Humoral Hypercalcemia Of Malignancy Research Articles

SAT256 Buschke Loewenstein Tumor Presenting With Hypercalcemia

Abstract Disclosure: K. Jones: None. P. Krutilova: None. J.B. McGill: None. Introduction: Humoral hypercalcemia of malignancy is known to be associated with squamous cell carcinomas (SCC), although rarely seen in the setting of skin cancer. We present an interesting case of a young patient with giant condyloma acuminatum complicated by SCC presenting with severe hypercalcemia. Case Description: A 37-year-old man presented with pain and purulent drainage due to bacterial superinfection of genital warts. He had recurrent and locally advanced condylomas, first occurring more than 10 years ago. Skin lesions in the genital and perianal area never resolved and he required multiple surgical interventions including sigmoid colostomy placement due to Fournier gangrene. His laboratory evaluation this admission was notable for an elevated calcium level (13.0 mg/dL [8.5-10.3], albumin 3.4 g/dL [3.5-5.0]), phosphorus 3.9 mg/dL [2.3-4.5], and normal kidney function. He did not have history of hypercalcemia and was not taking any calcium supplements. Hypercalcemia prompted work-up including: PTH 4 pg/mL [15-65], 25-OH vitamin D 36 ng/mL [30-80], unremarkable SPEP/UPEP, TSH 0.91 mcIUnit/mL [0.3-4.2]. Initial differential diagnosis included hypercalcemia due to granulomatous process and increased production of calcitriol vs. PTH-related protein (PTHrP) mediated hypercalcemia. 1,25-OH vitamin D was normal (33 pg/mL [18-64]) and PTHrP was elevated (6.7 pmol/L [<4.2]). The patient subsequently underwent biopsy of groin lesions which demonstrated SCC in situ. PET/CT only demonstrated hypermetabolic changes in the perineum and groins bilaterally. Inguinal lymph node biopsy was negative for malignancy. His hypercalcemia persisted despite administration of IV fluids and he was treated with IV zolendronic acid. Calcium level subsequently normalized (9.1 mg/dL). He underwent extensive excision of the tumor involving the right gracilis muscle, left testicle, portions of the perineum, and penile shaft skin. Discussion: While cases of hypercalcemia in malignancy are common, this is an unusual case of giant condyloma acuminata (GCA) heralding development of SCC by elevated calcium levels. GCA also known as Buschke-Loewenstein tumor is a rare disease with estimated incidence of 0.1% in the general population and a male-to-female ratio of 2.7:1, typically associated with human papilloma virus subtypes 6 and 11. It is a locally aggressive tumor with a potential for destructive growth and malignant transformation (estimated rate up to 56%), very high rate of recurrence after excision (66%), and overall mortality of approximately 20%. Early recognition and treatment of GCA is essential in order to prevent devastating complications. Purzycka-Bohdan D, Nowicki RJ, Herms F, et al. The Pathogenesis of Giant Condyloma Acuminatum (Buschke-Lowenstein Tumor): An Overview. Int J Mol Sci. 2022;23(9):4547. Published 2022 Apr 20. doi:10.3390/ijms23094547 Presentation: Saturday, June 17, 2023

THU534 Humoral Hypercalcemia Of Malignancy As Initial Presentation Of Hepatocellular Carcinoma And Monoclonal Gammopathy Of Undetermined Significance

