Journal of Clinical Pathology, 1979, 32, 234-239

Hypercalcaemia due to hyperparathyroidism in a

patient with chronic renal failure and renalcarcinomaJ. J. SZWED, L. J. GOTT, R. E. LEMPKE, AND IN SOOK SEO

From the Departments of Medicine, Surgery, and Pathology, Clowes Research Laboratories,Wishard Memorial Hospital, Indiana University Medical Center, Indianapolis, Indiana 46202, USA

SUMMARY A 65-year-old woman with a history of a left heminephrectomy for renal carcinomadeveloped hypercalcaemia 11 years after the operation. The same kidney was found to contain a

recurrent renal carcinoma. After the radical nephrectomy of the left kidney, hypercalcaemia remittedbut reappeared 11 months later. The right kidney was small but functioned at a level of creatinineclearance of 10-15 ml/min. Metastatic work-up was negative, and secondary causes of hypercalcaemiawere excluded. A neck exploration revealed a parathyroid adenoma. With parathyroid resection theserum calcium declined to normal, and the risk of hypercalcaemic nephropathy in the remainingkidney was precluded.

Hypercalcaemia is a common manifestation ofmalignancy of numerous organs, including the kid-ney (Albright and Reifenstein, 1948; Connor et al.,1956; Plimpton and Gellhorn, 1956; Gold andShnider, 1959; Lucas, 1960; David et al., 1963;Noenickx et al., 1962; Moses and Spencer, 1963;Samuelsson and Werner, 1963; Goldberg et al.,1964). Primary hyperparathyroidism is a relativelycommon disorder, usually benign, with a frequencyof 1 case per 1000 persons per year. The mostcommon manifestation of this disorder is hyper-calcaemia (Thorn et al., 1977). The association ofrenal carcinoma and hyperparathyroidism in thesame patient is uncommon and has rarely beendiagnosed before the death of the patient (Bernsteinet al., 1965; Salama et al., 1971; Nemoto et al.,1977).This report describes a patient with chronic renal

failure, who had had a total left nephrectomy for arecurrent renal carcinoma accompanied by hyper-calcaemia and, 11 months later, was found tohave recurrent hypercalcaemia. The recurrent hyper-calcaemia was not due to recurrent renal carcinomabut rather to a parathyroid adenoma. After removalof a parathyroid adenoma the hypercalcaemiaremitted.

Received for publication 5 September 1978

Case report

The patient is a woman who was found to have acarcinoma of the left kidney during evaluation ofvaginal prolapse in 1965 at age 54. The physicalexamination was normal except for obvious vaginalprolapse. The full blood count, urine analysis,serum electrolytes, serum calcium and phosphate,and creatinine clearance were normal. She under-went segmental resection of the left kidney (Fig. 1).On microscopic examination the tumour was a renalcarcinoma. There were no metastases nor was thereevidence of local invasion. At the time of theoperation the patient was described as being quite'irritable' by several physicians. She was dischargedfrom hospital and followed with yearly intravenouspyelograms.

In July 1976, 11 years after the first operation, shewas found to have progressive dilatation and club-bing of upper pole calyces, and an angiogram (Fig.2) showed a 7 x 4 x 5 cm tumour mass involvingone-half to two-thirds of the upper pole of the leftkidney. The right kidney appeared to be small butwithout gross tumour involvement. Investigationrevealed that the haemoglobin was 12-0 g/dl, WBC7-8 x 109/l with a normal differential. The urine wasclear with pH 6-0 and SG 1 -010; there were 10-20RBCs/hpf, 5-10 WBCs/hpf, and no casts norbacteria. Urine cultures were negative on three

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Hypercalcaemia due to hyperparathyroidism in a patient with chronic renal failure

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Fig. 1 A graph depicting the patient's course by following serum calcium, phosphate, PTH, and creatinine clearance.

