help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2095
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by VanHouten, J. N.
Right arrow Articles by Udelsman, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by VanHouten, J. N.
Right arrow Articles by Udelsman, R.
Related Collections
Right arrow Calcium and Bone Metabolism
Right arrow Endocrine Oncology
The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 2 580-583
Copyright © 2006 by The Endocrine Society

Hypercalcemia of Malignancy due to Ectopic Transactivation of the Parathyroid Hormone Gene

Joshua N. VanHouten, Namyi Yu, David Rimm, Jorge Dotto, Andrew Arnold, John J. Wysolmerski and Robert Udelsman

Department of Internal Medicine (J.N.V., N.Y., J.J.W.), Section of Endocrinology and Metabolism, and Departments of Pathology (D.R., J.D.) and Surgery (R.U.), Yale University School of Medicine, New Haven, Connecticut 06520; and Center for Molecular Medicine and Division of Endocrinology and Metabolism (A.A.), University of Connecticut School of Medicine, Farmington, Connecticut 06303-3101

Address all correspondence and requests for reprints to: John J. Wysolmerski, M.D., Section of Endocrinology and Metabolism, Department of Medicine, Yale University School of Medicine, TAC S131, 333 Cedar Street, New Haven, Connecticut 06520-8020.


   Abstract
Top
 Abstract
Introduction
 Subject and Methods
 Results
 Discussion
 References
 
Context: The physiology of PTH is well described, but regulation of PTH gene expression remains enigmatic. This is, at least in part, because of a lack of suitable cell culture systems.

Objective, Design, Setting, Patients, Interventions, and Main Outcome Measures: We report a case of severe hyperparathyroidism resulting from the ectopic production of PTH by a pancreatic malignancy. Cells from the primary tumor (PEPP1 cells) were established in culture to examine the etiology of ectopic PTH gene expression in this patient.

Results and Conclusions: We failed to find amplification or rearrangement of the PTH gene but documented hypomethylation of the PTH promoter in tumor tissue. We found that PEPP1 cells support expression of a reporter gene containing regulatory sequences from the human PTH gene promoter. Therefore, this is the first report documenting ectopic PTH production by a tumor as the result of transactivation of the PTH gene. PEPP1 cells may be useful for future studies aimed at elucidating the details of PTH gene regulation.


   Introduction
Top
 Abstract
 Introduction
Subject and Methods
 Results
 Discussion
 References
 
PTH IS SECRETED by chief cells of the parathyroid gland in response to changes in the circulating concentration of ionized calcium (1). PTH acts directly on the kidney and bone and indirectly on the gut through the renal production of 1,25-dihydroxy-vitamin D to regulate systemic calcium homeostasis (1). Overproduction of PTH by neoplastic or hyperplastic parathyroid tissue leads to primary or secondary hyperparathyroidism, both common medical conditions (2). Although much is known about the physiology of PTH, relatively little is known about the regulation of PTH gene expression. Mutations in several transcription factors have been implicated in syndromes of hypoparathyroidism (3, 4), and other specific factors have been shown to bind to the PTH gene promoter in vitro (5). However, it remains uncertain whether or how these, or other similar factors, might restrict expression of the PTH gene to parathyroid cells.


   Subject and Methods
Top
 Abstract
 Introduction
 Subject and Methods
Results
 Discussion
 References
 
Case report

A 74-yr-old woman presented to an outside hospital with progressive nausea, fatigue, polyuria, and polydipsia. Her serum calcium was 15.3 mg/dl (8.8–10.2); 5 months earlier it had been 9.3 mg/dl. Her serum level of intact PTH was elevated at 399 pg/ml (10–65). Computed tomography and positron emission tomography scans of the abdomen revealed pancreatic and liver masses. Despite treatment for hypercalcemia, she developed progressive obtundation and was transferred to Yale-New Haven Hospital for treatment of hypercalcemic crisis.

Upon admission to YNHH, she was unresponsive with a nonfocal neurological exam. Her medical history included type 2 diabetes, coronary artery disease, gastroesophageal reflux disease and hypertension. She had undergone mastectomy for breast cancer 18 yr previously and hysterectomy and bilateral salpingoophorectomy for benign uterine disease 9 yr previously. Admission laboratories revealed a serum calcium level of 18 mg/dl (8.8–10.2), an albumin level of 2.2 g/dl (3.5–5.0), an ionized calcium level of 10.1 mg/dl (4.12–4.95),and a biointact PTH level of 2,310 pg/ml (6–40).

