Scientific letter
Two uncommon cases of parathyroid hormone-related peptide mediated hypercalcemia in bladder carcinoma
Dos casos infrecuentes de hipercalcemia mediada por el péptido relacionado con la hormona paratiroidea en carcinoma de vejiga
Division of Endocrinology, UCLA David Geffen School of Medicine, Los Angeles, United States
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Kim, Dorothy Martinez" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Julie E." "apellidos" => "Kim" ] 1 => array:4 [ "nombre" => "Dorothy" "apellidos" => "Martinez" "email" => array:1 [ 0 => "dmartinez@mednet.ucla.edu" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Division of Endocrinology, UCLA David Geffen School of Medicine, Los Angeles, United States" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Dos casos infrecuentes de hipercalcemia mediada por el péptido relacionado con la hormona paratiroidea en carcinoma de vejiga" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Hypercalcemia of malignancy is a well-known disorder, often due to elevated parathyroid hormone-related peptide levels (PTHrP). PTHrP-mediated hypercalcemia has been rarely described in association with bladder carcinoma. Here we describe two such cases, each with a unique feature: the first case with concomitant primary hyperparathyroidism and the second case refractory to bisphosphonate therapy.</p><p id="par0010" class="elsevierStylePara elsevierViewall">In the first case, a 77-year-old female, with a history of primary hyperparathyroidism and recently diagnosed invasive, high-grade poorly differentiated metastatic bladder carcinoma with squamous features who underwent total cystectomy, presented with weakness, abdominal pain, and constipation. CT imaging of the abdomen revealed multiple rim-enhancing fluid collections in the lower abdomen and pelvis. Aspirate of the fluid collections revealed metastatic carcinoma with squamous differentiation, consistent with urothelium origin.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The patient had limited knowledge of her past medical history. She was able to state that she has primary hyperparathyroidism but she did not know when or how the diagnosis was made. However, she could say that she had had taken cinacalcet in the past but stopped because she could not afford the medication.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Laboratory evaluation was notable for calcium 3.09<span class="elsevierStyleHsp" style=""></span>mmol/L (2.15–2.57), albumin 30<span class="elsevierStyleHsp" style=""></span>g/L (39–50), ionized calcium 1.84<span class="elsevierStyleHsp" style=""></span>mmol/L (1.09–1.29), creatinine 106.1<span class="elsevierStyleHsp" style=""></span>μmol/L (53.0–115.0), phosphorus 0.68<span class="elsevierStyleHsp" style=""></span>mmol/L (0.74–1.42), intact parathyroid hormone 131<span class="elsevierStyleHsp" style=""></span>ng/L (11–51), vitamin D, 25 hydroxy 22.5<span class="elsevierStyleHsp" style=""></span>pmol/L (49.9–124.8) and vitamin D, 1,25 hydroxy 93.1<span class="elsevierStyleHsp" style=""></span>pmol/L (49.7–197.9). The PTHrP level was 87<span class="elsevierStyleHsp" style=""></span>ng/L (14–27).</p><p id="par0025" class="elsevierStylePara elsevierViewall">She was started on intravenous hydration, cinacalcet 30<span class="elsevierStyleHsp" style=""></span>mg daily, and cholecalciferol 800<span class="elsevierStyleHsp" style=""></span>IU daily. Two days later, calcium levels decreased to a nadir of 2.45<span class="elsevierStyleHsp" style=""></span>mmol/L and ionized calcium of 1.47<span class="elsevierStyleHsp" style=""></span>mmol/L. However, the patient's abdominal pain and constipation worsened. Repeat CT imaging showed bowel obstruction. With this, oral intake of food and medications, including cinacalcet, was stopped. Calcium then trended upwards to a calcium 2.92<span class="elsevierStyleHsp" style=""></span>mmol/L and ionized calcium of 1.74<span class="elsevierStyleHsp" style=""></span>mmol/L. Intravenous zoledronic acid 4<span class="elsevierStyleHsp" style=""></span>mg was administered with subsequent resolution of hypercalcemia.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The bowel obstruction persisted and the patient developed hydronephrosis, which led to kidney failure. Given the patient's overall poor prognosis and her goals of care, the patient was transitioned to comfort care and passed.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In the second case, a 65-year-old male with a high-grade bladder carcinoma metastatic to lymph nodes, who was admitted for transurethral resection of bladder tumor and percutaneous nephrostomy tube placement for bilateral hydronephrosis, was found to be hypercalcemic. The patient noted recent worsening of fatigue and constipation.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Laboratory evaluation was notable for calcium 3.24<span class="elsevierStyleHsp" style=""></span>mmol/L (2.15–2.57), ionized calcium 1.78<span class="elsevierStyleHsp" style=""></span>mmol/L (1.09–1.29), creatinine 176.8<span class="elsevierStyleHsp" style=""></span>μmol/L (53.0–115.0), phosphorus 1.42<span class="elsevierStyleHsp" style=""></span>mmol/L (0.74–1.42), albumin 27<span class="elsevierStyleHsp" style=""></span>g/L (39–50), and intact parathyroid hormone 6<span class="elsevierStyleHsp" style=""></span>ng/L (11–51). The PTHrP level was 49<span class="elsevierStyleHsp" style=""></span>ng/L (14–27).