QJM Advance Access originally published online on February 12, 2008
QJM 2008 101(4):329-330; doi:10.1093/qjmed/hcn010
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Humoral hypercalcaemia of benignancy. A case report
Diabetes Unit, St Richards Hospital
Spitalfield Lane, Chichester
PO19 6SE, UK
email: roselle.herring1{at}btinternet.com
Sir,
Humoral hypercalcaemia of benignancy is characterized by a benign tumour producing hypercalcaemia induced by parathyroid hormone related protein (PTHrP). This condition is rare. Five previous cases have been reported in English, an ovarian dermoid cysts, mammary hyperplasia1 two cases related with uterine leiomyoma,2 and one with phaeochromocytoma.3 A possible association with an intestinal leiomyomyoma has also been reported. We present a case of PTHrP secreting benign uterine leiomyoma. Association was confirmed by normalization of calcium levels after tumour resection.
Hypercalcaemia associated with malignancy is common, but is rarely associated with benign conditions. Hypercalcaemia of malignancy could be due to osteolytic metastasis or humoral, mediated by PTHrP. Tumours of lung, breast, prostate and some haematological malignancies are commonly associated with PTHrP-mediated hypercalcaemia.
Benign tumours arising from endocrine tissues can often secrete hormones that cause their characteristic presentation. Benign tumours of non-endocrine tissues producing functionally relevant hormones are rare, but there are limited reports PTHrP produced in benign tumours. Our case adds to this limited number of reports available in the English.
A 49-year-old pre-menopausal female presented to her general practitioner with lethargy. She was a school teacher, non-smoker and had two teenaged children. Her previous medical history included bronchial asthma and chronic eosinophilic pneumonitis. Regular medication consisted of a Seretide 100 Accuhaler (Fluticasone propionate 100 mcg and salmeterol 50 mcg). She was not taking any oral medication.
Blood tests revealed significantly raised calcium (3.37 mmol/l, range 2.1–2.6), with suppressed PTH (3.0 pg/ml, range 7.0–54.0) Alkaline phosphatase was normal (68 iu/l, range 25–120), 25 OH Vitamin D (36 nmol/l, range 15–100 nmol/l), urea was 4.3 mmol/l (range 2.5–6.5) with a creatinine of 90 umol/l (range 60–90) and 24 h urine calcium ratio was 4.6 mmol/l. Alkaline phosphate iso-enzyme was not measured. Ca 125, CA 19-9 and CEA were normal. Chest radiograph was reported as normal. Serum ACE was normal and a bone scan did not show any focal uptake. Ultrasound scan of abdomen and pelvis showed a large uterine fibroid. This was not previously known and was further defined on a CT scan. CT of Thorax, abdomen and pelvis confirmed no abnormalities in the chest or upper abdomen. There was a heterogenous enhancing mass in the lower pelvis measuring 7.5 x 6.4 x 5.3 cm3. No nodes were identified in the pelvis. The parathyroid gland was not imaged.
Whilst awaiting further investigations, hypercalcaemia was treated with intravenous zolodronate, which produced a prompt but short-lived reduction in serum calcium (Figure 1).
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Plasma PTHrP was elevated 4.6 pmol/l (<1.8 pmol/l). During this time she developed a microcytic anaemia, which coincided with the development of menorrhagia. Ferrous sulphate and folate were commenced.
In the absence of a clear focus of origin for PTHrP elsewhere, it was felt the uterine fibroid may be responsible for producing the peptide. Along with it the menorrhagia led to a total abdominal hysterectomy with bilateral salpingo-ooporectomy. Histology confirmed a smooth muscle tumour of uncertain malignant potential. Careful examination of tumour margins did not reveal any infiltration. Histological PTHrP was positive (measured at John Radcliff Hospital).
Following surgery serum calcium levels normalized within 2 weeks and remained normal for 6 months.
Parathyroid-related protein PTHrP was first isolated in 1988. It is encoded by a single gene and secreted in small amounts from a diverse number of cells, especially of squamous origin. It has autocrine and paracrine actions. It shares the same N-terminal end as parathyroid hormone and therefore can bind to the same receptor (the type I PTH receptor). However, it can also bind to other unique receptors leading to its diversity. Experiments using genetically altered mice have shown physiological effects of PTHrP with cartilage and bone development, smooth muscle functioning, placental transfer of calcium and mammary gland development. The relationship with calcium metabolism was clearly demonstrated during medical and surgical treatment of benign phaeochromocytomas. The authors showed concomitant changes in calcium metabolism and serum PTHrP levels.4
PTHrP has been identified in normal tissue of the reproductive tract. It is thought to be important during late pregnancy and lactation. The exact function is unknown but it has been postulated that it may cause vasodilatation and smooth muscle relaxation and may be involved in the rhythmicity of myometrial contractions before parturition.5
The commonest tumour of the female genital tract is the benign leiomyoma. Oestrogen and progesterone are known to play a role in their growth and they commonly present in later reproductive life around the time of menopause. Symptoms include menorrhagia, abdominal pain and infertility. Uterine leiomyomas may express PTHrP gene and can cause humoral hypercalcaemia. Therefore, PTHrP secretion from a uterine fibroid should be considered in women presenting with hypercalcaemia and suppressed PTH.
It is difficult to predict the behaviour in leiomyomas of uncertain malignant potential. Experience is relatively limited and thus criteria for malignancy are not well-established. Overall, 12–40% of epithelioid smooth muscle tumours have been reported to eventually demonstrate malignant behaviour. Features associated with malignancy include significant nuclear atypia and a mitotic rate above 3–4 per 10 HPFs.
References
1. Khosla S, van Heerden JA, Gharib H, Jackson IT, Danks J, Hayman JA, et al. Parathyroid hormone related protein and hypercalcaemia secondary to massive mammary hyperplasia. N Engl J Med (1990) 322:1157.[Web of Science][Medline]
2. Ravakhah K, Gover A, Mukunda BN. Humoral hypercalcaemia associated with uterine fibroid. Ann Intern Med (1999) 130:702.
3. Kimura S, Nishimura Y, Yamaguchi K, Shmada K, Uchida H. A case of pheochromocytoma producing parathyroid hormone related protein and presenting with hypercalcaemia. J Clin Endocrinol Metab (1990) 70:1559–63.
4. Mune T, Katakami H, Kato Y, Keigo Y, Matsukura S, Miura K. Production and secretion of parathyroid hormone related protein in phaeochromocytoma: participation of an alpha adrenergic mechanism. J Clin Endocrinol Metab (1993) 76:757–62.[Abstract]
5. Weir EC, Goad DL, Daifotis AG, Burtis WJ, Dreyer BE, Nowak RA. Relative overexpression of the parathyroid hormone related protein gene in human leiomyomas. J Clin Endocrinol Metab (1994) 78:784–89.[Abstract]
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