separate occasions. Serum electrolytes were: sodium135 mEq/l (135 mmol/l), potassium 4-1 mEq/l (4-1mmol/l), chloride 99 mEq/l (99 mmol/l), carbon-dioxide combining power 26 mEq/l (26 mmol/l).Total serum proteins 6-3 g/dl (63 g/l) with albumin3-6 g/dl (36 g/I). Serum calcium levels of 11 -2 mg/dl(2-8 mmol/l), 11 -0 mg/dl (2-75 mmol/l), and 11 -5 mg/dl (2-88 mmol/l) (normal range: 8&4-10-0 mg/dl;2 1-2-5 mmol/l) were found with corresponding serumphosphate levels of 3 2 mg/dl (1 03 mmol/l), 3 0 mg/dl (0 97 mmol/l), and 2-8 mg/dl (0 90 mmol/l). Theionised serum calcium was 2-54 mEq/l (1 27 mmol/l)preoperatively, falling to 2-22 mEq/l (1 11 mmol/l)postoperatively (normal range: 1-78-2-28 mEq/l;0-89-1-14 mmol/l), creatinine clearance was 100 ml/min. All other laboratory or radiological investiga-tions were normal.The remainder of the left kidney was resected in

September 1976 and found to contain a well-encapsulated neoplasm measuring 5-5 x 6-0 cm. Onsection it had a yellow, vascular cut surface with areasof haemorrhagic necrosis and microscopically wascomposed predominantly of polygonal clear cells(Fig. 3). No evidence of metastases was found atoperation. The renal vessels and ureter were free of

disease. Postoperatively the urine output ranged from50 to 100 ml/day for 48 hours and then rose to 1500ml/day; creatinine clearance stabilised at 10-15 ml[min during the next 10 days. The serum calciumlevel was 9 0 mg/dl (2 25 mmol/l) and serum phos-phate was 3-0 mg/dl (0 97 mmol/l) at discharge inOctober 1976.

Before operation in 1976 the patient's parathyroidhormone level had been 916 pg/ml. Postoperatively,the level declined to 800 pg/ml and has remained atapproximately the same elevated level to the presenttime. While the patient's renal function graduallyimproved with hypertrophy of the remaining kidney,the serum calcium began to rise again and in August1977 reached values of 10-5-11l5 mg/dl (2-63-2-88mmol/l); the ionised calcium was also elevated at2-60 mEq/l (1 -3 mmol/l). Initially, the hypercalcaemiawas thought to be due to the renal carcinoma, butthe postoperative rise in 1977 suggested that the-patient had a recurrence of tumour or had another,occult cause of hypercalcaemia. After another work-up for metastatic neoplasm was found to be negative-radiologically and biochemically, secondary causes-of hypercalcaemia were evaluated. Bone marrow andserum protein electrophoresis were both normal and

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J. J. Szwed, L. J. Gott, R. E. Lempke, and In Sook Seo

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Fig. 2 Renalangiogramdemonstrating largetumour of the leftkidney and the smallright kidney.

Fig. 3 Renal cellcarcinoma showingtypical clear cells withhighly vascularstroma(Haematoxylin andeosin x 100).

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Hypercalcaemia due to hyperparathyroidism in a patient with chronic renal failure

Fig. 4 Functioningparathyroid adenomacontaining chief cellsgrowing in sheets andglandular pattern(H and E x 100).

excluded the largest group of multiple myelomas,that is, secretary myelomas. Thyroid function studieswere normal. Sarcoidosis was not suggested by eitherhistory, physical findings, or radiological examina-tion. The patient was taking no vitamins nor diuretics,nor was she ingesting any milk products or antacidsin large quantities to our knowledge. It was, there-fore, concluded that a parathyroid adenoma mightbe present, although this diagnosis was supportedonly by the patient's chronic irritability, noted bymany observers, and her hypercalcaemia.