Abstract Disclosure: F. Jovanovic: None. A. Raghavan: None. A. Sudhakar: None. Background: Humoral hypercalcemia of malignancy can be initial metabolic manifestation of different neoplasms, and it is exceedingly rare in hepatocellular carcinoma (HCC).1 In this case report, we present a patient with humoral hypercalcemia secondary to HCC and monoclonal gammopathy of undetermined significance (MGUS) in the context of nonalcoholic steatohepatitis. Case Report: A 73-year-old Caucasian male with liver cirrhosis secondary to nonalcoholic steatohepatitis presented to the emergency department with a two-week history of constipation and progressive confusion. The patient was jaundiced on exam and tender to palpation in left and right middle abdominal quadrants. Laboratory findings on admission showed serum calcium 12.7 mg/dL (7.9–10.6), albumin 2.6 g/dL (3.5–5), platelets 85x103/µL (138–338), alkaline phosphatase 349 unit/L (50–136), alanine aminotransferase 234 unit/L (15-53), aspartate aminotransferase 133 unit/L (15–37), alpha-fetoprotein 1912.7 ng/mL (0–8), parathyroid hormone <3 pg/mL (14–72), and ammonia 40 mmol/L (11–32). The patient’s altered mental status improved with lactulose and rifaximin. Serum calcium levels persisted despite lactated Ringer’s solution, but improved with zoledronic acid 5 mg infusion to a nadir of 9.1 mg/dL during the hospital stay. The patient was administered repeat zoledronic acid before discharge, but was readmitted 5 days later with worsening mental status and corrected serum calcium 13.1 mg/dL. The CT abdomen and pelvis showed a mass (4.2 x 3.7 cm) in the lower right hepatic lobe. The send out labs returned with PTH-related peptide 48 pg/mL (11–20), 1,25 hydroxyvitamin D 20 pg/mL (20–45), and serum protein electrophoresis with a monoclonal M spike 1.33 g/dL in the gamma globulin region. The patient’s hypercalcemia was found to be PTH–independent and with the new hepatic mass on CT imaging, he was diagnosed with MGUS and humoral hypercalcemia secondary to HCC. The literature review shows only one case report with alcoholic cirrhosis and similar clinical presentation, which is in contrast to nonalcoholic steatohepatitis as seen in our patient.2 The patient’s family refused further treatment and opted for hospice care. Conclusion: We recommend that the patients with HCC and resistant hypercalcemia undergo diagnostic evaluation for monoclonal paraprotein as part of humoral hypercalcemia workup.

Hypercalcemia affected in metastatic breast cancer patients without bone metastasis: report of three cases

BackgroundSince humoral hypercalcemia of malignancy (HHM) in breast cancer patients without bone metastasis is rare, the clinical features of this condition are not fully understood.Case presentationDuring the recent 12 years, 3602 patients were diagnosed with breast cancer in our institution, and only three patients developed HHM without bone metastasis. They were all recurrent breast cancer patients with visceral metastases including the lung and the liver. It took no more than 2 months since symptomatic onset to hospitalization because of hypercalcemia. The maximum serum calcium concentrations were 15.0 mg/dL or higher. All patients had symptoms related to hypercalcemia. Treatment of hypercalcemia including hydration, calcitonin, bisphosphonate, and diuretics was initially effective in the three patients. However, two of three cases were eventually fatal because of unsuccessful treatment of breast cancer.ConclusionsThe common features of HHM without bone metastasis in breast cancer patients include acute onset, severe symptomatic hypercalcemia, and presence of visceral metastasis. Treatment of hypercalcemia decreased serum calcium level in a short period, while successful treatment of breast cancer was essential for a long-term management of HHM. This report provides a consideration to help elucidate the pathophysiology and medical care of breast cancer patients with HHM without bone metastasis.

LBSAT142 Discovery And Characterization Of A Potent And Orally Bioavailable Parathyroid Hormone Receptor Type-1 (PTHR1) Antagonist For The Treatment Of Hypercalcemia

