A case of renal pelvic squamous cell carcinoma accompanied with humoral hypercalcemia of malignancy (HHM)

A 78-year-old male was urgently admitted to our hospital because of consciousness disturbance. Laboratory data showed marked hypercalcemia (17.0 mg/dl), hypophosphatemia, low intact PTH level, high PTH relating peptide (PTHrP) level, normal osteocalcin and normal 1-25(OH)2D level. Computed tomography revealed a right renal tumor with extracapsular extension. Bone scintigram appeared normal. We performed right nephrectomy under the diagnosis of right renal tumor. Pathological diagnosis was poorly differentiated squamous cell carcinoma (SCC) of the right pelvis. Immunohistochemical study of the resected specimen for PTHrP was positive. Therefore, we diagnosed it as renal pelvic SCC with humoral hypercalcemia of malignancy (HHM). After nephrectomy, serum calcium returned to normal, but 5 months after nephrectomy, local recurrence appeared and serum calcium was re-elevated. She died 7 months after nephrectomy.     

Continuous PTH and PTHrP infusion causes suppression of bone formation and discordant effects on 1,25(OH)2 vitamin D.

Osteoblast activity and plasma 1,25(OH)2 vitamin D are increased in HPT but suppressed in HHM. To model HPT and HHM, we directly compared multiday continuous infusions of PTH versus PTHrP in humans. Continuous infusion of both PTH and PTHrP results in marked and prolonged suppression of bone formation; renal 1,25(OH)2D synthesis was stimulated effectively by PTH but poorly by PTHrP. INTRODUCTION: PTH and PTH-related protein (PTHrP) cause primary hyperparathyroidism (HPT) and humoral hypercalcemia of malignancy (HHM), respectively. Whereas HHM and HPT resemble one another in many respects, osteoblastic bone formation and plasma 1,25(OH)2 vitamin D are increased in HPT but reduced in HHM. MATERIALS AND METHODS: We performed 2- to 4-day continuous infusions of escalating doses of PTH and PTHrP in 61 healthy young adults, comparing the effects on serum calcium and phosphorus, renal calcium and phosphorus handling, 1,25(OH)2 vitamin D, endogenous PTH(1-84) concentrations, and plasma IGF-1 and markers of bone turnover. RESULTS: PTH and PTHrP induced comparable effects on renal calcium and phosphorus handling, and both stimulated IGF-1 and bone resorption similarly. Surprisingly, PTH was consistently more calcemic, reflecting a selectively greater increase in renal 1,25(OH)2 vitamin D production by PTH. Equally surprisingly, continuous infusion of both peptides markedly, continuously, and equivalently suppressed bone formation. CONCLUSIONS: PTHrP and PTH produce markedly different effects on 1,25(OH)2 vitamin D homeostasis in humans, leading to different calcemic responses. Moreover, both peptides produce profound suppression of bone formation over multiple days, contrasting with events in HPT, but mimicking HHM. These findings underscore the facts that the mechanisms underlying the anabolic skeletal response to PTH and PTHrP in humans is poorly understood, as are the signal transduction mechanisms that link the renal PTH receptor to 1,25(OH)2 vitamin D synthesis. These studies emphasize that much remains to be learned regarding the normal regulation of vitamin D metabolism and bone formation in response to PTH and PTHrP in humans.     

Immunohistochemical study of parathyroid hormone related protein (PTHrP) in renal cell carcinoma

Parathyroid hormone related protein (PTHrP) is the main factor of humoral hypercalcemia of malignancy (HHM). Using anti-PTHrP monoclonal antibody 4B3, we investigated the immunohistochemical localization of PTHrP in human normal renal tissues and renal cell carcinomas. Among normal renal tissues, distal tubules and collecting ducts showed positive immunostaining. Among 36 cases of renal cell carcinoma, PTHrP was detected in 30 cases (83%), and there was no significant correlation between the degree of the immunostaining and the serum calcium levels of the patients. As for the histopathological types of the renal cell carcinomas, granular cell subtypes tended to be more strongly positive than clear cell ones. In conclusion, it was not uncommon that PTHrP was commonly presented by renal cell carcinoma, and HHM occurred when the PTHrP transgressed the homeostatic mechanisms.     

Hypercalcemia associated with parathyroid hormone-related protein at the terminal stage of uncomplicated squamous cell carcinoma in the head and neck region.