A neck ultrasound revealed thyromegaly without evidence of a parathyroid mass. A parathyroid sestamibi scan demonstrated increased uptake in the left thyroid bed. It was thought that the patient likely had decompensated primary hyperparathyroidism, perhaps due to parathyroid carcinoma as well as an intraabdominal malignancy. However, the diagnosis of malignancy-associated hypercalcemia due to ectopic PTH production was also considered.

Neck exploration revealed a left thyroid adenoma and five normal parathyroid glands including a left intrathymic parathyroid gland that was resected. The intraoperative PTH assay was used to obtain bilateral internal jugular and peripheral vein samples, which were notable for the absence of a gradient, with all samples ranging from 1363 to 1518 pg/ml. The following day, a computed tomography-guided liver biopsy confirmed a high-grade malignancy consistent with either metastatic small-cell lung cancer or poorly differentiated neuroendocrine tumor. Immunohistochemical staining of the tumor cells was positive for PTH, suggesting a diagnosis of malignancy-associated hypercalcemia due to tumor production of PTH. In addition, a serum PTHrP level returned elevated at 11.7 pg/ml (<1.3 pmol/liter). Despite vigorous treatment with iv bisphosphonates, calcitonin, and forced saline diuresis, her serum calcium level could be reduced only transiently. Because her tumor was unresectable and her condition grave, the family opted for comfort measures and the patient died several days later from refractory hypercalcemia and multiorgan failure. An autopsy performed immediately after death revealed a poorly differentiated neuroendocrine tumor arising in the body of the pancreas with metastatic disease to the liver and retroperitoneal lymph nodes. Fresh tumor was harvested.

Isolation of tumor cells

All procedures were carried out with the approval of Yale University’s Institutional Review Board. Fresh tumor tissue was minced and incubated for 4 h at 37 C in DMEM/F12 (Invitrogen, Carlsbad, CA) containing 0.2% dispase, 0.2% collagenase (Worthington, Lakewood, NJ), 5% fetal bovine serum, 50 µg/ml gentamicin, and 500 ng/ml amphotericin-B (Sigma, St. Louis, MO). Cells were washed twice with DMEM/F12 and then plated in growth media (DMEM/F12 with 10% fetal bovine serum, 50 µg/ml gentamicin, and 500 ng/ml amphotericin-B). Cells derived from the pancreatic tumor were designated PEPP1 cells for pancreatic, ectopic PTH production.

Immunohistochemistry

Immunohistochemistry was performed using standard techniques on formalin-fixed, paraffin-embedded sections of the primary tumor and the liver metastasis; the thymic parathyroid served as a positive control. We used a polyclonal goat antihuman PTH (1–34) antiserum donated by A. Karaplis (McGill University, Montréal, Québec) and the Vectastain Elite ABC kit (Vector Laboratories, Burlingame, CA).

Analysis of gene expression

Total cellular RNA was isolated using TRIzol reagent (Invitrogen) and was further purified over RNEasy minicolumns (QIAGEN, Valencia, CA) with on-column DNase digestion. Quantitative RT-PCR (QRT-PCR) was performed by standard methods using the OpticonII DNA engine (MJ Research, Waltham, MA). The following human gene expression assays (Applied Biosystems, Foster City, CA) were used: PTH (Hs00174888_m1), PTHrP (Hs00174969_m1), homeo box-A3 (Hs00399177_m1), paired box transcription factor (Pax)-1 (Hs00196352_m1), Pax9 (Hs00196354_m1), eyes absent (Eya)1 (Hs00166804_m1), T-box1 (Tbx1) (Hs00271949_m1), specificity protein (Sp)-3 (Hs01595808_m1), calcium-sensing receptor (Hs00173436_m1), and glyceraldehyde-3-phosphate-dehydrogenase (GAPD, Hs99999905_m1). The following RT2 PCR primer sets (SuperArray, Frederick, MD) were used for SYBR-Green-based QRT-PCR: Sp1 (PPH01482A), nuclear factor Y (NFY)-{alpha} subunit (PPH07751A), NFYß (PPH00436A), NFY{gamma} (PPH16009A), and GAPD (PPH00150A). Probe-based QRT-PCR was performed with Brilliant QRT-PCR master mix (Stratagene, La Jolla, CA), and SYBR-Green-based QRT-PCR was performed with Brilliant SYBR-Green QRT-PCR master mix (Stratagene). Normal parathyroid RNA (Promega, Madison, WI) served as a positive control for PTH expression and a calibrator sample for relative quantitation of expression by the 2-{Delta}{Delta}CT method (6). Samples were run in triplicate.