Since the renal function was slowly improvingwith one kidney, it was decided to explore her neckfor a possible parathyroid adenoma. While the levelof serum calcium was not life-threatening, theresidual kidney was at risk and its function coulddeteriorate if the hypercalcaemia persisted. Atoperation three parathyroid glands were identified.A mass removed from the right superior region of thethyroid gland measured 1-8 x 1-0 x 05 cm in itsgreatest dimensions. It had a thin, connective tissuecapsule and a greyish-brown cut surface. Micro-scopically, it was an encapsulated lesion composedmainly of chief cells, which were growing in sheetsand in a glandular pattern (Fig. 4). The adenoma wasseparated by a fibrous band from a definite rim ofnormal parathyroid. No mitosis was present. Threenormal parathyroid glands were identified micro-scopically. The patient recovered uneventfully, and

the serum calcium levels returned to the 9-5-100 mg/dl (2 38-2 5 mmol/l) range with a serum phosphatereading 3 0-3 4 mg/dl (0 97-1 10 mmol/l) two monthsafter surgery. The patient now feels well, but herirritability persists. Her renal function continues toimprove gradually and her creatinine clearance isnow 45 ml/min.

Discussion

The relationship between malignancy and increasedparathyroid hormone (PTH) levels can be ascribedto the production of PTH by tumour tissue. Thedevelopment of hypercalcaemia and hypophos-phataemia in patients with malignant neoplasms hasbeen reported. On the basis of histological studies,reasonably convincing evidence has been producedthat a PTH-like substance can be formed in patientswith tumours and hypercalcaemia (Kohout, 1966). Ina series of 128 consecutive patients with malignantdisease studied at necropsy, 34 had hypercalcaemiaand all were found to have parathyroid hyperplasiaon microscopic examination, with an increase inchief cells and eosinophilic cells. In 16 of the 34, theweight of the parathyroid glands was slightly abovenormal. Therefore, the relationship between para-thyroid hyperplasia, PTH levels, and hypercalcaemiais such that true primary hyperparathyroidism canbe mimicked by malignancy.

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238 J. J. Szwed, L. J. Gott, R. E. Lempke, and In Sook Seo

In the Uppsala University Hospital study(Johansson and Werner, 1975), co-existing malignantdisease was found in 13 of 350 patients with histolo-gically proven parathyroid adenomas. The asso-ciation, if any, between parathyroid disease andmalignancy is unclear. However, they suggest threepossible mechanisms for a direct relationship be-tween hyperparathyroidism and malignancy.

First, the malignant process and 'primary' hyper-parathyroidism might have a causative factor incommon so that, for example, parathyroid tissuemight be sensitive to a viral agent inducing myelo-proliferative disease. There are no data to supportthis theory.

Secondly, the malignancy may cause hyper-parathyroidism by a variety of possible mechanisms.For instance, the malignant cells may produce pro-tein or proteins that directly stimulate the para-thyroid gland, or bind the parathyroid hormone orblock its effect, for example, on the kidney tubules.The protein might also bind serum calcium more orless specifically. It is interesting that such calcium-binding proteins have been identified (Lindgarde andZettervall, 1973).The third possibility is that primary hyperpara-

thyroidism might cause malignancy, though there isno direct evidence to support such a theory. Clubbet al. (1964) reported a case in which a serum 'para-protein' fraction disappeared after the removal of ahyperactive parathyroid adenoma, though theyreported later that the paraprotein reappeared in theserum two and a half years after the operation.Furthermore, several cases of monoclonal IgGgammopathy associated with hyperparathyroidismhave been reported (Dexter et al., 1972). Thoughhypercalcaemia disappeared in all three cases afterparathyroidectomy, the monoclonal gammopathypersisted with no evidence of malignancy. No matterwhat the true pathophysiological interactions areamong parathyroid disease, hypercalcaemia, andmalignant disease, the implication remains thathypercalcaemia in patients with a malignancy shouldnot be accepted as an inevitable sign of recurrenttumour.