BACKGROUND: Parathyroid hormone-related protein (PTHrP) is mainly responsible for hypercalcemia in squamous cell carcinomas (SCCs). METHODS: We retrospectively checked the appearance of hypercalcemia among 33 patients who died with head and neck SCC. Serum concentrations of C-terminal region of PTHrP (C-PTHrP) were measured in 15 of them. The intracellular PTHrP expression was immunohistochemically stained in 42 SCC sections obtained from the 33 before the appearance of hypercalcemia. RESULTS: Hypercalcemia appeared in 24 of the 33, and increased serum C-PTHrP levels were confirmed in 11 of 12 hypercalcemic patients. PTHrP was identified in all SCC sections, and a stronger intensity than in normal squamous epithelia was observed in 50% of those obtained within 1 year before the onset of hypercalcemia. CONCLUSION: A high incidence of PTHrP-induced hypercalcemia was shown among patients dying with head and neck SCCs. The intracellular increase in PTHrP might be observed preceding hypercalcemia.     

Contrasting mechanisms of hypercalcemia in patients with early and advanced humoral hypercalcemia of malignancy

The mechanisms of hypercalcemia were assessed in 15 patients with humoral hypercalcemia of malignancy (HHM) who had tumors at various stages of progression. In patients with early tumors, bone biopsies were generally normal and the hypercalcemia was due to an elevation in renal tubular resorption of calcium. Conversely, osteoclastic resorption was markedly increased in patients with advanced tumors, particularly those in whom the biopsies were obtained postmortem. Osteoclast surface (Oc.S) correlated positively with the stage of tumor progression (r = 0.80, p less than 0.002), degree of immobility (r = 0.87, p less than 0.002), and level of urinary cyclic AMP excretion (r = 0.60, p less than 0.02). When compared with a group of ambulant patients with primary hyperparathyroidism (HPT), osteoblast surface (Ob.S%) in HHM was depressed (median and range): 1.2% (0-11.6%) versus 5.3% (1.1-32.0%) (p less than 0.001). However, a relatively low Ob.S (4%) and raised Oc.S (43.5%) were also seen in an immobilized patient with severe HPT. These data suggest that the PTH-related peptides currently invoked in the pathogenesis of HHM may initially cause hypercalcemia by enhancing renal tubular calcium resorption. The increase in osteoclastic activity and depression of osteoblastic activity that subsequently occurs is probably due to the combined effects of immobilization and higher circulating levels of PTHrP on the skeleton. However, the release of other bone-resorbing factors by the tumor, which have a depressant effect on osteoblastic activity, remains possible.     

Exogenous PTH-related protein and PTH improve mineral and skeletal status in 25-hydroxyvitamin D-1alpha-hydroxylase and PTH double knockout mice.

We examined the effect of NH2-terminal fragments of PTHrP and PTH in young mutant mice deficient in both PTH and 1,25-dihydroxyvitamin D. Both proteins prolonged murine survival by increasing serum calcium, apparently by enhancing renal calcium transporter expression. The dominant effect on the skeleton was an increase in both endochondral bone and appositional formation without increased bone resorption. INTRODUCTION: PTH-related protein (PTHrP) was discovered as a hypercalcemic agent responsible for the syndrome of humeral hypercalcemia of malignancy, and PTH is the major protein hormone regulating calcium homeostasis. Both proteins have skeletal anabolic actions when administered intermittently. We examined effects of exogenous PTHrP(1-86) and PTH(1-34) in double null mutant mice deficient in both PTH and 25-hydroxyvitamin D-1alpha-hydroxylase [1alpha(OH)ase] to determine the action of these proteins in the absence of the two major regulators of calcium and skeletal homeostasis. MATERIALS AND METHODS: Mice heterozygous for the PTH null allele and for the 1alpha(OH)ase null allele were mated to generate pups homozygous for both null alleles. PTHrP(1-86) and PTH(1-34) were administered subcutaneously starting 4 days after birth. Serum biochemistry and skeletal radiology, histology, and histomorphometry were performed, and indices of bone formation, resorption, and renal calcium transport were determined by real time RT-PCR, Western blot, and immunohistochemical approaches. RESULTS: In the double mutant mice, which die within 3 weeks after birth with severe hypocalcemia, tetany, and skeletal defects, exogenous PTHrP and PTH enhanced survival of the animals by improving serum calcium. Both proteins increased renal calcium transporter expression and long bone length and augmented growth plate chondrocyte proliferation, differentiation, and cartilage matrix mineralization. Cortical and trabecular bone mass was increased with augmented osteoblast number and activity; however, bone resorption was not increased. CONCLUSIONS: PTHrP and PTH reduced hypocalcemia by enhancing renal calcium reabsorption but not by increasing bone resorption. The major skeletal effects of exogenous PTHrP and PTH were to increase bone anabolism.     