Abstract Hypercalcemia is a common disorder defined as a serum calcium concentration higher than the normal range of 8.5 - 10.5 mg/dL. The most common causes of hypercalcemia are over-secretion of parathyroid hormone (PTH) from one or more enlarged parathyroid glands, which can lead to primary hyperparathyroidism (PHPT), or over-secretion of parathyroid hormone related protein (PTHrP) from a cancerous tumor, which leads to humoral hypercalcemia of malignancy (HHM). PTH is an 84 amino acid peptide that regulates calcium and phosphate homeostasis through activation of its receptor, PTHR1. PTHrP has close homology to the N-terminal region of PTH and also activates PTHR1, inducing similar biological actions. Activation of PTHR1, a class B G-protein coupled receptor expressed in bone and kidney, leads to an increase in cAMP and PKA activation, inducing gene expression changes of important modulators of bone homeostasis. In the kidney, it increases renal phosphate excretion and calcium reabsorption. Hyperactivation of PTHR1 due to high levels of either PTH or PTHrP results in increased calcium release from the bone matrix, as well as increased calcium reabsorption in the kidney, causing hypercalcemia. Surgery is the first line therapy for PHPT, but patients that cannot or choose not to have surgery are prescribed calcimimetics and/or bisphosphonates. Calcimimetics decrease circulating calcium levels but have no effect on bone homeostasis, while bisphosphonates improve bone homeostasis but have little effect on circulating calcium levels. HHM patients are prescribed bisphosphonates or denosumab, both of which possess undesirable side effects. We hypothesize that blocking PTH/PTHrP action via a PTHR1 antagonist may provide an improved therapeutic mechanism to treat PHPT and HHM, and potentially other diseases of hypercalcemia. Using an iterative medicinal chemistry approach, Crinetics has identified several nonpeptide PTHR1 antagonists via both binding and functional in vitro assays. One of these compounds, Antagonist 1 (ANT-1), has low nanomolar binding affinity for both human and rat PTHR1 and is potent in human, monkey, rat, mouse and canine PTHR1 functional antagonist assays in vitro. ANT-1 has good oral exposure in preclinical species and desirable drug-like properties, including lack of inhibition of cytochromes P450 and the hERG ion channel, and stability in liver microsomes. In rat models of PTH- and PTHrP-induced hypercalcemia, ANT-1 dose-dependently suppresses ionized blood calcium, providing support that a nonpeptide PTH antagonist has potential use as an effective therapeutic for hypercalcemia caused by PHPT and HHM. Currently, ANT-1 and other potential candidate molecules are being evaluated in a battery of safety studies to select the optimal molecule(s) suitable for evaluation in human clinical trials. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Hypercalcemia in the setting of HTLV-1 infection and a normal PTHrP level

SummaryHuman T-cell lymphotropic virus-1 (HTLV-1) causes adult T-cell leukemia and lymphoma (ATLL) and is a rare but important cause of hypercalcemia. A 53-year-old male with HTLV-1-associated myelopathy presented with acute on chronic bilateral lower extremity weakness and numbness. Initial blood work revealed hypercalcemia with corrected calcium of 16.2 mg/dL (8.5–11.5) with normal levels of phosphorus and alkaline phosphatase. Workup for hypercalcemia revealed parathyroid hormone (PTH) of 14 pg/mL (10–65), 25 hydroxy vitamin D at 19.6 ng/mL (30–100), 1,25 dihydroxy vitamin D at 6.7 pg/mL (19.9–79.3), thyroid-stimulating hormone of 1.265 μIU/mL (0.5–5), undetectable PTH-related protein (PTHrP) and lactate dehydrogenase of 433 U/L (100–220). The urine calcium creatinine ratio was 0.388. Reverse transcriptase PCR was positive for HTLV-1 and negative for HTLV-2. Peripheral blood flow cytometry and lymph node biopsy confirmed ATLL. He received treatment with fluids, calcitonin and denosumab after which serum calcium levels fell (nadir: 7.7 mg/dL) and then normalized. Humoral hypercalcemia in this setting is mediated by receptor activator of nuclear factor-kappa B ligand (RANKL), PTHrP and other cytokines. PTHrP levels depend on levels of the TAX gene product, cell type and lymphocyte-specific factors. Thus, a low level, like in our patient, does not rule out HTLV-1 infection/ATLL as the cause of hypercalcemia. Hypercalcemia is known to be responsive to monoclonal antibodies against RANKL given the compound’s role in mediating hypercalcemia in these cases.Learning pointsHuman T-cell lymphotropic virus-1 infection and adult T-cell leukemia and lymphoma are associated with high rates of hypercalcemia and hypercalcemic crises.Hypercalcemia in these cases is mediated by osteoclastic bone resorption carried out by several agents including receptor activator of nuclear factor-kappa B ligand, parathyroid hormone-related protein (PTHrP), macrophage inflammatory protein 1 alpha, interleukins, etc. A normal PTHRrP does not rule out humoral hypercalcemia of malignancy in this setting, as indicated by this case.Hypercalcemia in such settings is highly responsive to monoclonal antibodies against RANKL given the role the ligand plays in resorptive hypercalcemia.

