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Pathological Case of the Month
Lisa M. Schweiger, MD;
Helen Y. Hsiang, MD
From the Department of Pediatrics, University of Florida College of Medicine, Gainesville, and Sacred Heart Children's Hospital, Pensacola, Fla (Dr Schweiger); and the Division of Pediatric Endocrinology, Nemours Children's Clinic, Pensacola (Dr Hsiang). Dr Schweiger is now in private practice in San Diego, Calif.
Arch Pediatr Adolesc Med. 2002;156:83-84.
A PREVIOUSLY healthy 13-year-old girl had nausea, vomiting, fatigue, weakness, and a 1.13-kg weight loss over 1 week without fever or diarrhea. Menarche was at 12 years of age, and she had regular periods.
The patient was admitted to the hospital with a diagnosis of acute gastritis and dehydration. She was afebrile, normotensive, mildly dehydrated, and in no distress. Her sexual maturation was Tanner stage IV. Pelvic examination was deferred initially, and the remaining physical examination results were normal. Results of initial laboratory tests were normal except for a total serum calcium level of 14.1 mg/dL, an ionized calcium level of 7.46 mg/dL (reference range, 4.60-5.30 mg/dL), and a serum phosphorus concentration of 2.2 mg/dL. The urine calcium/creatinine ratio was elevated at 0.53 (reference range, 0.05-0.25), and the result of a pregnancy test was negative. A technetium Tc-99m sestamibi scan showed no evidence of parathyroid adenoma or ectopic parathyroid. A thyroid function test, electrocardiogram, and an abdominal radiograph were all normal. The patient responded well to therapy for symptomatic control of hypercalcemia (ie, intravenous fluids, potassium phosphate, furosemide, calcitonin, and pamidronate). The total serum calcium level fell to 9.6 mg/dL.
The patient's serum parathyroid hormone (intact) level was low (<10 pg/mL) when total calcium was 13.4 mg/dL. The parathyroid hormone–related protein level was elevated at 45.5 pg/mL (reference level, <12.9 pg/mL), and 1,25-dihydroxyvitamin D was slightly elevated at 110 pg/mL (reference range, 15-90 pg/mL). A right lower pelvic mass was found on pelvic examination. Pelvic ultrasound examination found a 15 x 10 x 10 cm solid/cystic mass involving the right ovary. A 15 x 12 x 12 cm (865 g) solid right adnexal mass was found on laparotomy (Figure 1). Frozen sections were highly suspicious for malignancy. The patient underwent a right salpingo-oophorectomy, pelvic and periaortic lymphadenectomy, omentectomy, multiple peritoneal biopsies, and a left ovarian biopsy. The pathologist reported stage IA small-cell carcinoma of the ovary (Figure 2), and specimens stained positive for parathyroid hormone–related protein (1.96 pmol per gram of tissue). All nodes, omentum, peritoneum, and pelvic fluid were negative for parathyroid hormone–related protein. The left ovarian biopsy revealed a benign stromal cortical nodule. The patient developed transient hypocalcemia postoperatively, which was corrected by calcium supplement for a brief period.
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Figure 1.
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Figure 2.
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At follow-up 10 months later, the patient had completed 6 cycles of chemotherapy with paclitaxel, carboplatin, and oral etoposide without any evidence of recurrence. Serum calcium concentrations were followed as a tumor marker and remained at 8.9 to 9.4 mg/dL. Cancer antigen 125 and alkaline phosphatase levels were normal. Pelvic ultrasound examinations showed no recurrence.
At 13 months' follow-up, the patient had recurrence of hypercalcemia (serum calcium level, 11 mg/dL). A laparotomy showed recurrent small cell carcinoma involving the left ovary, left fallopian tube, rectosigmoid surface, bladder, peritoneum, and abdominal wall. The patient underwent a left salpingo-oophorectomy, hysterectomy, and tumor debulking with no residual tumor visible. She resumed chemotherapy with ifosfamide and topotecan hydrochloride without success. The patient died 36 months after the initial diagnosis.
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Denouement and Discussion: Acute Symptomatic Hypercalcemia Associated With Ovarian Small Cell Carcinoma
Figure 1. A 15 x 12 x 12 cm (865 g) solid, tan-gray, hemorrhagic right ovarian mass with cystic degeneration removed from a 13-year-old girl with symptoms of hypercalcemia.