A 7‐day continuous infusion of PTH or PTHrP suppresses bone formation and uncouples bone turnover

Human in vivo models of primary hyperparathyroidism (HPT), humoral hypercalcemia of malignancy (HHM), or lactational bone mobilization for more than 48 hours have not been described previously. We therefore developed 7‐day continuous‐infusion models using human parathyroid hormone(1–34) [hPTH(1–34)] and human parathyroid hormone–related protein(1–36) [hPTHrP(1–36)] in healthy human adult volunteers. Study subjects developed sustained mild increases in serum calcium (10.0 mg/dL), with marked suppression of endogenous PTH(1–84). The maximal tolerated infused doses over a 7‐day period (2 and 4 pmol/kg/h for PTH and PTHrP, respectively) were far lower than in prior, briefer human studies (8 to 28 pmol/kg/h). In contrast to prior reports using higher PTH and PTHrP doses, both 1,25‐dihydroxyvitamin D₃ [1,25(OH)₂D₃] and tubular maximum for phosphorus (TmP/GFR) remained unaltered with these low doses despite achievement of hypercalcemia and hypercalciuria. As expected, bone resorption increased rapidly and reversed promptly with cessation of the infusion. However, in contrast to events in primary HPT, bone formation was suppressed by 30% to 40% for the 7 days of the infusions. With cessation of PTH and PTHrP infusion, bone‐formation markers abruptly rebounded upward, confirming that bone formation is suppressed by continuous PTH or PTHrP infusion. These studies demonstrate that continuous exposure of the human skeleton to PTH or PTHrP in vivo recruits and activates the bone‐resorption program but causes sustained arrest in the osteoblast maturation program. These events would most closely mimic and model events in HHM. Although not a perfect model for lactation, the increase in resorption and the rebound increase in formation with cessation of the infusions are reminiscent of the maternal skeletal calcium mobilization and reversal that occur following lactation. The findings also highlight similarities and differences between the model and HPT. © 2011 American Society for Bone and Mineral Research     

Paraneoplastic hypercalcemia in a patient with adenosquamous cancer of the colon.

Hypercalcemia is a well-known manifestation of paraneoplastic syndromes associated with a variety of malignancies. However, colon cancer has only rarely been associated with hypercalcemia of malignancy. We present the case of a patient with recurrent adenosquamous carcinoma of the ascending colon found to have hypercalcemia. The patient is a 76-year-old white woman who initially presented with colon cancer in the cecum and underwent a right hemicolectomy. All lymph nodes and surgical margins were free of tumor. Pathological examination at that time revealed adenosquamous carcinoma of the colon. Eight months later she complained of dizziness, anorexia, and constipation and was found to have a calcium level of 13.6 mg/dL. CT scan revealed a mass measuring 10.5 to 12.7 cm in the right hepatic lobe, and a bone scan was normal. Her intact parathyroid hormone (PTH) level was 6 pg/mL (normal 12-72) and her PTH-related protein (PTHrP) level was 25.7 pmol/L (normal <1.3). She then underwent a hepatic resection. The serum PTH, calcium, and PTHrP levels normalized after resection. Hypercalcemia of malignancy in colon cancer is rare and has an association with adenosquamous histology. The hypercalcemia is attributed to PTHrP, and here we demonstrate this in the serum and tumor specimens. The effects of PTHrP are shown to be short-lived postoperatively. We find only 14 other cases in the literature of hypercalcemia related to a colonic neoplasm, and this is the only patient reported to be surviving. The diagnosis of a paraneoplastic syndrome mediated via PTHrP should be considered when hypercalcemia is encountered in the setting of metastatic colon carcinoma.     

Hyperparathyroidism, humoral hypercalcemia of malignancy, and the anabolic actions of parathyroid hormone and parathyroid hormone-related protein on the skeleton.

