PTHrP-producing tumor: squamous cell carcinoma of the liver accompanied by humoral hypercalcemia of malignancy,increased IL-6 and leukocytosis

A 77-year-old man was admitted to our hospital showing symptoms of general fatigue and appetite loss. He had leukocytosis, thrombocytosis and hypercalcemia with elevated serum levels of parathyroid hormone related peptide (PTHrP) and interleukin-6 (IL-6). An increase in tumor markers SCC and CYFURA21-1 was observed. The liver contained a huge tumor, which was proved to be PTHrP producing squamous cell carcinoma by immuno-histochemical analysis. Since the tumor did not express IL-6, it was assumed to be induced by PTHrP in osteoblasts. This is the first report of PTHrP producing squamous cell carcinoma of the liver.     

A paraneoplastic syndrome of hypercalcemia and leukocytosis associated with solid tumors: production of interleukin 1 alpha (IL-1 alpha) and granulocyte colony-stimulating factor (G-CSF) by clonal squamous cell carcinoma cells

We have demonstrated that T3M-1 cells and T3M-5 cells, derived from squamous carcinomas of patients with leukocytosis and hypercalcemia, produced excessively G-CSF, IL-1 alpha and a small amount of PTH-like factor. We confirmed that G-CSF and IL-1 alpha (hemopoietin 1) enhanced granulocytopoiesis and caused marked leukocytosis in vivo. Furthermore, we also demonstrated that PTH-rP and IL-1 alpha (a potent osteoclast-activating factor) synergistically stimulated bone resorption in vitro and also synergistically increased serum calcium concentration in vivo. Since we have demonstrated that at least two clonal cell lines derived from patients with hypercalcemia and leukocytosis produced G-CSF and IL-1 alpha, we presume that hypercalcemia and leukocytosis associated with some solid tumors may constitute a new paraneoplastic syndrome.     

Parathyroid hormone-related peptide producing cholangiocellular carcinoma with a marked psammoma formation

Humoral hypercalcemia caused by parathyroid hormone-related peptide (PTHrP), associated with cholangiocellular carcinoma (CCC), has rarely been documented. There have been no reports of CCC associated with extensive calcification of the tumor with psammoma body formation. A 66-year-old man was admitted with a large calcified tumor in the liver detected on an abdominal X-ray. An ultrasound-guided fine needle biopsy specimen of the liver tumor showed evidence of adenocarcinoma. He had hypercalcemia with an elevated PTHrP level. The patient died because of disseminated intravascular coagulation and progressive hepatic failure. A postmortem examination revealed a large poorly differentiated CCC in the liver. Immunohistochemical examination showed the presence of PTHrP-positive tumor cells. The calcified lesion consisted of a number of accumulated psammoma bodies. We present a case of PTHrP producing CCC with a marked psammoma formation.     

Concurrent primary hyperparathyroidism and humoral hypercalcemia of malignancy in a patient with multiple endocrine neoplasia type 1

We report a patient with multiple endocrine neoplasia type 1 presenting with elevation of parathyroid hormone-related protein (PTHrP) from a metastatic pancreatic neuroendocrine tumor (PNET), and parathyroid hormone (PTH) from primary hyperparathyroidism, resulting in severe hypercalcemia. Parathyroid hormone-related protein production by the PNET was confirmed by immunohistochemical analysis. Hypercalcemia and elevated PTHrP improved markedly with hepatic artery chemoembolization of liver metastasis. Thus, in multiple endocrine neoplasia type 1, correct identification of the cause of hypercalcemia as PTHrP production from a PNET or PTH production from a parathyroid tumor has important therapeutic implications.     

A case of adenocarcinoma complicated with massive leukocytosis and hypercalcemia]

A 66-year-old man was admitted to our hospital complaining of non-productive cough and low-grade fever. Chest X-ray examination revealed a mass shadow in the right hilum. Transbronchial lung biopsy of the tumor mass yielded a diagnosis of adenocarcinoma. Despite repeated chemotherapy using CDDP and VDS, metastasis to the right adrenal gland and right femur occurred, and was accompanied by hypercalcemia and hypophosphatemia. Serological study revealed elevated levels of PTH-rP and G-CSF. Six months after adenocarcinoma was diagnosed, multiple skin metastases of the cancer were observed. Immunohistochemical staining for PTH-rP and G-CSF indicated that production of cytokines had caused a paraneoplastic syndrome including hypercalcemia and leukocytosis. It appeared that the elevation of G-CSF was induced by IL-6 produced from PTH-rP in cancer tissue. Documentation of similar cases is required.     

