Multiple bone lesions and hypercalcemia presented in diffuse large B cell lymphoma: mimicking multiple myeloma?

We encountered a 58-year-old female patient who developed hypercalcemia and multiple bone lesions. She complained of lumbodorsal pain, nausea and vomiting on admission. Radiographic examination revealed multiple osteolytic lesions. She was diagnosed diffuse large B cell lymphoma (BLBCL) by bone marrow examination and biopsy of cervical lymph node. She underwent eight cycles of chemotherapy and is now in the stable stage. Osteogenic potential of mesenchymal stem cells from bone marrow was found to be correlated with the expression of Dickkopf1 (DKK-1) in the bone marrow plasma and lymphoma cells before and after treatment. PTH-related protein (PTHrP) expression was detectable in the lymphoma cells and was elevated in the serum. The receptor activator of nuclear factor κB ligand expression was found to be elevated in the bone marrow plasma and mesenchymal stem cells. These findings suggest that factors affecting the differentiation of both osteoblasts and osteoclasts involved in the pathogenesis of hypercalcemia and bone lesions of lymphoma. This was similar to that of multiple myeloma in which bone lesions and hypercalcemia are frequently observed.     

Severe hypercalcemia in a child with acute nonlymphocytic leukemia: the role of parathyroid hormone-related protein and proinflammatory cytokines

Among the hematological malignancies, hypercalcemia has often been reported in lymphoid malignancies such as multiple myeloma and adult T cell leukemia/lymphoma, but it has only rarely been described in acute nonlymphocytic leukemia. We describe here a 14-month-old girl with acute monocytic leukemia complicated by severe hypercalcemia (4.6 mmol/l) at presentation. A bone survey showed generalized bone resorption, but no localized osteolytic lesions. A search for the etiology of the hypercalcemia revealed that the serum levels of parathyroid hormone-related protein (PTHrP) and also proinflammatory cytokines with stimulatory effects on osteolytic bone resorption - TNF-alpha, IL-6 and M-CSF - were elevated. The patient achieved complete remission with induction chemotherapy, and the levels of PTHrP and the cytokines became normalized. In this case, PTHrP and cytokines might have acted cooperatively to exacerbate bone resorption, resulting in severe hypercalcemia.     

Megakaryoblastic transformation of polycythemia vera with hypercalcemia

Polycythemia vera (PV) is known to occasionally transform into acute leukemia. Administration of alkylating agents seems to be associated with an increased risk of leukemic transformation of PV. Hypercalcemia is a serious complication of malignancies, but it is uncommon in acute leukemia. In the majority of malignancies with hypercalcemia, elevated parathyroid hormone-related protein (PTHrP) is thought to be the main cause of hypercalcemia. We report a rare case of megakaryoblastic transformation of PV with hypercalcemia. A 62-year-old man was diagnosed as having PV in 1983, and he had received ranimustine and busulfan. He developed acute megakaryoblastic leukemia 17 years after the initial diagnosis of PV. Serum calcium was elevated, the serum level of intact parathyroid hormone (PTH) was suppressed, and the level of intact PTHrP was slightly elevated. He had no lytic bone lesions; however, uncoupling of bone turnover due to an increase in bone resorption and a decrease in bone formation was detected by using biochemical markers. Since the level of PTHrP was slightly elevated from the normal value, we speculated that PTHrP produced in the local field by leukemic cells might have been more abundant than circulating PTHrP. Pamidronate and adrenocortical hormone were effective in reducing the serum calcium level. However, the patient died shortly after the start of induction chemotherapy. The prognosis of cases of PV that has transformed into acute leukemia is generally poor because the majority of such cases are refractory to chemotherapy.     

Gastric cancer associated with overexpression of parathyroid hormone-related peptide (PTHrP) and PTH/PTHrP receptor in relation to tumor progression

Parathyroid hormone-related peptide (PTHrP) is involved in cell proliferation in both neoplastic and non-neoplastic tissues. We describe an autopsy case of gastric cancer in a patient who showed serum hypercalcemia and overexpression of PTHrP and PTH/PTHrP receptor in the metastatic tumor cells. The primary gastric tumor was poorly differentiated adenocarcinoma, and multiple metastases were present in the bone, multiple visceral organs, peritoneum, and lymph nodes. PTHrP and its mRNA were detected only in the metastatic tumor cells, but not in primary gastric tumor. PTH/PTHrP receptor was also demonstrated immunohistologically in metastatic tumor cells. This case suggests that the expression of PTHrP is related to tumor progression and the poor prognosis in tumors associated with humoral hypercalcemia.     

