Parathyroid carcinoma in a dialysis patient

CASE REPORT

Parathyroid Carcinoma in a Dialysis Patient Satishkumar Jayawardene, MRCP, William J. Owen, FRCS, and David J.A. Goldsmith, FRCP ● A 75-year-old woman who had been receiving dialysis for 3 years and had a long history of chronic renal failure attributable to reflux nephropathy was investigated for progressive hypercalcemia in the context of very high intact parathormone (iPTH) levels. Imaging showed two functional parathyroid glands in the neck. At parathyroidectomy, four variously enlarged parathyroid glands were found and completely resected, without autotransplantation. The histology of one of the glands showed invasive parathyroid carcinoma. Parathyroid carcinoma is a very rare condition, with only 16 previous cases involving dialysis patients described in the literature. We review the literature to draw together presentational and therapeutic information on the management of this problem in the setting of renal replacement therapy. © 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Parathyroid; hyperparathyroidism; carcinoma; renal failure; female.

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LTHOUGH hyperparathyroidism is common in dialysis patients, parathyroid carcinoma is not. Very few cases have been reported. We report a second case from our unit and provide a comprehensive literature review. CASE REPORT A 60-year-old woman came to the renal department in 1980 with proteinuria, hypertension, and renal impairment (creatinine, 190 ␮mol/L) caused by reflux nephropathy. There was a family history of diabetes (sister) and chronic renal failure caused by reflux nephropathy (two sisters), but no endocrine history. She was hypercalcemic in 1980 (uncuffed albumin-corrected plasma calcium was 2.76 mmol/L). Bone appearances from a radiologic skeletal survey were normal. Plasma parathyroid hormone (PTH) (nonspecific assay) was 0.54 ␮g/L (normal, ⬍0.1 to 0.73 ␮g/L). Over the next 12 years, BP control was inconsistent and often poor despite vigorous therapy. She remained mildly hypercalcemic (range, 2.54 to 2.80 mmol/L). Because of this, she did not receive vitamin D therapy until, in 1992, she reached end-stage renal failure and started peritoneal dialysis, after which for phosphate control she also started oral calcium carbonate therapy. By 1994, plasma calcium had risen to 3.01 ␮mol/L and intact PTH (iPTH) (specific assay) was 1,303 nmol/L (normal, 15 to 65 nmol/L). A thalliumtechnetium parathyroid subtraction scan showed two enlarged functional parathyroid glands on the neck, which findings were replicated by a parathyroid ultrasound scan. Nothing was palpable in the neck. At surgical parathyroidectomy (PTX), four enlarged glands were removed in their entirety. Histology of the four removed glands showed nodularity, but in one there was also monotonous cellularity and clear evidence of cellular invasion into the gland capsule and into one blood vessel (Figs 1 through 3). No mitoses were seen. In the immediate postoperative period, plasma calcium decreased from 3.18 mmol/L to 1.89 mmol/L. Plasma alkaline phosphatase rose from 218 to 543 IU/L. She needed calcium carbonate and large doses of oral 1-alfacalcidol postoperatively to maintain safe blood calcium levels. PTH

was detectable postoperatively (within 6 weeks, 25 nmol/L) but remained within the normal range despite post-PTX hypocalcemia. Over the next 4 years to the current day, plasma calcium has slowly risen to 2.54 ␮mol/L, with a mildly elevated PTH (161 nmol/L). The patient is now on hospital-based hemodialysis with no cervical or general symptoms. Recent isotope and ultrasound imaging of the neck and a positron-emission tomography scan have not shown any evidence of local tumor recurrence.

DISCUSSION

The diagnosis of primary malignant change of the parathyroid glands is very rare; the first case was reported in 1938,1 and to date, only approximately 300 cases are in the literature. It is thought that the incidence of parathyroid carcinoma in primary hyperparathyroidism is in the range of 0.5% to 5%.2,3 There is a well-known but very rare association between familial hyperparathyroidism, as part of multiple endocrine neoplasia (MEN) and parathyroid carcinoma.4 The cause of the more common, sporadic, cases is unclear. The female: male ratio in these sporadic cases was 2:1.5 Parathyroid hyperplasia as a precursor to carcinoma has been reported and suggested previ-

From the Renal Unit, Surgery Department, Guy’s Hospital, London, United Kingdom. Received February 15, 2000; accepted in revised form May 26, 2000. Address reprint requests to David J.A. Goldsmith, FRCP, Consultant Nephrologist, Renal Unit, Guy’s Hospital, London SE1 9RT, United Kingdom. E-mail: David. [email protected] © 2000 by the National Kidney Foundation, Inc. 1523-6838/00/360-0030$3.00/0 doi:10.1053/ajkd.2000.17733

