrected calcium levels consistently in the range of 10.5–11.5 mg/dL for the remainder of hospitalization, the patient’s mental status failed to improve. He expired on hospital day 24. Conclusions. Squamous cell carcinoma of the penis is rare in the United States, with only about 2,000 cases diagnosed annually. Though squamous cell carcinomas are collectively the most common cause of PTHrP-related hypercalcemia, there are only a few cases of PTHrP-related hypercalcemia due to squamous cell carcinoma of the penis documented in the peer reviewed literature. As in our patient’s case, other penile carcinoma patients with PTHrP-related hypercalcemia have had regionally advanced or metastatic disease and limited therapeutic response to bisphosphonates. Our patient’s survival after occurrence of hypercalcemia was also similar to other published cases of penile carcinoma complicated by PTHrP-related hypercalcemia. This case confirms the potential for penile carcinoma to cause HHM through hypersecretion of PTHrP like squamous cell carcinomas of the lung, head, and neck. Denosumab may be a more effective treatment option than a bisphosphonate based on the therapeutic experience in this case and others. PTHrP-related hypercalcemia appears to be a strong indicator of limited life expectancy for penile carcinoma as for other malignancies.