PTH secretion

Intact PTH was measured in conditioned media using a two-site immunoradiometric assay (Immutopics, San Clemente, CA). Three samples of conditioned media collected on different days were analyzed in duplicate.

PTH gene copy number

Genomic DNA was isolated from PEPP1 cells and HEK 293T cells using DNAzol (Molecular Research Center, Cincinnati, OH). Fifty nanograms of DNA were amplified by QRT-PCR using primers for the human PTH gene (5'-TCGAAG TGGGGAGCTAATGGGAA-3' and 5'-CTCCAAGGGCAACAAAATTGTTGCA-3') and the human GAPD gene (5'-CGTGGAGTCCACTGGCGTCTCACC-3' and 5'-GTCATACTTCTC ATGGTTCACACCC-3'). The number of copies of the PTH gene in pancreatic tumor cells was calculated by the 2-{Delta}{Delta}CT method, using GAPD as an endogenous reference gene, and HEK 293T cells, which are known to be hypotriploid (7), were used as a calibrator sample.

Southern blotting

Genomic DNA was extracted from tumor and control normal tissues and Southern blot analysis was preformed as previously described (8, 9). Twenty micrograms DNA were digested at 37 C for 2 h for each enzyme, BamHI, HindIII, EcoRI, MspI (New England Biolabs, Beverly, MA), and Hpa II (NEB) at 10U/µl. The probe was a 775-bp BglII fragment from the human PTH gene (8, 10).

PTH gene promoter assays

We used a reporter construct (hPTHp-GFP) in which green fluorescent protein (GFP) expression is driven by a previously described 5.5-kb fragment of the human PTH gene (11). Cells were transfected with hPTHp-GFP or pCDNA3.I (to control for background fluorescence of transfected cells) using the GenePORTER transfection reagent (Genlantis, San Diego, CA) and were cotransfected with pGL3-control (Promega) to control for transfection efficiency. After 48 h, fluorescence intensity and luciferase activity were measured in the same cells. hPTHp-GFP fluorescence was first corrected for background fluorescence (cells transfected with pCDNA3.1) and then normalized to luciferase activity to correct for transfection efficiency. Each transfection included nine replicates per cell type and was repeated three times.


   Results
Top
 Abstract
 Introduction
 Subject and Methods
 Results
Discussion
 References
 
Ectopic expression of the PTH gene

The primary tumor was a high-grade neuroendocrine carcinoma of the pancreas (Fig. 1AGo). Immunohistochemistry documented PTH protein expression in the pancreatic tumor (Fig. 1DGo) and liver metastasis (Fig. 1CGo). As expected, the patient’s thymic parathyroid also stained for PTH (Fig. 1BGo), whereas her thymus tissue did not (not shown), validating the specificity of the PTH antibody. QRT-PCR revealed that the primary tumor and liver metastasis expressed PTH mRNA at a level approximately two to three times that of normal human parathyroid tissue (Fig. 1EGo). PTH mRNA expression was undetectable in adjacent normal pancreas and liver. PEPP1 cells, cultured from the primary tumor, grew readily for more than 10 passages and retained expression of PTH mRNA (Fig. 1EGo). Furthermore, conditioned media from these cells contained 12.6 ± 2.2 pM PTH (124.8 ± 21.8 pg/ml). Control PANC-1 pancreatic carcinoma cells, HEK 283T human embryonic kidney cells, and 8701BC breast cancer cells did not express PTH mRNA, and their conditioned media did not contain PTH protein. Because the patient’s circulating level of PTHrP was also elevated, we assayed her tumor for PTHrP gene expression. As expected, the primary tumor tissue, metastatic liver tumor, and PEPP1 cells expressed PTHrP mRNA by QRT-PCR, whereas the normal pancreas tissue and normal liver tissue did not (data not shown). We also assayed the pancreatic tumor, liver metastasis, and PEPP1 cells for expression of the calcium-sensing receptor, which was negative.


Figure 1
View larger version (48K):
[in this window]
[in a new window]
  		FIG. 1. The primary tumor (hematoxylin and eosin staining shown in A) was a high-grade neuroendocrine carcinoma with small-cell features. PTH was detected immunohistochemically in the positive control (thymic parathyroid) tissue (B), metastatic tumor cells in the liver biopsy (C), and the primary tumor (D). QRT-PCR (E) shows ectopic expression of PTH mRNA in the primary tumor, liver metastasis, and cultured PEPP1 tumor cells. PTH mRNA was undetectable in adjacent normal pancreas and liver tissues. PTH mRNA levels are represented as fold expression relative to normal human parathyroid gland and are normalized to human GAPD.