Abstract #1181995: A rare case of humoral hypercalcemia of malignancy caused by a Gallbladder Adenocarcinoma

Humoral hypercalcemia of malignancy (HHM) is a common paraneoplastic syndrome occurring secondary to oversecretion of parathyroid hormone-related peptide (PTHrP). It is usually seen in solid tumors particularly squamous cell carcinoma of the head, neck, and lungs. Gallbladder adenocarcinoma is an unusual cause of HHM. We present a rare case of hypercalcemia secondary to elevated PTHrP secretion in a patient with gallbladder adenocarcinoma.

Abstract #1176775: Humoral Hypercalcemia of Malignancy Is a Rare Complication of Bladder Carcinoma

Humoral hypercalcemia of malignancy (HHM) accounts for approximately 80% of hypercalcemia caused by malignancies. We present an unusual case of squamous cell carcinoma (SCC) of the bladder as the etiology of HHM.

Development of a PTHrP chemiluminescent immunoassay to assess humoral hypercalcemia of malignancy

BackgroundParathyroid hormone related peptide (PTHrP) measurements are helpful in the evaluation and management of individuals suspected of humoral hypercalcemia of malignancy (HHM). AimTo develop a chemiluminescent assay for PTHrP quantitation, establish reference intervals, and evaluate its clinical performance. MethodPTHrP 1–86 was measured using a polyclonal rabbit antibody (capture) and an acridinium ester labeled goat polyclonal antibody for chemiluminescent detection. ResultsAssay imprecision was < 9% (intra-assay) and < 15% (inter-assay). The analytical measuring range was 0.16–50.5 pmol/L. No significant cross-reactivity was observed for PTH (1–84), PTHrP (107–139), and PTHrP (1–36); whereas PTHrP (38–94) showed 8.3% cross-reactivity. Comparison with the pre-existing Mayo assay showed a positive bias: new assay = 2.24 (pre-existing assay)-0.30 and r2 = 0.96. The reference interval was ≤ 0.7 pmol/L, however, a cut-off of ≤ 4.2 pmol/L yielded increased specificity (98%). Comparison of patients with HHM versus those without HHM resulted in an area under the ROC curve of 0.99. A significant inverse relationship between eGFR and PTHrP was observed (r = 0.738). PTHrP concentrations in patients with Chronic Kidney Disease (CKD) were ≤ 4.2 pmol/L. ConclusionThis assay is specific for PTHrP 1–86. A clinical decision limit of 4.2 pmol/L was sensitive and specific for patients with HHM.

Two Cases of Severe Hypercalcaemia Associated with Cholangiocarcinoma Successfully Treated by Resection in One and Selective Internal Radiation Therapy (SIRT) in the Other

Introduction: Humoral hypercalcaemia of malignancy (HHM) in patients with cholangiocarcinoma is rarely reported with only 36 cases reported in the literature. We present two patients with marked hypercalcaemia both associated with large intrahepatic cholangiocarcinoma without bony metastases.

Parathyroid hormone-related protein in breast cancer bone metastasis.