Clinical application of metabolic bone markers in hematologic malignancies

Hematologic malignancies such as multiple myeloma, adult T cell leukemia and malignant lymphoma are often complicated with bone lesions and/or hypercalcemia. The abnormal bone metabolism in these diseases are modified by co-existing cachexia, malnutrition, sex hormone deficiency and abnormal parathyroid function or by chemotherapy in a complex manner. Metabolic bone markers are not only clinically useful for evaluation and diagnosis of such bone abnormalities but may also be used to monitor the disease activity itself, particularly in multiple myeloma which almost inevitably involves bone destructive lesions.     

Hypercalcemia and multiple osteolytic lesions associated with proinflammatory cytokines in a patient with acute lymphoblastic leukemia

A 70-year-old man was admitted to the hospital with left ankle pain, also exhibiting severe consciousness disturbance. Laboratory findings showed not only hypercalcemia, but also increased serum levels of PTHrP and a few of proinflammatory cytokines, such as TNF-alpha, and IL-6. The X-ray and CT examinations revealed multiple osteolytic lesions, including the left tibia and fibula. Bone marrow aspiration revealed increased lymphoblasts (48%), and the patient was diagnosed as having acute lymphoblastic leukemia (ALL, L2). The hypercalcemia was successfully treated with calcitonin and bisphosphonate, and subsequently his consciousness status recovered rapidly. The bone marrow lymphoblast count decreased following combination chemotherapy, and a tendency towards improvement of the left ankle pain was also noted. However, he died of acute pneumonia and gastrointestinal bleeding. The postmortem findings showed leukemic cell involvement of the left tibia. The present case suggested that not only humoral hypercalcemia or local osteolytic hypercalcemia, but also proinflammatory cytokines were associated with multiple osteolysis and hypercalcemia.     

骨源性淋巴瘤伴继发性甲状旁腺机能亢进症1例报告并文献复习

目的：探讨骨源性非霍奇金淋巴瘤(NHL)(弥漫型大B细胞性)伴继发性甲状旁腺机能亢进的诊断及机制。方法：对1例全身骨痛伴昏迷患者进行了骨髓图、骨髓病理及免疫组织化学、血液生化和CT检查，并复习文献就其诊治问题进行讨论。结果：CT显示多部位骨质破坏，血钙及甲状旁腺激素水平显著升高，骨髓病理及免疫组织化学检查证实为骨源性NHL(弥漫型大B细胞性)，最终诊断为骨源性NHL(弥漫型大B细胞性)伴继发性甲状旁腺机能亢进。结论：骨源性NHL的诊断有赖于病理组织学、免疫学和细胞遗传学检查以及CT及核素扫描。淋巴瘤细胞分泌甲状旁腺激素相关蛋白或相关多肽(PTHrP)，细胞因子与PTHrP的释放及溶骨损害是引起高钙血症的原因。     

Use of Imatinib Mesylate for Favorable Control of Hypercalcemia Mediated by Parathyroid Hormone-Related Protein in a Patient with Chronic Myelogenous Leukemia at Blast Phase

The case of a 72-year-old woman with chronic myelogenous leukemia in blast phase (BP) with hypercalcemia is reported. Bone x-ray examination revealed multiple osteolytic lesions throughout the body. The serum level of parathyroid hormone-related protein (PTHrP) was elevated, and PTHrP messenger RNA (mRNA) was detectable in the peripheral blood mononuclear cells (PBMNC) at BP but was not detectable at chronic phase (CP).Treatment with conventional chemotherapy did not completely control either serum calcium level or serum PTHrP level. Treatment with imatinib mesylate (imatinib) alone rapidly normalized these parameters in parallel with a decrease in the number of blast cells. The treatment also maintained the patient in good condition for approximately 3 months, even though the number of blast cells, serum calcium level, serum PTHrP level, and PTHrP mRNA level increased at the terminal stage. Mutations of the p53, K-Ras, and BCR-ABL genes in PBMNC at BP were absent. A noteworthy feature in this patient was that PBMNC at BP but not at CP showed high Lyn mRNA expression. Taken together the findings showed that production of PTHrP by blast cells was favorably controlled by imatinib therapy alone. Imatinib may prolong survival time at BP even though the patients have the complication of PTHrP-mediated hypercalcemia.     