 
Differential methylation of the PTH gene

We found that the PTH gene was not amplified in cultured tumor cells (Fig. 2AGo). Furthermore, these cells had a normal diploid karyotype (not shown). Southern analysis using multiple restriction enzyme digests (not shown) of the pancreatic and liver tumor samples revealed no evidence of rearrangement involving a 16-kb span of DNA containing the entire PTH gene and more than 5 kb of upstream flanking sequences. However, paired digestion using MspI and the methylation sensitive enzyme, HpaII, did reveal a pattern consistent with hypomethylation of the PTH gene in both the pancreatic and liver tumors but not in the normal liver control sample (Fig. 2BGo). Such hypomethylation would not be expected in nonparathyroid tissues and is indicative of active PTH gene transcription in the tumor tissues (12).


Figure 2
View larger version (31K):
[in this window]
[in a new window]
  		FIG. 2. The copy number of the PTH gene in PEPP1 pancreatic tumor cells was determined by QPCR (A). PEPP1 cells had approximately two copies of the PTH gene, using HEK 293T cells, which are triploid, as a calibrator sample. Southern blotting (B) of DNA from normal liver tissue (NL), metastatic liver tissue (Met), or primary pancreatic tumor tissue (Prim), revealed that the PTH gene is hypomethylated in the tumor tissues. A 6.3-kb band was seen in normal and tumor DNA digested with MspI, but this band was not seen in the normal tissue when the DNA was digested with the methylation-sensitive isoschizomer of MspI, HpaII. The presence of the 6.3-kb PTH band in the HpaII-digested DNA from the tumor tissues is indicative of hypomethylation of the PTH gene.

 
Transactivation of the human PTH promoter

Given the lack of structural abnormalities in the PTH gene in the tumor, we next asked whether ectopic PTH expression was mediated through a trans-acting mechanism. We assayed the activity of a reporter construct consisting of a 5.5-kb fragment of the human PTH gene promoter placed upstream of the green fluorescent protein cDNA. This portion of the PTH promoter has been shown to contain regulatory sequences necessary for proper parathyroid-specific transgene expression in mice (11). As shown in Fig. 3Go, fluorescence was negligible in all cell types tested except for the PEPP1 cells, suggesting that these cells contained transcription factors capable of activating tissue-specific regulatory elements of the PTH gene promoter. Therefore, we next examined the expression of 11 transcription factors implicated in either parathyroid gland development (Tbx1, Hoxa3, paired box transcription factor 1, Pax9, Eya1, and Gcm2) (13) or binding to the human PTH promoter (Sp1, Sp3, NFY{alpha}, NFYß, and NFY{gamma}) (5). Each of these transcription factors was either undetectable in tumor tissue and/or PEPP1 cells or was expressed at similar levels in both the tumor and adjacent normal tissues (data not shown). Thus, none of these transcription factors were likely responsible for PTH gene expression in this tumor.


Figure 3
View larger version (12K):
[in this window]
[in a new window]
  		FIG. 3. Assay of GFP-derived fluorescence in cells transfected with the hPTHp-GFP reporter. One can see that the PTH promoter was active in the PEPP1 pancreas tumor cells but was inactive in the pancreas carcinoma cell line, PANC-1, in HEK 293T cells and the breast cancer cell line, 8701-BC. The latter three cell lines do not express the endogenous PTH gene (not shown).

 

   Discussion
Top
 Abstract
 Introduction
 Subject and Methods
 Results
 Discussion
References
 
We describe a case of fatal, decompensated hyperparathyroidism caused by ectopic production of PTH by a metastatic neuroendocrine tumor of the pancreas. Ectopic production of PTH is an extremely rare cause of humoral hypercalcemia of malignancy. Although there are 14 such cases reported in the medical literature (8, 14–23), only four of these reports documented that tumor cells actually expressed the PTH gene (8, 21, 22, 23). In only one other case, that of an ovarian carcinoma, did the investigators document a molecular etiology for PTH gene expression (8), namely amplification and rearrangement of the PTH gene (8). We did not detect any evidence for similar amplification or rearrangements in the PTH gene in the tumor from our patient. Instead, her tumor activated the expression of an otherwise normal PTH gene, suggesting that PEPP1 cells recapitulate critical aspects of the regulatory environment of parathyroid cells.