Primary pulmonary squamous cell carcinoma associated with elevated IL-6, leukocytosis, hypercalcemia, phagocytosis, reactive lymphadenopathy and glomerular mesangial cell proliferation via the production of PTH-rP and G-CSF

We report an autopsied case of a 74-year-old man with primary pulmonary squamous cell carcinoma (SCC) associated with leukocytosis, hypercalcemia, phagocytosis in the bone marrow, reactive lymphadenopathy and mesangial cell proliferation in the glomerulus. Laboratory examination revealed increased serum levels of parathyroid hormone-related peptide (PTH-rP), granulocyte colony stimulating factor (G-CSF), interleukin-6 (IL-6) and soluble interleukin 2 receptor (s-IL2R). An autopsy showed moderately differentiated SCC at the left lower lobe of the lung, of which tumor cells distinctly showed cytoplasmic immunoreactivity to anti-G-CSF and anti-PTH-rP antibodies. Thus, pulmonary SCC seemed to produce both G-CSF and PTH-rP, causing leukocytosis, hypercalcemia, and IL-6 production from the bone. IL-6 also might have stimulated the proliferation of SCC and glomerular mesangial cells, and induced phagocytosis, reactive lymphadenopathy and hepatosplenomegaly by interacting with the mononuclear phagocytic system.     

Lung cancer associated with hypercalcemia induced by concurrently elevated parathyroid hormone and parathyroid hormone-related protein levels

In general, many cases of malignancy-associated hypercalcemia are due to HHM. In patients with humoral hypercalcemia of malignancy (HHM), it has been reported that plasma parathyroid hormone-related protein (PTHrP) and cyclic adenosine monophosphate (cAMP) levels were elevated, while plasma PTH and active vitamin D(3) levels were suppressed. Our patient showed hypercalcemia with a concurrent increase in plasma and tumor tissue PTHrP and PTH concentrations and also high cAMP and low 1-25(OH)(2)VD(3) levels in the plasma. These data suggest that the hypercalcemia exhibited by our patient was consistent with HHM due to lung cancer and its liver metastasis. Moreover, diagnostic imaging and autopsy findings showed no appreciable lesions of the parathyroid gland. In addition, histopathologic examination of the primary and metastatic tumors revealed the existence of PTH immunohistochemically stained with anti-PTH antibodies, suggesting an ectopic-PTH-producing lung tumor. From these data, our patient was diagnosed with a rare case of lung cancer, which produced both ectopic PTH and PTHrP.     

The level of serum granulocyte colony-stimulating factor in cancer patients with leukocytosis.

The level of serum granulocyte colony-stimulating factor (G-CSF) obtained from patients with leukocytosis (greater than 10,000/microliters) between May 1989 and April 1991 was measured by enzyme immunoassay. Studied were 18 patients with malignant neoplasms (median age, 64 years) and 14 patients with hematologic disease (median age, 59 years). Increased serum G-CSF values ranging from 70 to 374 pg/ml were noted in 7 of 15 lung cancer cases, a case of malignant thymoma and a blastic crisis of chronic myelogenous leukemia. The rest of the cases showed a normal value (less than 60 pg/ml). There was no correlation between the neutrophil count and G-CSF level. In lung cancer cases with high G-CSF values, neither a characteristic histologic type nor common elevation of tumor markers could be seen. The neutrophil alkaline phosphatase score was significantly increased and hypercalcemia was presented in high G-CSF cases. G-CSF may contribute at least in part to unknown leukocytosis observed in malignant neoplasms, especially in lung cancer.     

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.     

A case of pheochromocytoma producing parathyroid hormone-related protein and presenting with hypercalcemia

A 54-yr-old man with a left adrenal pheochromocytoma showed mild hypercalcemia and elevated nephrogenous cAMP. Serum levels of PTH and 1,25-dihydroxyvitamin D3 were not elevated. Postoperatively, serum calcium and nephrogenous cAMP declined to normal ranges. Pathologically, the tumor was a benign pheochromocytoma. The clinical findings resembled those of humoral hypercalcemia of malignancy (HHM), and PTH-related protein (PTHrP) immunoreactivity was detected in the tumor extract at a concentration of 80.7 pmol/g wet wt, which is high compared to levels in malignant tumors causing HHM. Production of PTHrP was further confirmed by the demonstration of PTHrP mRNA with Northern blot hybridization analysis. Gel filtration of the extract revealed the presence of at least two different molecules with both immunological and biological activities. One of the peaks appeared close to PTHrP-(1-34), and the other between cytochrome-c and BSA. The latter showed a higher bioactivity to immunoreactivity ratio. These data indicate the multiplicity of PTHrP molecules in pheochromocytoma and support the idea that PTHrP produced by pheochromocytoma causes hypercalcemia in a similar fashion as HHM.     