In our patient with resected renal carcinoma andparathyroid adenoma, the situation was complicatedby the fact that there was also chronic renal failure.Since this lowers total serum calcium levels, theparathyroid-induced hypercalcaemia failed to be--come apparent until postoperatively the renalfunction improved. The only symptom that thepatient had for many years was 'irritability', and-though this may be a clue to the duration of herhyperparathyroidism, it is impossible to ascertainwhether parathyroid disease was present in 1965.Moreover, it is interesting that the irritability still

persists. Eight months postparathyroidectomy thepatient continues to do well. The creatinine clear-rance is 45 ml/min and the serum calcium is normal.

References

Albright, F., and Reifenstein, E. C., Jr. (1948). TheParathyroid Glands and Metabolic Bone Disease.Williams and Wilkins, Baltimore.

Bernstein, D. S., Thorn, G. W., and Jackson, J. H. (1965).Hypercalcemia associated with sarcoidosis, hyper-nephroma and parathyroid adenoma: an unusual casewith a nineteen-year follow-up. Journal of ClinicalEndocrinology and Metabolism, 25, 1436-1440.

Clubb, J. S., Posen, S., and Neale, F. C. (1964). Dis-appearance of a serum paraprotein after parathyroi-dectomy. Archives of Internal Medicine, 114, 616-620.

Connor, T. B., Thomas, W. C., Jr., and Howard, J. E.(1956). The etiology of hypercalcemia associated withlung carcinoma (Abstract). Journal of Clinical Investi-gation, 35, 697-698.

David, N. H., Verner, J. V., and Engel, F. L. (1962).Thediagnostic spectrum of hypercalcemia. Case report anddiscussion. American Journal of Medicine, 33, 88-110.

Dexter, R. N., Mullinax, F., Estep, H. L., and Williams,R. C., Jr. (1972). Monoclonal IgG gammopathy andhyperparathyroidism. Annals of Internal Medicine, 77,759-764.

Gold, G. L., and Shnider, B. I. (1959). Some unusualsyndromes associated with neoplastic disease. Annals ofInternal Medicine, 51, 890-896.

Goldberg, M. F., Tashjian, A. J., Jr., Order, S. E., andDammin, G. J. (1964). Renal adenocarcinoma contain-ing a parathyroid hormone-like substance and associa-ted with marked hypercalcemia. American Journal ofMedicine, 36, 805-814.

Johansson, H., and Werner, I. (1975). Dysproteinemia,malignancy, and hyperparathyroidism. (Letter). Annalsof Internal Medicine, 83, 121-122.

Kohout, E. (1966). Serum calcium levels and parathyroidglands in malignant disorders. Cancer, 19, 925-934.

Lindgarde, F., and Zettervall, 0. (1973). Hypercalcemiaand normal ionized serum calcium in a case of mye-lomatosis. Annals of Internal Medicine, 78, 396-399.

Lucas, P. F. (1960). Acute hypercalcaemia from carcino-matosis without bone metastasis. British MedicalJournal, 1, 1330-1331.

Moses, A. M., and Spencer, H. (1963). Hypercalcemia inpatients with malignant lymphoma. Annals of InternalMedicine, 59, 531-536.

Nemoto, R., Schimizu, S., Kuwahara, M., Harada, T.,Kato, T., Takanaschi, R., and Tsuchida, S. (1977).Primary hyperparathyroidism with triple cancersconsisting of renal cell carcinoma, nasopharynxcarcinoma and thyroid carcinoma. Journal of Urology,117, 369-370.

Noeninckx, F., Six, R., and Van Laethem, L. (1962).Tumeur maligne de l'ovaire a effet hypercalcemiant etphosphaturique. Acta Clinica Belgica, 17, 406-412.

Plimpton, C. H., and Gellhorn, A. (1956). Hypercalcemia

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in malignant disease without evidence of bone des-truction. American Journal ofMedicine, 21, 750-759.