So what have we learned from the Takeuchi case? It has been 80 years since malignancy-associated hypercalcemia was described. It has been 45 years since HHM was first described. It has been 15 years since PTHrP was identified, and 12 years since PTHrP immunoassays became available for clinical research. We now know almost everything about HHM in pathophysiological terms, and we can reproduce the cardinal features of the syndrome in laboratory animals and humans. The Takeuchi case reminds us that we still have a few things to learn about HHM. Specifically, "Why is the regulation of 1,25(OH)2D different in patients with HHM and HPT?" and "Why is normal osteoblast-osteoclast coupling dysregulated in HHM?" or more fundamentally, "What regulates osteoblast-osteoclast coupling, and why is it deranged in HHM?" Given the rate of accumulation of new information about HHM, about the anabolic effects of PTH and PTHrP, and about osteoblast-osteoclast coupling over the past 10 years, there is reason to be optimistic that the answers to these questions will soon become clear.     

The synthetic human parathyroid hormone-related protein is inhibited by a parathyroid hormone antagonist in rats in vivo

The structure of a novel protein, parathyroid hormone-related protein (PTHrP), secreted by human tumors associated with hypercalcemia has recently been determined. Administration of a synthetic fragment of this protein in vivo reproduces features of the clinical paraneoplastic syndrome of humoral hypercalcemia of malignancy and produces biologic responses closely similar to those obtained with parathyroid hormone (PTH). A PTH antagonist designed to reversibly occupy PTH receptors inhibited major actions of the tumor peptide in vivo, including phosphaturia, urinary cAMP excretion, and increased serum ionized calcium. These studies indicate that PTHrP and PTH mediate their bioactivities through shared receptors in vivo and establish a potential specific mechanism-based approach utilizing PTH antagonists for the therapy of tumor-associated hypercalcemia.     

A case of lung cancer with hypercalcemia which was incidentally complicated with primary hyperparathyroidism due to parathyroid adenoma.

In lung cancer patients, hypercalcemia is a fairly common metabolic problem associated with malignancy. However, the occurrence of hypercalcemia in lung cancer patients means an ominous prognostic sign. As hypercalcemia often causes early death, quick diagnosis and treatment for hypercalcemia are required. A 69-year-old woman was admitted to our hospital with anorexia caused by hypercalcemia. On admission, serum level of PTH was elevated and PTHrP was normal. From the results of CT findings and transbronchial lung biopsy, the cause of the hypercalcemia was determined as lung cancer incidentally complicated with primary hyperparathyroidism. First, serum calcium level was returned to normal through hydration with saline and bisphosphonates. Next, left hemithyroidectomy for primary hyperparathyroidism was performed. Histologically, the tumor was diagnosed as parathyroid adenoma. Fifteen days later, left lower lobectomy for primary lung cancer was performed under a video-assisted thoracoscopic approach. Histologically, the tumor was diagnosed as a moderately differentiated adenocarcinoma. Four years and three months after the operation, the patient is alive and well with no sign of recurrence. When a lung cancer patient is complicated with hypercalcemia, we need to consider that primary hyperparathyroidism is a possible cause of the hypercalcemia.     

Mucin-producing parathyroid carcinoma.

A 67-year-old white male presented with symptomatic hypercalcemia (15.6 mg/dl) in December 1989. He had undergone thyroidectomy for removal of a mucin-producing adenocarcinoma of the thyroid in 1967, and after eight years of follow-up during which time no other neoplasms were detected, he was reported as a unique case of this syndrome. Mild hypercalcemia (less than 11.0 mg/dl) was first noted in 1987, and this had remained stable until shortly before the acute presentation. Multiple lung nodules were observed radiographically and presumed to be granulomatous until increased size was observed shortly before presentation. Serum intact PTH was 190 pg/ml (n 10-55), but at neck exploration no parathyroid tissue was found and surgery did not resolve the hypercalcemia. Serum PTHrP was undetectable. Biopsies from all three lobes of the right lung revealed numerous nodules of metastatic adenocarcinoma with cords of tumor cells surrounded by mucin. The histology was similar to that obtained 23 years earlier. Following left upper lobe resection with removal of a 3-cm nodule, hypercalcemia resolved. The tumor stained strongly positive with a peroxidase stain for PTH using a polyclonal antibody. Northern blot hybridization of total RNA from the tumor confirmed the presence of message for PTH but not PTHrP. The original diagnosis has been revised to that of a unique case of mucin-producing parathyroid cancer with an extraordinarily long latency period before recurrence.     