Parathyroid hormone-related protein (PTHrP) was discovered as the tumor product causing the humoral hypercalcemia of malignancy. Its structural similarity to the hormone, PTH, with 8 of the first 13 amino acids identical, was sufficient to explain the sharing by PTHrP and PTH of a common receptor, PTH1R, although the remainder of the sequences are unique. PTHrP has important roles in development of several organs, including breast and bone, and functions as a paracrine factor postnatally in these and other tissues. In addition to its hormonal role in cancer, PTHrP is produced by two thirds of primary breast cancers and 90% of bone metastases from breast cancer, leading to the concept that its production in bone by breast cancer cells promotes bone resorption, thus favoring tumor establishment and expansion, and an exit from tumor dormancy in bone through downregulation of leukemia inducing factor receptor (LIFR). Cancer production of PTHrP is increased by bone-derived growth factors, with particular attention paid to TGFβ, as well as by promoter-driven transcriptional effects, such as the hedgehog signaling factor, GLI2, and microenvironment effects including changes in underlying stiffness of substrates for cells. Although interest has been focused on PTHrP-induced bone resorption in bone metastasis, a mechanistically separate, protective effect against tumor progression has been proposed. Although there is conflicting mouse data, there are clinical studies suggesting that increased production of PTHrP by breast cancers confers upon them a less invasive phenotype, an effect distinct from the bone resorption-stimulating action that favors bone metastasis.

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.

From Good to Bad: The Opposing Effects of PTHrP on Tumor Growth, Dormancy, and Metastasis Throughout Cancer Progression.

Parathyroid hormone related protein (PTHrP) is a multifaceted protein with several biologically active domains that regulate its many roles in normal physiology and human disease. PTHrP causes humoral hypercalcemia of malignancy (HHM) through its endocrine actions and tumor-induced bone destruction through its paracrine actions. PTHrP has more recently been investigated as a regulator of tumor dormancy owing to its roles in regulating tumor cell proliferation, apoptosis, and survival through autocrine/paracrine and intracrine signaling. Tumor expression of PTHrP in late stages of cancer progression has been shown to promote distant metastasis formation, especially in bone by promoting tumor-induced osteolysis and exit from dormancy. In contrast, PTHrP may protect against further tumor progression and improve patient survival in early disease stages. This review highlights current knowledge from preclinical and clinical studies examining the role of PTHrP in promoting tumor progression as well as skeletal and soft tissue metastasis, especially with regards to the protein as a regulator of tumor dormancy. The discussion will also provide perspectives on PTHrP as a prognostic factor and therapeutic target to inhibit tumor progression, prevent tumor recurrence, and improve patient survival.

178 A Curious Case of Hypercalcemia

Humoral hypercalcemia of malignancy is rarely seen in urothelial cancer. In this report, we present a case of an 81-year-old female patient who presented with a markedly elevated calcium level leading to severe altered mental status and was found to have urothelial cancer. To our knowledge, only three cases of urothelial carcinoma with squamous cell differentiation have been reported.