</p><p id="par0045" class="elsevierStylePara elsevierViewall">The patient received intravenous zoledronic acid 4<span class="elsevierStyleHsp" style=""></span>mg with improvement in serum calcium. He subsequently received two more monthly doses of intravenous zoledronic acid 4<span class="elsevierStyleHsp" style=""></span>mg. He was treated with a chemotherapy regimen of methotrexate, vinblastine, doxorubicin, and cisplatin.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Six months later, he was admitted after a mechanical fall resulting in a minimally displaced fracture of the right greater trochanter. He was again noted to be hypercalcemic with calcium 2.94<span class="elsevierStyleHsp" style=""></span>mmol/L, ionized calcium 1.6<span class="elsevierStyleHsp" style=""></span>mmol/L, creatinine 884<span class="elsevierStyleHsp" style=""></span>μmol/L, and PTHrP 56<span class="elsevierStyleHsp" style=""></span>ng/L. Two doses of intravenous pamidronate 60<span class="elsevierStyleHsp" style=""></span>mg were administered with minimal improvement in calcium. Given the lack of response to the bisphosphonate, subcutaneous denosumab 120<span class="elsevierStyleHsp" style=""></span>mg was administered with subsequent normalization of calcium levels.</p><p id="par0055" class="elsevierStylePara elsevierViewall">The hospital course was complicated by urosepsis and progressive deconditioning. In addition, further imaging showed progression of metastatic disease with increased lymph node involvement and multiple new liver lesions, suspicious for metastatic disease. Given these two factors, he was deemed not to be an appropriate candidate for further systemic therapy. His mental status gradually worsened and he was transitioned to comfort care and passed. Autopsy revealed metastatic carcinoma with complete involvement of the bladder mucosa as well as involvement of pleura, lung, pericardium, multiple lymph nodes, diaphragm, liver, spleen, bilateral adrenal glands, bowel serosa, omentum, prostate, pericystic tissue, abdominal wall, and peritesticular tissue.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Hypercalcemia of malignancy is a well-known disorder. It is most commonly caused by elevated parathyroid hormone related peptide levels (PTHrP), but there can be other etiologies such as due to elevated 1,25-dihydroxy-vitamin D production, osteolytic hypercalcemia, or rarely due to concurrent elevated PTHrP and 1,25-dihydroxy-vitamin D production.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">1,2</span></a> PTHrP-mediate hypercalcemia has been associated with a variety of cancers, both solid organ and hematologic malignancies. In a retrospective study of malignancies affected by PTHrP-mediated hypercalcemia, 85.2% of cases were in solid organ malignancies, of which squamous cell carcinoma of the lung were most common. Only 1.7% of cases were in bladder carcinomas.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">3</span></a> PTHrP-mediated hypercalcemia associated with bladder carcinoma is indeed rare and has been reported in case reports.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">4</span></a> The two cases described here have the unique features of (1) a case of primary hyperparathyroidism and PTHrP-mediated hypercalcemia in bladder carcinoma and (2) a case of PTHrP-mediated hypercalcemia refractory to bisphosphonates.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Coexistent primary hyperparathyroidism and PTHrP-mediated hypercalcemia is uncommon. Although this combination has been reported in a variety of malignancies, to our knowledge, we have come across only one other such case report of coexistent primary hyperparathyroidism and PTHrP-mediated hypercalcemia in a patient with transitional cell carcinoma of the bladder.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">5</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Definitive management of hypercalcemia of malignancy requires treatment of the malignancy. In the interim, management of hypercalcemia first begins with aggressive hydration to promote urinary calcium excretion and then if necessary, bisphosphonate therapy to inhibit bone resorption. Less commonly, hypercalcemia does not improve with these interventions. Recently, denosumab, a monoclonal antibody that binds to RANKL to ultimately limit bone resorption, has been studied as a therapy for hypercalcemia of malignancy refractory to bisphosphonates.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">6,7</span></a> In the second patient case, the hypercalcemia was initially responsive to bisphosphonate therapy but subsequently became refractory. This may have been a result of a higher burden of disease, as noted on autopsy with significant metastases in numerous sites.</p><p id="par0075" class="elsevierStylePara elsevierViewall">In conclusion, hypercalcemia of malignancy due to elevated PTHrP is a well-known condition; however, it is not commonly associated with bladder carcinoma. Here we describe two such cases, with two additional features of coexistent primary hyperparathyroidism and refractoriness to bisphosphonate therapy.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0080" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:7 [ 0 => array:3 [ "identificador" => "bib0040" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical practice. 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