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Thorn, G. W., Adams, R. D., Braunwald, E., Isselbacher,K. J., and Petersdorf, R. G. eds. (1977). Harrison'sPrinciples of Internal Medicine, 8th edition, pp. 2014-2022. McGraw-Hill, New York.

Requests for reprints to: Dr James J. Szwed, WishardMemorial Hospital, Renal Section, OPW 439, 1001 West10th Street, Indianapolis, Indiana 46202

The February 1979 IssueTHE FEBRUARY 1979 ISSUE CONTAINS THE FOLLOWING PAPERS

The priority test request form A. R. HENDERSON

An approach to quality and performance controlin a computer-assisted clinical chemistry laboratoryP. E. UNDRILL AND S. C. FRAZER

Urinary total porphyrins by ion exchange analysis:Reference values for the normal range and remarkson preformed porphyrins in acute porphyria urineJ. FOGSTRUP AND T. K. WITH

An interfering factor in the automated analysis ofcalcium P. GOSLING AND H. G. SAMMONS

Serum protein profile in sickle cell disease u. P.ISICHEI

Comparison of enzyme-linked immunosorbent assay(ELISA) technique and complement-fixation testfor estimation of cytomegalovirus IgG antibodyJ. C. BOOTH, GILLIAN HANNINGTON, T. A. G. AZIZ,AND H. STERN

Comparison of passive haemagglutination andhaemagglutination-inhibition techniques for detec-tion of antibodies to rubella virus C. J. BIRCH,B. P. GLAUN, V. HUNT, L. G. IRVING, AND I. D. GUST

Hepatitis Be antigen and antibody in hepatitis Bsurface antigen positive blood donors A. BARR,S. H. BLACK, C. J. BURRELL, B. DOW, AND I. MACVARISH

Rapid serotyping ofgroups A, B, and C meningococciby rocket-line immunoelectrophoresis and co-agglutination D. DANIELSSON AND P. OLCE'N

Anaerobic organisms in postoperative woundsP. J. SANDERSON, M. W. D. WREN, AND A. W. F.

BALDWIN

Effect of pH on sporicidal and microbicidalactivity of buffered mixtures of alcohol and sodiumhypochlorite JANET E. DEATH AND D. COATES

Anti blood group-M autoantibodies with livedoreticularis, Raynaud's phenomenon, and anaemiaJ. M. SANGSTER, M. G. KENWRIGHT, M. P. WALKER,AND A. C. PEMBROKE

Periodic acid-Schiff reaction and prognosis inlymphoblastic leukaemia J. S. LILLEYMAN, V. MILLS,P. J. SUGDEN, AND J. A. BRITTON

A rapid method for electron microscopic examina-tion of blood cells ANTONIO COPPOLA

A comparison of thiomersal and 50(% alcohol aspreservatives in urinary cytology M. E. BEYER-BOON,P. W. ARENTZ, AND R. S. KIRK

Gastrin cells and fasting serum gastrin levels induodenal ulcer patients JUAN PIRIS AND R. WHITE-HEAD

Histological appearances of the gastric mucosa15-27 years after partial gastrectomy ANN SAVAGEAND S. JONES

A new technique for Gram staining paraffin-embedded tissue KRAESTEN ENGBJEK, KIRSTENSTAEHR JOHANSEN, AND MERETE EGHOLM JENSEN

Technical methodsStorage of reagent platelets for anti-platelet anti-body testing in the 51Cr platelet lysis assay G. E.LIZAK AND F. C. GRUMET

Use of sheep erythrocytes as solid phase supports indouble antibody immunoassay systems JOHN KANEAND ERIC GOWLAND

Demonstration of creatine phosphokinase in humanmyocardial slices R. J. TRICKEY AND M. J. DAVIES

Letter to the Editor

Book reviews

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