A Case of Recurrent Breast Cancer with Humoral Hypercalcemia of Malignancy

A Case of Recurrent Breast Cancer with Humoral Hypercalcemia of Malignancy

Actualización: Fisiopatología, Diagnóstico y Manejo de la Hipercalcemia Maligna

Resumen&#x0D; La hipercalcemia maligna es una complicación metabólica común de algunos tumores en estadios avanzados y se define por un valor de calcio sérico mayor a 10.5 mg/dl. Se encuentra principalmente en pacientes con cáncer de mama, pulmón, carcinoma renal, carcinoma de células escamosas de cualquier órgano y neoplasias sanguíneas, sin embargo; puede estar presente en casi cualquier tipo de cáncer. La hipercalcemia maligna humoral es el principal mecanismo fisiopatológico de la hipercalcemia maligna, no obstante también puede asociarse a metástasis osteolíticas y con menos frecuencia a producción ectópica de calcitriol y hormona paratiroidea. La hipercalcemia maligna se clasifica en leve con valores de calcio sérico entre 10.5-11.9 mg/dl, moderada de 12-13.9 mg/dl y severa &gt; a 14 mg/dl; la hipercalcemia leve suele ser asintomática mientras que en la formas moderada y severa se asocian con una presentación clínica variada que van desde síntomas gastrointestinales, neurológicos hasta aquellos asociados con hipovolemia. Respecto al tratamiento este se debe enfocar en la fisiología del trastorno y se recomienda la hidratación agresiva, el uso de medicamentos como calcitonina, bifosfonatos o denosumab y en aquellos casos necesarios diuréticos, glucocorticoides y diálisis. El pronóstico de los pacientes con hipercalcemia maligna es pobre y se asocia con altas tasas de mortalidad.

Parathyroid Hormone Related Protein - A Skeletal Biomarker – A Review

The discovery of Parathyroid hormone-related protein (PTHrP) was through its structural and functionalhomology with parathyroid hormone. It is secreted by cancers and it interacts with parathyroid hormonereceptors in kidney and bone to cause humoral hypercalcemia of malignancy and paraneoplastic syndrome andplays an important role in cellular differentiation and proliferation, embryonic development, transepithelialcalcium transport and in the regulation of smooth muscle contraction.Its intracrine, paracrine and endocrinemodes of action play a central role in organogenesis and drives numerous physiologic and pathologicconditions.It is initially translated as a preprohormone which is posttranslationally processed to yield afamily of mature secretory forms. The aminoterminal portion of the molecule is homologous to parathyroidhormone.As PTHrP plays a vital role in the regulation of endochondral bone development it was surmisedthat it could also serve as an ideal biologic skeletal maturity indicator to detect peak pubertal growth spurt.

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.

Humoral hypercalcemia of malignancy caused by renal pelvic urothelial carcinoma with broad squamous differentiation: An autopsy case

Humoral hypercalcemia of malignancy caused by renal pelvic urothelial carcinoma with broad squamous differentiation: An autopsy case

Oral cinacalcet responsiveness in non-parathyroid hormone mediated hypercalcemia of malignancy

Hypercalcemia of malignancy develops in approximately 20–30% of patients with advanced cancer and is an ominous sign. This condition is subdivided into three categories: i) humoral hypercalcemia of malignancy (80% of cases), mediated by systemic parathyroid hormone-related protein; ii) osteolytic metastases (20% of cases), mediated by inflammatory cytokines locally released by tumor cells and/or peri-tumor macrophages; and iii) ectopic production of 1,25-dihydroxyvitamin D (<1% of cases), leading to intestinal hyperabsorption of calcium and increased osteoclastic bone resorption. Humoral hypercalcemia of malignancy is seen in a variety of solid tumors, while osteolytic metastases are most common in breast cancer and multiple myeloma. Hypercalcemia of malignancy mediated by 1,25-dihydroxyvitamin D is primarily seen in lymphomas, having only rarely been reported in solid tumors. Pharmacologic management of humoral hypercalcemia of malignancy and osteolytic metastases mainly involves inhibition of bone resorption with intravenous bisphosphonates, subcutaneous denosumab, and subcutaneous calcitonin. Glucocorticoid therapy is the mainstay for management of increased 1,25-dihydroxyvitamin D. Unfortunately, management of hypercalcemia of malignancy often requires inpatient admission in the acute setting, and loss of effectiveness of antiresorptive therapy is common. We propose oral cinacalcet may be an efficacious therapy for hypercalcemia of malignancy related to elevated 1,25-dihydroxyvitamin D, and we present supporting data from two cases involving solid tumors. Furthermore, we hypothesize that this effect is primarily mediated by cinacalcet's interaction with the calcium-sensing receptor in the intestine with lesser effects at bone and kidney. Lastly, the role of 1,25-dihydroxyvitamin D in hypercalcemia malignancy may be underappreciated in solid tumors.

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.