Rearrangements of the PTH gene promoter with the cyclin D1 gene in parathyroid adenomas suggest that DNA sequences necessary for tissue-specific expression of the PTH gene reside in the 5' regulatory region of the gene (24). In addition, the 5.5-kb fragment of the human PTH gene used in this study has previously been shown to be sufficient to direct specific expression of cyclin D1(11) and GFP (Arnold, A., unpublished data) to the parathyroid glands of transgenic mice. The ability of our patient’s tumor cells to express the hPTHp-GFP reporter gene suggests that her tumor expressed a transcription factor(s) that was able to interact with this portion of the PTH promoter to activate PTH gene expression. Despite the specific absence of parathyroid glands in glial cells missing 2 (Gcm2)-null mice and patients with loss-of-function mutations in Gcm2 (3, 4), this transcription factor was not expressed in the tumor cells, confirming that whereas Gcm2 may be necessary for parathyroid development, it is not necessary for PTH gene expression. Likewise, none of the other transcription factors previously implicated in parathyroid development (13) or binding to the PTH promoter (5) explained the activation of the gene in these tumor cells. Study of the transcriptional regulation of the PTH gene has been hampered by the lack of parathyroid cell lines. PEPP1 cells, derived from our patient’s tumor, may prove useful for the study of PTH gene expression.


   Acknowledgments
 
We thank Ms. Kristin Corrado and Ms. Pamela Dann for expert technical assistance and Drs. Arthur Broadus and Karl Insogna for a critical review of the manuscript.


   Footnotes
 
This work was supported by National Institutes of Health Grants DK064206 (to J.V.), DK55501 (to J.W.), CA94175 (to J.W.), and the Murray-Heilig Fund in Molecular Medicine (to A.A.). Experiments were facilitated by the Yale Core Center for Musculoskeletal Disorders (NIH Grant AR6032) and the Yale Diabetes Endocrine Research Center (NIH Grant DK45735).

The authors have nothing to declare.

First Published Online November 1, 2005

Abbreviations: GAPD, Glyceraldehyde-3-phosphate-dehydrogenase; GFP, green fluorescent protein; hPTHp, human PTH gene promoter; NFY, nuclear factor Y; Pax, paired box transcription factor; QRT-PCR, quantitative RT-PCR; Sp, specificity protein.

Received September 20, 2005.

Accepted October 26, 2005.


   References
Top
 Abstract
 Introduction
 Subject and Methods
 Results
 Discussion
 References
 