American Journal of Kidney Diseases, Vol 36, No 4 (October), 2000: E26

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JAYAWARDENE, OWEN, AND GOLDSMITH

Fig 1. Representative section from the parathyroid histology specimen showing invasion of the gland capsule and invasion into a blood vessel by parathyroid carcinoma cells. (H&E stain, original magnification ⴛ400.)

ously.6 In the context of chronic renal disease, some parathyroid hyperplasia is virtually ubiquitous; up to two thirds of long-term dialysis patients have needed surgical PTX to control renal bone disease.7 It is not known whether intensive control of hyperparathyroidism, or the prevention of more than mild hyperparathyroidism, would reduce the likelihood of subsequent parathyroid malignancy. This condition is so rare that any trial to examine this hypothesis is not possible. Where parathyroid nodular tissue from renal patients has been examined to establish whether

Fig 2. Representative section from the parathyroid histology specimen showing invasion of the gland capsule and invasion into a blood vessel by parathyroid carcinoma cells. (H&E stain, original magnification ⴛ400.)

the proliferating cells are monoclonal or polyclonal, there has been a very significant prevalence of monoclonally expanded parathyroid nodules.8 Several genetic alterations have been reported in parathyroid carcinoma, such as deletion of the retinoblastoma gene on chromosome 13.8 There have been 15 reports featuring a total of 17 cases (including this report) in which patients with chronic/end-stage renal failure have developed parathyroid carcinoma in their orthotopic parathyroid glands in the context of benign parathyroid hyperplasia nodularity.6,9-21 These are

PARATHYROID CARCINOMA IN A DIALYSIS PATIENT

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Fig 3. Representative section from the parathyroid histology specimen showing invasion of the gland capsule and invasion into a blood vessel by parathyroid carcinoma cells. (H&E stain, original magnification ⴛ400.)

summarized in Table 1. In a review by Miki et al,18 their tabulated case 11 taken from a paper by Ljutic et al22 on the effect of total PTX is the same case as subsequently published in full 5 years later by Boyle et al.6 This case is shown in our article as number 16 in Table 1, and our case under discussion in this article is shown as number 17. In 2 of these 17 cases, there was simultaneous occurrence of primary parathyroid carcinomata (synchronicity), which is otherwise only seen in the MEN syndromes. In the 17 patients reported, there is a very clear female predominance (13 female:4 male) despite there being more male patients on dialysis in most renal units (1.6:1 in our unit), and a 23:20 male:female gender ratio for surgical PTX.22 The reason for this gender imbalance for parathyroid carcinoma Table 1. Case Reference Year Age at diagnosis Gender Duration of dialysis (years) Increased Ca preoperatively Number of cancerous glands Metastases Status Follow-up

is unknown. The mean age of the chronic renal failure and sporadic cases is similar, but the age range for renal cases is broader, reflecting the fact that renal disease can occur at all ages (full age range, 34 to 75 years for renal; median age range, 44 to 55 years for sporadic cases). Although profound hypercalcemia is common in parathyroid malignancy, this is significantly tempered in dialysis patients with parathyroid malignancy; this presumably reflects hyperphosphatemia, dialytic induction of negative calcium fluxes, and possibly other less well-defined factors. Thus, five of the previously reported cases did not have preoperative hypercalcemia. Nonfunctional parathyroid carcinoma is exceptionally rare.2,3 The diagnosis of parathyroid carcinoma (in

Details of the 17 Published Cases of Renal Patients With Parathyroid Carcinoma

1 9 1982 62 F

2 10 1983 44 F

3 11 1985 34 M

4 12 1985 42 F

5 13 1989 64 F

6 14 1989 53 F

7 15 1990 46 M

8 15 1990 55 F

9 16 1990 46 F

10 16 1990 52 F

11 17 1995 46 F

12 18 1996 40 F

13 19 1996 64 M

14 20 1998 46 M

15 21 1999 55 F

16 6 1999 45 F

17 This case 2000 75 F

3

?

5

7

9

7

11

5

3

2

20

5

Pre-dial

8

13

Pre-dial

3

No

Yes

Yes

Yes

No

Yes

No

No

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

Yes

Two No Alive 5/12

One No Dead 17/12

One Lung Dead 84/12

One No Alive 12/12

Two No Alive 36/12

One No Alive 4/12

One No ? ?

One No ? ?

One No Alive 84/12

One No Alive 48/12

One Lung ? ?