Hypercalcemia in disseminated coccidioidomycosis: expression of parathyroid hormone-related Peptide is characteristic of granulomatous inflammation

Background.?Hypercalcemia is an uncommon complication of disseminated granulomatous infections. The pathogenesis of hypercalcemia associated with infection is not clear. Methods.?We investigated a case of disseminated coccidioidomycosis with hypercalcemia. We used a sensitive radioimmunoassay to measure serum parathyroid hormone-related peptide (PTHrP) and a mouse monoclonal antibody to PTHrP to immunostain biopsies. Results.?We found elevated serum levels of PTHrP while the patient was hypercalcemic that became undetectable when serum calcium normalized. We also found that the inflammatory cells and some surrounding tissues in skin biopsies expressed PTHrP. PTHrP was expressed by all biopsied lesions of patients with coccidioidomycosis that we examined, whether localized to the lung or disseminated, but no other cases were hypercalcemic. PTHrP was also expressed by the 3 mycobacterial granulomas we examined, and in a lymph node from a patient with sarcoidosis. Conclusions.?The expression of PTHrP is a property of infectious granulomas regardless of etiology or the tissue involved, suggesting that PTHrP expression is part of the normal granulomatous immune response. Hypercalcemia may result if there is disseminated infection and multiple granulomas. We propose that excess production of PTHrP is the cause of hypercalcemia in granulomatous infections.     

An elderly case of non-Hodgkin's lymphoma (NHL) with hypercalcemia]

A 93 year-old woman was admitted due to anorexia and unconsciousness. Biochemical examination of serum showed hypercalcemia (corrected Ca; 16.6 mg/dl). The level of intact parathyroid hormone (i-PTH) was suppressed, whereas parathyroid hormone-related peptide (PTHrp) was to 5.0 pM (normal range: below 0.6 pM). IL-6 and renal cAMP were also elevated. We started to ameliorate hypercalcemia by saline infusion, furosemide and calcitonin. However, hypercalcemia was not improved and the patient died of DIC and renal failure. Autopsy revealed primary lesion of NHL (diffuse large B cell type) to be in the stomach with infiltration of lymphoma into the liver, pancreas, spleen, adrenal glands, jejunum, and lumbar vertebrae. The results of immunohistochemical examination demonstrated the expression of PTHrP in lymphoma cells. PTHrP was also found in lymphoma cells of the spleen by the RT-PCR technique. These findings indicated that hypercalcemia was caused by overexpression of PTHrP from lymphoma cells.     

B cell malignancies presenting with unusual bone involvement and mimicking multiple myeloma. Study of nine cases

Nine unusual cases of B cell malignancies presenting with lytic bone lesions on radiography and/or hypercalcemia, and mimicking multiple myeloma are reported in this study. These cases included acute lymphoblastic leukemia (one patient), non-Hodgkin's lymphoma (five patients), chronic lymphocytic leukemia (two patients), and Waldenstr?m's disease (one patient). Quantitative bone biopsy performed in two patients (one with non-Hodgkin's lymphoma and one with Waldenstr?m's disease) demonstrated a dramatic increase in osteoclastic resorption close to tumor cells in both cases, similar to or even more marked than that observed in multiple myeloma. Finally, significant production of bone resorbing activity was found in short-term liquid culture specimens of tumor cells in eight of the nine cases. These observations clearly indicate that in B cell disorders other than multiple myeloma, the malignant B cells can produce significant bone resorbing activity in vitro and result in excessive osteoclastic resorption and lytic bone lesions, frequent hypercalcemia, and an overall disease picture clinically mimicking multiple myeloma.     

Parathyroid hormone (PTH)-related protein, PTH, and 1,25-dihydroxyvitamin D in dogs with cancer-associated hypercalcemia.

Circulating N-terminal PTH-related protein (PTHrP), N-terminal PTH, and 1,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations were measured in normal dogs and dogs with cancer-associated hypercalcemia (CAH), parathyroid adenomas, and miscellaneous tumors. PTHrP was undetectable (less than 1.8 pM) in normal dogs and increased in dogs with CAH due to adenocarcinomas derived from apocrine glands of the anal sac (44.9 +/- 27 pM), lymphoma (8.3 +/- 4.4 pM), and miscellaneous carcinomas (13.3 +/- 11.4 pM). The PTHrP concentration decreased in dogs with lymphoma and anal sac adenocarcinomas after successful treatment of CAH. The PTHrP concentration had a significant linear correlation with total serum calcium in dogs with anal sac adenocarcinomas and hypercalcemia, but not in dogs with lymphoma and hypercalcemia. Serum N-terminal PTH concentrations were usually in the normal range (12-34 pg/ml) for all groups of dogs except dogs with parathyroid adenomas (83 +/- 38 pg/ml). The serum PTH concentration increased after successful treatment of CAH. Serum 1,25-(OH)2D concentrations were decreased, normal, or increased in dogs with CAH, and 1,25-(OH)2D levels decreased after treatment of CAH. In summary, circulating concentrations of PTHrP are consistently increased in dogs with CAH, and PTHrP appears to play an important role in the induction of hypercalcemia.     