Parathyroid Hormone-Related Protein Expression in Human Gastric Adenocarcinomas Not Associated with Hypercalcemia

Objective: Our evaluation of a patient with a parathyroid hormone-related protein (PTHrP)-producing gastric adenocarcinoma and hypercalcemia prompted us to study the expression of PTHrP in 13 additional patients with gastric cancer and in 10 control cases. Our objective was to investigate by immunohistology the expression of PTHrP in gastric cancer.
Methods: Immunohistology studies were conducted with two murine monoclonal antibodies to synthetic peptides of human PTHrP, 9H7, and 8BI2. The 9H7 antibody was raised to the carboxyterminal amino acid fragment (109-141) of PTHrP, and the 8B12 antibody was raised to the ammo-terminal amino acid fragment (1-34) of PTHrP.
Results: Paraffin-embedded tumor specimens from 13 of 14 cases of gastric adenocarcinoma stained positively with the antibody to the carboxy terminus of the PTHrP peptide, but none stained positively with the antibody directed against the amino terminus. None of 10 control cases stained positively with either antibody. The staining was predominately evident in the cytoplasm of the tumor cells. Except for the sentinel case, none of the other patients with gastric adenocarcinoma had hypercalcemia. Thus, gastric adenocarcinoma seems to rarely result in systemic hypercalcemia.
Conclusions: Our studies demonstrated that abnormal PTHrP production can occur in malignant cells without producing hypercalcemia. PTHrP may play a role in the pathogenesis of gastric adenocarcinoma that is independent of its hypercalcemic effects. PTHrP measurements may be clinically valuable in patients with cancer who are not hypercalcemic.     

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.     

A case of myeloma with hypercalcemia caused by high serum concentrations of both parathyroid hormone-related peptide (PTHrP) and macrophage inflammatory protein-1α (MIP-1α)

A 62-year-old woman was admitted with dry mouth, general fatigue, and severe back pain. Biochemistry examination showed extreme hypercalcemia (21.2 mg/dL). Bone marrow examination was negative, but needle biopsy of a metastatic lung tumor revealed abnormal plasma cells; thus, multiple myeloma stage III-A was finally diagnosed. Serum concentrations of both parathyroid hormone-related peptide (PTHrP) and macrophage inflammatory protein-1α (MIP-1α) were markedly elevated (PTHrP 7.2 pmol/L, normal <1.1 pmol/L; MIP-1α 84.9 pg/mL, normal <46.9 pg/mL). Her myeloma appeared to have simultaneously caused two mechanisms producing hypercalcemia: humoral hypercalcemia of malignancy (HHM) by PTHrP and local osteolytic hypercalcemia (LOH) by MIP-1α. Therefore, the combination of two calcium-modulating abnormalities likely aggravated her hypercalcemia.     

Intractable hypercalcemia due to a metastatic carcinoid secreting parathyroid hormone-related peptide and interleukin-6: response to octreotide.

We describe a patient with a malignant carcinoid tumor who presented with severe, intractable hypercalcemia that would not respond to conventional therapy with fluids and pamidronate. His plasma concentrations of parathyroid-hormone-related peptide (PTHrP) and interleukin-6 (IL-6) were elevated. The patient was treated with subcutaneous injections of octreotide with a good response, resulting in normocalcemia. Plasma PTHrP and IL-6 fell with the octreotide but remained elevated above the upper limit of normal. We conclude that although rare, hypercalcemia may be associated with carcinoid tumors and may be mediated through the secretion of cytokines and or PTHrP. Treatment with octreotide may be effective in treating hypercalcemia in such patients.     

Humoral hypercalcemia of benignancy secondary to parathyroid hormone-related protein secreting uterine leiomyoma

A 48-year-old women admitted with polyuria and polydipsia. She was found to be hypercalcemic despite suppressed parathormone (iPTH) levels. Subsequently checked parathormone related-protein (PTHrP) level was 2.5 pmol/L (expected normal level <1.3 pmol/L). An extensive workup for a malignancy revealed no abnormality, except for an uterine leiomyoma, 7.1 cm in size. Total abdominal hysterectomy and salpingo-oophorectomy were performed. After the surgical removal of uterine leiomyoma, serum calcium (9.3 mg/dL), iPTH (29.4 pg/mL), and PTHrP (<1.3 pmol/L) levels were normalized. The diagnosis of humoral hypercalcemia of benignancy secondary to PTHrP was confirmed. One month later, her calcium and iPTH levels were normal and 1 year later still remain within the normal ranges. Our case indicates that PTHrP associated hypercalcemia does not solely result from a malignant tumor. Benign tumors like uterine leiomyoma might also cause humoral hypercalcemia.     

Pancreatic neuroendocrine tumor with extensive vascularisation and parathyroid hormone-related protein (PTHrP)--associated hypercalcemia of malignancy.