Rapidly relapsing squamous cell carcinoma of the renal pelvis associated with paraneoplastic syndromes of leukocytosis, thrombocytosis and hypercalcemia

A case history is reported here in which leukocytosis, thrombocytosis and hypercalcemia associated with rapidly relapsing squamous cell carcinoma (SCC) of the renal pelvis were observed. In a 58-year-old man, SCC of the renal pelvis was documented during nephrolithotomy, and right nephrectomy was performed. Local relapse of the tumor occurred rapidly in 2 months' time and hypercalcemia, leukocytosis and thrombocytosis worsened in accordance with tumor volume. Cranial computerized tomography (CT), thorax CT and bone scintigraphy were negative for metastasis. The serum parathyroid hormone level was 28 pg/ml (normal 9- 55 pg/ml). To disclose leukocytosis and thrombocytosis, peripheral smear and bone marrow aspiration were performed and no pathologic finding regarding any hematologic disorder was found; the samples were also BCR-ABL negative and Philadelphia chromosome negative. Production of several factors by tumor cells may be responsible for this paraneoplastic syndrome. The association of SCC of the renal pelvis with this triple paraneoplastic syndrome is an extremely rare occurrence.     

Parathyroid hormone-related protein induced coupled increases in bone formation and resorption markers for 7 years in a patient with malignant islet cell tumors.

Parathyroid hormone-related protein (PTHrP) and PTH share the common PTH/PTHrP receptor. Although an elevated level of circulating PTHrP in patients with malignancies causes hypercalcemia as does PTH, chronic and systemic effects of PTHrP on bone metabolism in humans are not well understood because tumor-burden patients showing hypercalcemia usually have a poor prognosis. We investigated bone and calcium metabolism in a patient with malignant islet cell tumors showing hypercalcemia due to the elevated plasma PTHrP level for 7 years. Hypercalcemia and hypercalciuria continued throughout the clinical course in spite of frequent infusions of bisphosphonates. Bone resorption markers and a bone formation marker were consistently elevated as seen in primary hyperparathyroidism, a disease caused by an autonomous hypersecretion of PTH. Based on biochemical measurements including bone markers and serum 1,25-dihydroxyvitamin D, the clinical features of this case essentially are the same as those of primary hyperparathyroidism except for the elevated level of plasma PTHrP with suppressed intact PTH level. Therefore, it is suggested that chronic and systemic effects of PTHrP on bone as well as calcium metabolism are indistinguishable from those of PTH in human.     

High PTHrP level induced hypercalcemia and acute renal failure in a multiple myeloma patient

Multiple myeloma causes various renal injuries by direct invasion of myeloma cells, AL amyloidosis and hypercalcemia. Hypercalcemia induced by myeloma has been thought to be a result of local osteolysis. Recently, however, it was noted that no significant difference existed in the degree of bone-destruction between hypercalcemic and normocalcemic multiple myeloma. The exact mechanisms of hypercalcemia induced by multiple myeloma remain unconfirmed. In the present study, we report a 70-year-old man, suffering from acute renal failure due to multiple myeloma and severe hypercalcemia. While the serum PTH level was low, PTHrP was markedly increased. Bone scintigraphy implied systemic increase in bone turnover in addition to cold spots corresponding to punched out lesions on bone Xp. After the intravenous administration of bisphosphonate, hypercalcemia and hot accumulation on bone scintigraphy were improved while the PTHrp level and bone destruction by myeloma cells were not improved. The present case suggests involvement of PTHrP in hypercalcemia of multiple myeloma.     

Angiotensin II increases parathyroid hormone-related protein (PTHrP) and the type 1 PTH/PTHrP receptor in the kidney

Angiotensin II (AngII) participates in the pathogenesis of kidney damage. Parathyroid hormone (PTH)-related protein (PTHrP), a vasodilator and mitogenic agent, is upregulated during renal injury. The aim of this study was to investigate the potential relation between AngII and PTHrP system in the kidney. Different methods were used to find that both rat mesangial and mouse tubuloepithelial cells express PTHrP and the type 1 PTH/PTHrP receptor (PTH1R). In these cells, AngII increased PTHrP mRNA and protein production. In contrast, PTH1R mRNA was increased in mesangial cells and downregulated in tubular cells, but its protein levels were unmodified in both cells. AT(1) antagonist, but not AT(2), abolished AngII effects on PTHrP/PTH1R. The in vivo effect of AngII was further investigated by systemic infusion (a low dose of 50 ng/kg per min) into normal rats. In controls, PTHrP immunostaining was mainly detected in renal tubules. In AngII-infused rats, PTHrP staining increased in renal tubules and appeared in the glomerulus and the renal vessels. After AngII infusion, PTHR1 staining was markedly increased in all these renal structures at day 3 but remained elevated only in tubules at day 7. The AT(1) antagonist, but not the AT(2), significantly diminished AngII-induced PTHrP and PTHR1 overexpression in the renal tissue, associated with a decrease in tubular damage and fibrosis. The results indicate that AngII regulates renal PTHrP/PTH1R system via AT(1) receptors. These findings demonstrate that PTHrP upregulation occurs in association with the mechanisms of AngII-induced kidney injury.     