Intravascular B-cell lymphoma with hypercalcemia as the initial presentation

Intravascular B-cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma, which is characterized by the growth of lymphoma cells within blood vessel lumina without nodular lesions, and which predominantly affects elderly patients. IVLBCL is characterized by B-symptoms and a variety of systemic symptoms due to focal obstruction of blood flow, but may be difficult to diagnose due to its peculiar intravascular localization and the lack of nodular lesions. While hypercalcemia is one of the complications of various types of cancerous diseases, it has rarely been reported as the first presentation of IVLBCL. In this report, we present the case of a 71-year-old male with IVLBCL who showed hypercalcemia accompanied by elevation of serum parathyroid hormone-related protein (PTH-rP) as the initial presentation. Interestingly, immunohistochemical staining revealed that the intravascular lymphoma cells expressed high levels of PTHrP. Six courses of immunochemotherapy, consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), and two courses of high-dose methotrexate induced complete remission (CR) and retained CR for 4 months. We also reviewed other IVBCL cases in which hypercalcemia was the initial presentation. We suggest that IVLBCL, although rare, should be considered as a possible causative in hypercalcemia of unknown underlying disease.     

Hypercalcemia associated with parathyroid hormone-related protein produced by B-cell type primary malignant lymphoma of the kidney

 A patient with primary non-Hodgkin's (B-cell type) lymphoma of the kidney developed hypercalcemia at the terminal stage of the disease. Although the plasma parathyroid hormone level was low, urinary cyclic AMP excretion was elevated. Serum osteocalcin (BGP) was suppressed and the plasma level of 1,25(OH)₂D was within the normal range. Serum concentrations of PTH-related protein (PTHrP)-like immunoreactivity (PRP-LI) were elevated, and the tissue concentration of PRP-LI in the postmortem lymph node showed high level along with elevated serum PRP-LI, furthermore the production of PTHrP by the tumor was demonstrated by immunohistochemistry and Northern blotting analysis. These findings indicate that the hypercalcemia of the patient was caused by the PTHrP-producing B-cell lymphoma. Hypercalcemia was restored to normocalcemia by bisphosphonate treatment. Our case will add further information on humoral hypercalcemia in B-cell lymphoma, which rarely has been demonstrated to produce PTHrP. Received: 17 July 1997 / Accepted: 2 February 1998     

PTHrP inhibits BMP-6 expression through the PKA signaling pathway in breast cancer cells

Background  

PTHrP, a mediator of humoral hypercalcemia of malignancy, is considered as a potential activator to induce breast cancer cells metastasizing to bone. However, recent clinical evidences and basal research results prove that PTHrP expression in primary tumors indicates good prognosis. BMP-6, as a member of TGF-β superfamily, is closely correlated with tumor differentiation and skeletal metastasis.     

不同年龄组多发性骨髓瘤患者的骨损表现

目的：观察不同年龄组多发性骨髓瘤患者的骨损临床表现以及预后.方法：将本院70例多发性骨髓瘤患者按年龄分成＜65岁和≥65岁2组，观察骨损表现形式（溶骨性损害、广泛的骨质疏松）、发生部位（颅骨、颈椎、胸肋骨、腰骶椎、骨盆、四肢长骨）、高钙血症和骨损的关系以及相关预后、骨损和血β2-微球蛋白（β2-MG）的关系.结果：≥65岁组溶骨性损害发生率要高于＜65岁组.前者溶骨性损害常见部位是颅骨和胸肋骨;后者常见部位是腰椎和胸肋骨.并发高钙血症的老年患者预后可能较差.＜65岁组β2-MG异常患者中，非骨痛起病者预后好于骨痛起病者.结论：骨损表现及其相关预后指标在不同年龄组多发性骨髓瘤患者中意义不同。     

Successful treatment of non-Hodgkin's lymphoma with consciousness disturbance due to hypercalcemia by the calcium-free hemodialysis and combined chemotherapy

A 63 year-old male, who was first diagnosed as primary macroglobulinemia (IgM-kappa type) developed non-Hodgkin's lymphoma after 10 month clinical course. He had huge, multiple intrahepatic nodular lesions and had consciousness disturbance due to marked hypercalcemia. Since the treatment with gluco-corticoid and calcitonin was not effective for the improvement of patient's general condition, calcium-free hemodialysis was performed. After 2-hour dialysis, serum-Ca level was decreased from 15. 2mg/dl to 10.0mg/dl. Histology of the aspiration biopsy specimen obtained from the liver showed malignant lymphoma, diffuse, large cell type (B cell origin). Combined chemotherapy (CHOP) was started and was quite effective not only for the regression of the primary lesions but also for the normalization of the serum-Ca level. The existence of PTH-like substance produced by the tumor cell was suspected and may be related to the hypercalcemia in this case. Finally, our results demonstrated that calcium-free hemodialysis is safe and highly effective for the management of hypercalcemia caused by malignancy.     

Parathyroid hormone-related protein-(1--36) stimulates renal tubular calcium reabsorption in normal human volunteers: implications for the pathogenesis of humoral hypercalcemia of malignancy

All would agree that hypercalcemia occurs among patients with humoral hypercalcemia of malignancy (HHM) as a result of osteoclastic bone resorption. Some studies suggest that enhanced renal calcium reabsorption, which plays an important pathophysiological role in the hypercalcemia occurring in primary hyperparathyroidism, is also important pathophysiologically in HHM. Other studies have not agreed. In large part, these differences result from the inability to accurately assess creatinine and calcium clearance in critically ill subjects with HHM. To circumvent these issues, we have developed steady state 48-h PTH-related protein (PTHrP) infusion and 8-h hypercalcemic calcium clamp protocols. These techniques allow assessment of the effects of steady state PTHrP and calcium infusions in normal healthy volunteers in a setting in which renal function is stable and measurable and in which the filtered load of calcium can be matched in PTHrP- and calcium-infused subjects. Normal subjects were infused with saline (placebo), PTHrP, or calcium. Subjects receiving PTHrP, as expected, displayed mild hypercalcemia (10.2 mg/dL), suppression of endogenous PTH-(1--84), and phosphaturia. Subjects receiving the hypercalcemic calcium clamp displayed indistinguishable degrees of hypercalcemia and PTH suppression. Despite their matched degrees of hypercalcemia and PTH suppression, the two groups differed importantly with regard to fractional calcium excretion (FECa). The hypercalcemic calcium clamp group was markedly hypercalciuric (FECa averaged 6.5%), whereas FECa in the PTHrP-infused subjects was approximately 50% lower (between 2.5--3.7%), and no different from that in the normal controls, which ranged from 1.5--3.0%. These studies demonstrate that PTHrP is able to stimulate renal calcium reabsorption in healthy volunteers. These studies suggest that PTHrP-induced renal calcium reabsorption, in concert with the well established acceleration of osteoclastic bone resorption, contributes in a significant way to the hypercalcemia observed in patients with HHM.     

Hypercalcemia and parathyroid hormone-related protein in hepatocellular carcinoma

ABSTRACT— A two-site immunoradiometric assay (IRMA) of parathyroid hormone-related protein (PTHrP) was employed to react with circulating concentrations of PTHrP in 14 patients with hepatocellular carcinoma (HCC) and hypercalcemia (> 10.6 mg/dl). Eleven of them had unresectable lesions and three received transcatheter arterial chemo-embolization (TACE) treatment. Patients had no evidence of bony metastases and only one had evidence of a parathyroid lesion (by bone scan and serum parathyroid hormone level, respectively). The urinary cAMP level was increased in all patients, but the serum 1,25-dihydroxyvitamin D and plasma cAMP levels varied. Twelve patients had elevated alpha-fetoprotein (AFP) (> 400 ng/ml) and two of them had mildly elevated AFP levels (11 and 147 ng/ml). Their PTHrP concentrations were elevated (7.1 to 33.2 pmol/l), compared with normal levels obtained in our laboratory (< 3.5 pmol/l). A significant decrease in plasma PTHrP (from 27.4 to 5.2 pmol/1), serum calcium concentrations (from 16.3 to 9.4 mg/dl) and AFP levels (from 64 787 to 3129 ng/ml) was observed on the day following TACE treatment. These results, by using an improved technique, extend the findings that hypercalcemia in patients with HCC is associated with increased renal reabsorption of calcium and increased bone resorption of PTHrP generated by HCC.