One Lung Alive 115/12

One No Alive 12/12

One No ? ?

One No Alive 18/12

One No Dead 84/12

One No Alive 60/12

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the absence of metastases) must rest on the presence of at least two of three features: breach of the glandular capsule, abnormal mitoses, and invasion of surrounding tissues (eg, blood vessels, esophagus). This is crucial to the correct evaluation of the true frequency of this disease. It can be a difficult judgment to make, especially when the locally invasive behavior of autotransplanted, or fragmented, glands is taken into account. In Korzets et al’s23 excellent account, 5 of 19 gland fragments autotransplanted into the arm displayed invasive features on resection (also known as parathymatosis).23 This behavior and the frequency of recurrent glandular hyperactivity necessitating a further resection of parathyroid tissue if the patient remains on dialysis are compelling arguments for total PTX without autotransplantation.22 Surgical intervention with PTX was necessary in all cases; in most, the diagnosis of carcinoma was only reached after the operation when histology was reviewed. In 9 of the 17 renal cases, this was all that was necessary. In six cases, PTX with block dissection of the thyroid/neck was needed to remove all visibly invasive tumor. In two other cases, cervical lymph node excision was also performed. Survival in nonrenal parathyroid malignancy is very variable; 5-year survival rates are 44% to 69%, and the longest recorded survival in the literature is 33 years.2,3 In the renal cases, the longest recorded survival is 115 months,18 although self-evidently, dialysis is also a significant life-shortening influence. No patient has undergone renal transplantation. Local cervical recurrence is common, often requiring further debulking surgery to control the adverse metabolic features that often are the cause of death (eg, aggressive ectopic calcification-calciphylaxis24). Distant metastases (most commonly pulmonary) are rare and have a bad prognosis. Nonsurgical treatments are limited in their effectiveness and include systemic chemotherapy, biphosphonates, mithromycin, and most excitingly but very rarely to date, calcimimetic compounds25 and immunomodulation.26 Since the total PTX some 5 years ago, our patient’s biochemistry results show a slow progressive rise in PTH and calcium. As we have indicated, there is nothing to indicate tumor

JAYAWARDENE, OWEN, AND GOLDSMITH

recurrence or metastases, and these biochemical trends are just as compatible with hyperplasia of small glandular fragments left at the time of surgery.22 We present a case of parathyroid carcinoma in a dialysis patient, the second from our unit, and the oldest case so far reported in the renalassociated literature. For the first time, a fully comprehensive review of the literature is also presented. With the increased survival of patients on dialysis, it is possible to imagine that this very rare situation may become more common in time. The low but definite risk of local tissue invasion by, and malignant change in, these chronically overstimulated glands is a potential reason to avoid the surgical practice of total PTX with gland remnant autotransplantation.22,23,27,28 Whether better ways in which to normalize the calcium-phosphate and vitamin D-parathyroid axes in renal disease will prevent long-term parathyroid hyperplasia in most patients, and thereby reduce the chronic overactivity stimuli provoking the malignant change, is also unknown. REFERENCES 1. Armstrong HG: Primary carcinoma of the parathyroid gland with report of a case. Bull Acad Med Toronto 11:105110, 1938 2. Katz AD, Hopp D: Parathyroidectomy: Review of 338 consecutive cases for histology, location, and reoperation. Am J Surg 144:411-415, 1982 3. Hundahl SA, Fleming ID, Fremgen AM, Menck HR: Two hundred eighty-six cases of parathyroid carcinoma treated in the U.S. between 1985-1995: A National Cancer Data Base Report. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 86:538-544, 1999 4. Tominaga Y, Takagi H: Molecular genetics of hyperparathyroid disease. Curr Opin Nephrol Hypertens 5:336341, 1996 5. Cordeiro AC, Montenegro FL, Kulcsar MA, Dellanegra LA, Tavares MR, Michaluart P Jr, Ferraz AR: Parathyroid carcinoma. Am J Surg 175:52-55, 1998 6. Boyle NH, Ogg CS, Hartley RB, Owen WJ: Parathyroid carcinoma secondary to prolonged hyperplasia in chronic renal failure and in coeliac disease. Eur J Surg Oncol 25:100-103, 1999 7. Harris SA, Brown EA: Patients surviving more than 10 years on haemodialysis: The natural history of the complications of treatment. Nephrol Dial Transplant 13:1226-1233, 1998 8. Fukagawa M: Cell biology of parathyroid hyperplasia in uremia. Am J Med Sci 317:377-382, 1999 9. Berland Y, Olmer M, Lebreuil G, Grisoli J: Parathyroid carcinoma, adenoma and hyperplasia in a case of chronic