  1. Chen RA, Goodman WG 2004 Role of the calcium-sensing receptor in parathyroid gland physiology. Am J Physiol Renal Physiol 286:F1005–F1011
  2. Bilezikian JP, Silberberg SJ 2003 Primary hyperparathyroidism. In: Favus MJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. 5th ed. Washington, DC: American Society for Bone and Mineral Research; 230–234
  3. Thomee C, Schubert SW, Parma J, Le PQ, Hashemolhosseini S, Wegner M, Abramowicz MJ 2005 GCMB mutation in familial isolated hypoparathyroidism with residual secretion of parathyroid hormone. J Clin Endocrinol Metab 90:2487–2492[Abstract/Free Full Text]
  4. Ding C, Buckingham B, Levine MA 2001 Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB. J Clin Invest 108:1215–1220[CrossRef][Medline]
  5. Alimov AP, Park-Sarge OK, Sarge KD, Malluche HH, Koszewski NJ 2005 Transactivation of the parathyroid hormone promoter by Sp proteins and the nuclear factor Y complex. Endocrinology 146:3409–3460[Abstract/Free Full Text]
  6. Applied Biosystems 1997 Relative quantitation of gene expression: ABI Prism 7700 sequence detection system, user bulletin 2, revision B
  7. Bylund L, Kytola S, Lui WO, Larsson C, Weber G 2004 Analysis of the cytogenetic stability of the human embryonal kidney cell line 293 by cytogenetic and STR profiling approaches. Cytogenet Genome Res 106:28–32[CrossRef][Medline]
  8. Nussbaum SR, Gaz RD, Arnold A 1990 Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone. N Engl J Med 323:1324–1328[Medline]
  9. Arnold A, Staunton CE, Kim HG, Gaz RD, Kronenberg HM 1988 Monoclonality and abnormal parathyroid hormone genes in parathyroid adenomas. N Engl J Med 318:658–662[Abstract]
  10. Arnold A, Kim HG, Gaz RD, Eddy RL, Fukushima Y, Byers MG, Shows TB, Kronenberg HM 1989 Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest 83:2034–2040
  11. Imanishi Y, Hosokawa Y, Yoshimoto K, Schipani E, Mallya S, Papanikolaou A, Kifor O, Tokura T, Sablosky M, Ledgard F, Gronowicz G, Wang TC, Schmidt EV, Hall C, Brown EM, Bronson R, Arnold A 2001 Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice. J Clin Invest 107:1093–1102[Medline]
  12. Levine MA, Morrow PP, Kronenberg HM, Phillips 3rd JA 1986 Tissue and gene specific hypomethylation of the human parathyroid hormone gene: association with parathyroid hormone gene expression in parathyroid glands. Endocrinology 119:1618–1624[Abstract/Free Full Text]
  13. Maret A, Bourdeau I, Ding C, Kadkol SS, Westra WH, Levine MA 2004 Expression of GCMB by intrathymic parathyroid hormone-secreting adenomas indicates their parathyroid cell origin. J Clin Endocrinol Metab 89:8–12[Abstract/Free Full Text]
  14. Botea V, Edelson GW, Munasinghe RL 2003 Hyperparathyroidism, hypercalcemia, and calcified brain metastatic lesions in a patient with small cell carcinoma demonstrating positive immunostain for parathyroid hormone. Endocr Pract 9:40–44[Medline]
  15. Samaan NA, Ordonez NG, Ibanez ML, Goepfert H, Smith K 1983 Ectopic parathyroid hormone production by a squamous carcinoma of the tonsil. Arch Otolaryngol 109:91–94[Abstract/Free Full Text]
  16. Mayes LC, Kasselberg AG, Roloff JS, Lukens JN 1984 Hypercalcemia associated with immunoreactive parathyroid hormone in a malignant rhabdoid tumor of the kidney (rhabdoid Wilms’ tumor). Cancer 54:882–884[CrossRef][Medline]
  17. Arps H, Dietel M, Schulz A, Janzarik H, Kloppel G 1986 Pancreatic endocrine carcinoma with ectopic PTH-production and paraneoplastic hypercalcaemia. Virchows Arch A Pathol Anat Histopathol 408:497–503[CrossRef][Medline]
  18. Buller R, Taylor K, Burg AC, Berman ML, DiSaia PJ 1991 Paraneoplastic hypercalcemia associated with adenosquamous carcinoma of the endometrium. Gynecol Oncol 40:95–98[CrossRef][Medline]
  19. Koyama Y, Ishijima H, Ishibashi A, Katsuya T, Ishizaka H, Aoki J, Endo K 1999 Intact PTH-producing hepatocellular carcinoma treated by transcatheter arterial embolization. Abdom Imaging 24:144–146[CrossRef][Medline]
  20. Uchimura K, Mokuno T, Nagasaka A, Hayakawa N, Kato T, Yamazaki N, Kobayashi T, Nagata M, Kotake M, Itoh M, Tsujimura T, Iwase K 2002 Lung cancer associated with hypercalcemia induced by concurrently elevated parathyroid hormone and parathyroid hormone-related protein levels. Metabolism 51:871–875[CrossRef][Medline]
  21. Yoshimoto K, Yamasaki R, Sakai H, Tezuka U, Takahashi M, Iizuka M, Sekiya T, Saito S 1989 Ectopic production of parathyroid hormone by small cell lung cancer in a patient with hypercalcemia. J Clin Endocrinol Metab 68:976–981[Abstract/Free Full Text]
  22. Strewler GJ, Budayr AA, Clark OH, Nissenson RA 1993 Production of parathyroid hormone by a malignant nonparathyroid tumor in a hypercalcemic patient. J Clin Endocrinol Metab 76:1373–1375[Abstract]
  23. Rizzoli R, Pache JC, Didierjean L, Burger A, Bonjour JP 1994 A thymoma as a cause of true ectopic hyperparathyroidism. J Clin Endocrinol Metab 79:912–915[Abstract]
  24. Mallya SM, Arnold A 2000 Cyclin D1 in parathyroid disease. Front Biosci 5:D367–D371



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
L. J. Suva
PTH Expression, Not Always where You Think ...
J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 396 - 397.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by VanHouten, J. N.
Right arrow Articles by Udelsman, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by VanHouten, J. N.
Right arrow Articles by Udelsman, R.
Related Collections
Right arrow Calcium and Bone Metabolism
Right arrow Endocrine Oncology

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals