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Journal of Cancer Research and Therapeutics, Vol. 5, No. 1, January-March, 2009, pp. 46-48 Case Report Hypercalcemia and treated breast cancers: The diagnostic dilemma Rao Vishal, Chaukar Devendra, D'Cruz AnilK Depatment of Head and Neck Surgery, Tata Memorial Hospital, Dr. Ernest Borges Road, Parel, Mumbai - 400 012, India. Code Number: cr09011 Abstract The relationship of hypercalcemia with cancer is well described in the literature. Breast cancer is the commonest malignancy associated with hypercalcemia; the detection of hypercalcemia in these patients usually signifies metastatic disease and is associated with a poor prognosis. However, the treating oncologist should keep in mind that a strong correlation exists between breast cancer and primary hyperparathyroidism. We present a case of a patient of treated breast cancer who, in the absence of metastatic bone disease, developed hypercalcemia due to hyperparathyroidism secondary to a parathyroid adenoma.Keywords: Breast cancer, hypercalcemia, differential diagnosis Introduction Breast cancer is the leading cancer in women and the second leading cause of cancer-related deaths across the world. [1] There has been an alarming increase in the incidence of breast cancers the world over, including in India. Hypercalcemia is known to occur in up to 20-30% of the patients with cancer at some point during the course of their illness. [2] Breast cancer is one of the malignancies most commonly associated with hypercalcemia. The detection of hypercalcemia in a patient with cancer generally signifies poor prognosis, primarily because the presence of hypercalcemia usually indicates skeletal metastasis. However, there is also a strong correlation between breast cancer and hyperparathyroidism (HPT) and the treating clinician must always keep this in mind. [3],[4] In breast cancer patients who have hypercalcemia in the absence of skeletal metastasis, an increased incidence of primary hyperparathyroidism has been found, which has been attributed to the presence of parathyroid adenomas. These cases have shown a better prognosis. [3] Breast cancer and hyperparathyroidism share several common characteristics, which has led to the postulation of common etiological pathways. However, the exact pathogenesis and the relationship between breast cancers and hyperparathyroidism still remains obscure. Here, we present a case of treated breast cancer who developed hypercalcemia and was subsequently diagnosed with a parathyroid adenoma. We also review the relevant literature.Case Report This 67-year-old postmenopausal lady presented to the breast services at our institute with a nonhealing ulcer over the left breast. Biopsy revealed an intraductal grade III carcinoma. She was treated with neoadjuvant chemotherapy (cyclophosphomide, epirubucin, and 5-flurouracil x 3 cycles), followed by mastectomy and axillary clearance. Following surgery, she received an additional three cycles of chemotherapy. This was followed by radiotherapy, with a total dose of 45 Gy delivered over 20 fractions to the breast and periglandular area. Six months after completion of treatment she developed pedal edema and breathlessness of sudden onset. Investigations suggested a diagnosis of congestive cardiac failure, possibly due to cardiotoxicity following chemotherapy. She was admitted to the intensive care unit (ICU) for further management. After discharge from the ICU, repeat biochemical investigations were normal except for persistently raised serum calcium levels (12.5 mg/dl). Consultation was sought with the endocrinologist in view of the persistent hypercalcemia. A complete workup was undertaken. Serum albumin and serum phosphorus were within normal limits. The renal function tests and serum vitamin D were within the normal range. Bone scan revealed no evidence of skeletal metastasis. The patient was largely asymptomatic, except for a few vague nonspecific complaints like bone pain and lethargy. In view of the persisting hypercalcemia, the serum parathormone (PTH) level was measured and was found to be markedly raised (880 pg/dl). Ultrasonography of the neck showed a left inferior parathyroid lesion that was suggestive of an adenoma. In view of the presence of congestive cardiac failure, the patient was operated upon under cervical block anesthesia. A left parathyroid adenoma measuring 3 x 2 cm was excised via a transcervical approach. The serum calcium showed an immediate decline, with serum calcium being within normal limits on postoperative day 1. The patient was followed up regularly and serum calcium measured after one