PARATHYROID CARCINOMA IN A DIALYSIS PATIENT

renal insufficiency on dialysis. Clin Nephrol 18:154-158, 1982 10. Anderson BJ, Samaan NA, Vassilopoulou-Sellin R, Ordonez NG, Hickey RC: Parathyroid carcinoma: Features and difficulties in diagnosis and management. Surgery 94: 906-915, 1983 11. Ireland JP, Fleming SJ, Levison DA, Cattell WR, Baker LR: Parathyroid carcinoma associated with chronic renal failure and previous radiotherapy to the neck. J Clin Pathol 38:1114-1118, 1985 12. Sherlock DJ, Newman J, Holl-Allen RT: Parathyroid carcinoma presenting as tertiary hyperparathyroidism. Postgrad Med J 61:243-244, 1985 13. Krishna GG, Mendez M, Levy B, Ritchie W, Marks A, Narins RG: Parathyroid carcinoma in a chronic hemodialysis patient. Nephron 52:194-195, 1989 14. Kodama M, Ikegami M, Imanishi M, Uemara T, Takada M, Kohri K, Kurita T: Parathyroid carcinoma in a case of chronic renal failure on dialysis. Urol Int 44:110-112, 1989 15. Iwamoto N, Yamazaki S, Fukuda T, Kondo M, Yamamoto N, Ono T, Hiratake Y, Yasui A: Two cases of parathyroid carcinoma in patients on long-term hemodialysis. Nephron 55:429-431, 1990 16. Rademaker P, Meijer S, Oosterhuis JW, Verney A, Zwiestra R, Vd Hem G, Geerlings W: Successful surgical treatment of parathyroid carcinoma in two haemodialysis patients. Nephrol Dial Transplant 5:545-548, 1990 17. Tominaga Y, Numano M, Uchida K, Sato K, Asano H, Haba T, Katayama A, Mukoyama A, Suzuki K, Tanaka Y: Lung metastasis from parathyroid carcinoma causing recurrent renal hyperparathyroidism in a hemodialysis patient: Report of a case. Surg Today 25:984-986, 1995 18. Miki H, Sumitomo M, Inoue H, Kita S, Monden Y: Parathyroid carcinoma in patients with chronic renal failure on maintenance hemodialysis. Surgery 120:897-901, 1996 19. Liou MJ, Lin JD, Huang MJ, Hyang JY, Hsueh C,

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Jeng LB: Parathyroid carcinoma with postoperative prolonged hypocalcemia in a patient with chronic renal failure. J Formos Med Assoc 95:337-341, 1996 20. Djema AI, Mahmoud MD, Collin P, Heymann MF: [Tertiary hyperparathyroidism: Parathyroid cancer with liver metastases in a hemodialyzed patient]. Nephrologie 19:121123, 1998 21. Takami H, Kameyama K, Nagakubo I: Parathyroid carcinoma in a patient receiving long-term hemodialysis. Surgery 125:239-240, 1999 22. Ljutic D, Cameron JS, Ogg CS, Turner C, Hicks JA, Owen WJ: Long-term follow-up after total parathyroidectomy without parathyroid reimplantation in chronic renal failure. Q J Med 87:685-692, 1994 23. Korzets Z, Magen H, Kraus L, Bernheim J, Bernheim J: Total parathyroidectomy with autotransplantation in hemodialysed patients with secondary hyperparathyroidism: Should it be abandoned? Nephrol Dial Transplant 2:341346, 1987 24. Fischer AH, Morris DJ: Pathogenesis of calciphylaxis: Study of three cases with literature review. Hum Pathol 26:1055-1064, 1995 25. Collins MT, Skarulis MC, Bilezikian JP, Silverberg SJ, Spiegel AM, Marx SJ: Treatment of hypercalcemia secondary to parathyroid carcinoma with a novel calcimimetic agent [see comments]. J Clin Endocrinol Metab 83: 1083-1088, 1998 26. Stevenson GT: Immunotherapy of non-metastatic complication of malignant disease. Lancet 353:340-340,1999 27. Ellis HA: Fate of long-term parathyroid autografts in patients with chronic renal failure treated by parathyroidectomy: A histopathological study of autografts, parathyroid glands, and bone. Histopathology 13:289-309, 1988 28. McKeown PP, McGarity WC, Sewell CW: Carcinoma of the parathyroid gland: Is it overdiagnosed? A report of three cases. Am J Surg 147:292-298, 1984