We report the case of a 34 year old male presenting with symptomatic hypercalcemia due to excessive PTHrP secretion from a pancreatic neuroendocrine carcinoma with extensive hypervascularization and without any evidence for metastatic disease. In the early phase of the disease conventional chemotherapy with streptozocin and doxorubicin was able to control functional activity as well as tumor growth. However, after 2 years tumor escape was indicated by severe therapy-resistant hypercalcemia. Therapeutic options were reduced due to the excessive tumor vascularization and the patient died from his disease after a short period of intensified therapy. The role of PTHrP in hypercalcemia of malignancy (HHM) and its association with neuroendocrine pancreatic tumors as well as possible therapeutic options are reviewed.     

Esophageal carcinoma with humoral hypercalcemia and leukocytosis successfully treated by a two-stage operation: report of a case

We herein report a patient demonstrating esophageal carcinoma with humoral hypercalcemia and leukocytosis. A 56-year-old Japanese man complained of a 2-month history of pyrexia. The radiological and endoscopic findings showed advanced esophageal carcinoma with a giant intraabdominal lymph node metastasis. Preoperative examination suggested that the tumor, consisting of squamous cell carcinoma, produced both parathyroid hormone-related protein and granulocyte colony-stimulating factor. We first performed an extirpation of the giant metastatic tumor to reduce the degree of humoral secretion and to improve his general condition. Thereafter, the hypercalcemia, leukocytosis, and other associated symptoms all improved. As a result, we were then able to safely perform an esophagectomy 2 months later. The patient has been doing well during the 10-month follow-up period, and is presently alive more than 1 year since hypercalcemia and leukocytosis were first observed. This is the first report of esophageal carcinoma with humoral hypercalcemia and leukocytosis that was successfully treated by an operation.     

The Role of PTHrP in Skeletal Metastases and Hypercalcemia of Malignancy

Since its discovery as the principal mediator of humoral hypercalcemia of malignancy, parathyroid hormone-related protein (PTHrP) has emerged as a key player in skeletal complications associated with solid tumor metastasis to bone. In addition to functioning as an endocrine factor, this pleiotropic peptide mediates its actions locally on tumor and stromal cells in paracrine, autocrine, and intracrine fashion when cancer metastasizes to the bone compartment. Multiple splice variants and newly described PTHrP fragments confer diverse functions to PTHrP that extend beyond binding to its common receptor with parathyroid hormone. Here, we summarize the causal role of PTHrP in humoral hypercalcemia of malignancy and its local involvement in the progression of osteolytic and osteoblastic cancer bone metastases. Clinical and preclinical findings describing how PTHrP regulates tumor and stromal cell interactions are summarized, with emphasis on emerging evidence of PTHrP’s role in tumorigenesis and cancer cell proliferation. Finally, we examine therapeutic opportunities and limitations to targeting PTHrP directly and indirectly in cancer patients.     

Circulating PTH and PTHrP levels before and after treatment of tumor induced hypercalcemia with Pamidronate Disodium (APD).

The effect of lowering ionized calcium on circulating parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) was assessed in twenty patients with hypercalcemia of malignancy following treatment with Pamidronate Disodium. Ionized calcium levels fell rapidly in all treated patients. PTH concentrations were initially suppressed below normal in 18 patients, but rose from 0.48 +/- 0.42 pmol/L to 3.63 +/- 3.13 pmol/L (p less than 0.01) after treatment, reaching higher than normal values in some patients even in the presence of persistent hypercalcemia. PTHrP concentrations did not change significantly after treatment. These findings are consistent with an increased sensitivity of parathyroid tissue to changes in ionized calcium following prolonged exposure to hypercalcemia. Regulation of tumor secretion of PTHrP by calcium was not apparent within the range of calcium concentrations in this study.     

Carcinosarcoma of the esophagus producing granulocyte-colony stimulating factor: report of a case

A 51-year-old man was admitted to the hospital for dysphagia, pyrexia, and leukocytosis. The serum level of granulocyte-colony stimulating factor (G-CSF) was elevated. Barium esophagography and endoscopy revealed a polypoid tumor in the middle portion of the esophagus. After an esophagectomy, the leukocyte count and serum G-CSF level normalized. The pathological diagnosis was carcinosarcoma of the esophagus with two components: namely, squamous cell carcinoma and sarcoma. Moreover, cancer cells were positive for G-CSF antibody. These findings confirmed that the esophageal carcinosarcoma in this case was a G-CSF-producing tumor. Although a G-CSF-producing esophageal carcinosarcoma is very rare, this disease should be considered when a patient has symptoms such as leukocytosis and pyrexia without an associated infection.