Two cases of squamous cell carcinoma of upper urinary tract with hypercalcemia

We report two cases of squamous cell carcinoma of upper urinary tract with hypercalcemia. Case 1; a 54 year old female with primary squamous cell carcinoma (SCC) of right ureter showed marked hypercalcemia and leukocytosis. High levels of serum parathyroid hormone-related peptide (PTHrP) and granulocyte colony stimulating factor (G-CSF) were detected. Although chemotherapy of cisplatin and 5-fluorouracil with radiotherapy was effective, thereafter recurrence was occurred in renal pelvis, and the patient died 17 months after the initiation of therapy. Case 2; a 54 year old male of primary SCC of right renal pelvis with local lymphadenopathy and anterior mediastinal metastases showed marked hypercalcemia. High levels of PTHrP were detected. Although the patient was administered UFT with palliative radiotherapy to the anterior mediastinum, he died 2 months after the initiation of therapy. To our knowledge, the case 1 is the third case that of the high levels of serum PTHrP and G-CSF simultaneously in squamous cell carcinoma of upper urinary tract.     

A hypercalcemic nude rat model that completely mimics human syndrome of humoral hypercalcemia of malignancy

Summary Tumors causing humoral hypercalcemia of malignancy (HHM) were implanted to athymic nude rats. In one of these rat models transplanted with uterine cancer (UCC), a complete reproduction of human HHM syndrome was achieved: hypercalcemia, hypophosphatemia with increased urinary phosphate and cyclic AMP excretion, and suppressed serum 1,25-dihydroxy-vitamin D (1,25(OH)₂D) level. In another hypercalcemic nude rat model implanted with oral cavity cancer (OCC), all the features were similar except for markedly elevated serum 1,25(OH)₂D. Hypercalcemia disappeared by surgical removal of the tumors in both models, confirming the humoral mechanisms for causing these features. Furthermore, in UCC tumor-bearing rats, hypophosphatemia, increased renal phosphate excretion, and reduced serum 1,25(OH)₂D concentration were already present when these rats were only marginally hypercalcemic. These results raise the possibility that the changes in renal tubular phosphate handling and vitamin D metabolism in HHM are not secondary to hypercalcemia but are due to direct effects of the humoral factor(s) that cause this syndrome. Extracts of both tumors exhibited stimulation of cyclic AMP production in osteoblastlike cells, UMR 106, which could be almost completely inhibited by parathyroid hormone (PTH) antagonist, human PTH(3–34). By comparing the nature and characteristics of humoral factor(s) from UCC and OCC models, mechanisms responsible for causing these abnormalities can be explored. Thus, these nude rat models can be useful for elucidating the underlying mechanism of the development of HHM.     

Parathyroid-hormone-related protein-mediated hypercalcemia in benign congenital mesoblastic nephroma

Parathyroid hormone-related protein (PTHrP) mediated hypercalcemia of malignancy is rare in children, and even more so in the setting of a benign tumor. We report two infants with PTHrP-mediated hypercalcemia secondary to congenital mesoblastic nephroma and their outcome after removal of the benign tumor. Pre-operatively hypercalcemia was corrected with saline hydration, furosemide, calcitonin and/ or pamidronate. Following resection of the tumor serum PTHrP normalized. Immunohistochemical staining of tumor cells was positive for PTHrP. Post-operatively the infants developed elevated serum parathyroid hormone with low- normal serum Ca and P, and undetectable urinary Ca and P, probably due to their movement into bone. Children needed treatment with calcitriol, Ca and P supplementation for 6-12 weeks until PTH normalized and urinary Ca and P were detected, suggesting bone replenishment. We conclude that benign congenital mesoblastic nephroma can secrete PTHrP that can cause severe hypercalcemia; and following excision one should anticipate the development of a transient modified “hungry bone”-like condition requiring Ca, P and calcitriol therapy for several weeks accompanied by careful monitoring of mineral homeostasis.