month was normal. She remained asymptomatic for 3 months postoperatively but was then brought to the hospital with complaints of acute disorientation and drowsiness. She was diagnosed to have brain metastases and succumbed to the disease soon after. Discussion Hypercalcemia associated with cancer has been attributed to four causes: a) local osteolytic hypercalcemia; b) humoral hypercalcemia of malignancy (HHM) due to systemic secretion of parathyroid hormone (PTH)-related protein (PTHrP) by the tumor; c) secretion of an enzyme (by lymphomas) that converts 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D, leading to increased calcium absorption; and d) ectopic secretion of PTH. [1] Recently, radiation exposure has also shown to be an important risk factor for developing hypercalcemia due to HPT. [5] Breast cancers are one of the most common malignancies to be associated with hypercalcemia. Most often the hypercalcemia is due to osteolytic metastases and hence portends a bad prognosis. [6],[7] However a significant number of the patients with breast cancers (up to 15%) show hypercalcemia in the absence of metastasis. [3] It is of considerable importance to note that this subset of patients with hypercalcemia due to primary hyperparathyroidism show a better prognosis. [8] Fierabracci et al . found a 7% incidence of primary HPT in patients with treated breast cancers. [9] Recent data suggests a strong correlation between breast cancer and hyperparathyroidism. Although the exact pathogenesis is not clear, it has been attributed to the possibility of a common etiological pathway shared by the two conditions; this hypothesis is supported by the fact that a) both conditions affect older women, b) both conditions are associated with ionizing radiation, and c) both conditions have steadily increased over the last four decades. [4] However, the debate on the exact relationship between hyperparathyroidism and breast cancers continues. Controversy still exists on whether the presence of one condition puts the patient at risk of developing the other. Various factors have been postulated that predispose breast cancer patients to hypercalcemia; among these possible causative factors are drug-induced hypercalcemia from drugs such as salmon calcitonin, [10] tamoxifen, [11] and danazol; [12] pseudohyperparathyroidism; [13] familial hypocalciuric hypercalcemia; [7] HHM; primary HPT due to adenoma; and osteolytic bone metastasis. Breast cancer patients without bony metastasis who present with hypercalcemia due to primary HPT must always be evaluated by the physician as the treatment of HPT is very rewarding. PTH estimation shows markedly high values in these patients, which is suggestive of a parathyroid adenoma and this can be further confirmed by performing localization studies. Therefore, when evaluating cancer patients presenting with hypercalcemia, in addition to cancer-related mechanisms other causes unrelated to the cancer should also be considered, such as primary hyperparathyroidism, use of thiazide diuretic drugs, granulomatous diseases, etc. [2] PTH assay should be the first-line investigation and should be measured routinely in all cases of hypercalcemia, along with the calcium profile, to establish a diagnosis of HPT. This is a vital step in the workup of these patients, as most cancer-related syndromes have a normal PTH levels, making the diagnosis of HPT improbable. Most patients with HHM have increased levels of circulating PTHrP and the diagnosis is usually obvious on clinical grounds. [2] Routine estimation of PTHrP can therefore be avoided, reserving it for cases in which the cause of hypercalcemia is obscure. Plasma 1,25-(OH)2D should be measured when sarcoidosis, other granulomatous disorders, or the 1,25-(OH)2D lymphoma syndrome is considered in the differential diagnosis. [2] The role of bone scan is mainly in the assessment of skeletal metastasis in patients with hypercalcemia. Although hypercalcemia is common in patients with metastatic breast cancer, the absence of metastasis and the presence of an increased PTH level should warrant a through workup to rule out primary HPT due to a parathyroid adenoma. The treating clinicians (including the medical and surgical oncologist) should keep this possibility in mind and, when following up breast cancer patients, they should pay particular attention to serum calcium, specifically screening for calcium levels if necessary In breast cancer patients with hypercalcemia, but without evidence of metastasis, primary HPT due to a parathyroid adenoma should be ruled out. References
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