Figure 2. Small cell carcinoma of the ovary showing characteristic sheets of small round cells, frequent mitoses, and folliclelike structures.
Childhood hypercalcemia is usually chronic and asymptomatic. We described an adolescent girl with sudden onset of symptomatic hypercalcemia associated with ovarian small cell carcinoma.
The signs and symptoms of hypercalcemia1-2 include nausea, vomiting, polyuria, polydipsia, dehydration, anorexia, and constipation. As calcium levels continue to rise, there may be altered consciousness, weakness, paresthesias, decreased QT interval, hypertension, and even paralysis. Most of the early signs and symptoms are nonspecific. Therefore, the diagnosis is easily confused with more common pediatric problems.
The differential diagnoses of hypercalcemia in children and adolescents1-3 include primary hyperparathyroidism, hypervitaminosis D, familial hypocalciuric hypercalcemia, immobilization, neoplasia, and sarcoidosis. In addition, drugs (eg, thiazides, lithium carbonate, vitamin A analogues, alkalies), hyperthyroidism, or renal failure must be considered.
Although rare, the possibility of malignancy-related hypercalcemia in children1-2 should also be considered. Tumors may increase serum calcium via osseous metastases, increased production of 1,25-dihydroxyvitamin D, or production of parathyroid hormone–related protein, which acts like parathyroid hormone to increase bone resorption and renal conservation of calcium.1-2,4-5 Lymphomas or leukemia may be associated with hypercalcemia in children. Small cell carcinoma of the ovary is an extraordinarily rare tumor, typically occurring in the second to fourth decades of life and often presenting with hypercalcemia.6-7
First described in 1982, small cell carcinoma of the ovary has been reported in females aged 7 to 43 years.6 In a review of 150 patients, 60% to 70% had preoperative hypercalcemia that was asymptomatic in all but 4 patients. One patient even underwent neck exploration with negative results before the ovarian tumor was discovered. Symptoms and signs on presentation included abdominal swelling, discomfort, menstrual irregularity, or an asymptomatic pelvic mass. The small cell carcinoma of the ovary was unilateral in 99% of patients, but half already had evidence of metastases. The tumors were large (average size, 15.3 cm), nodular, solid, tan-gray, and might have had areas of hemorrhage, necrosis, or cystic degeneration. Microscopically, tumor cells were usually small with round nuclei, scanty cytoplasm, and frequent mitoses. The cells typically grew in diffuse sheets that were frequently separated by folliclelike structures, and they often stained positive for parathyroid hormone–related protein.6, 8 The conventional treatment was surgery. Many combinations of chemotherapy and radiotherapy had been attempted with variable results.6-7 In patients with stage IA disease (confined to 1 ovary, not through the capsule), one third remained disease free for 1 to 13 years after surgery, one half died within 2 years, and the remainder had recurrences. Almost all tumors above stage IA were fatal. Factors associated with a more favorable prognosis for stage IA tumors include an age of 30 years or older, normal preoperative calcium levels, tumor size less than 10 cm, and the absence of large cells.
In summary, small cell carcinomas of the ovary occur in young women and are associated with hypercalcemia and a high degree of malignancy. The pelvis should be investigated in every young woman with unexplained hypercalcemia to avoid overlooking an ovarian tumor.
AUTHOR INFORMATION
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Accepted for publication September 15, 1999.
We thank Edward C. Kohaut, MD, Nemours Children's Clinic, Pensacola, Fla, and Franklin Abbott, MD (Department of Radiology), William R. Bell, Jr, MD, and Everett Havard, MD (Department of Pathology), Sacred Heart Hospital, Pensacola, for their kind and expedient assistance.
Reprints: Helen Y. Hsiang, MD, 5153 N Ninth Ave, Pensacola, FL 32504 (e-mail: hhsiang{at}nemours.org).
REFERENCES
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1. Rudolph AM, Hoffman JIE, Rudolph CD. Hypercalcemia. In: Rudolph's Pediatrics. 20th ed. Stamford, Conn: Appleton & Lange; 1996:1884-1847.
2. Aurbach GD, Marx SJ, Spiegel AM. Hypercalcemia. In: Wilson JD, Foster DW, eds. William's Textbook of Endocrinology. 8th ed. Philadelphia, Pa: WB Saunders Co; 1992:1445-1456.
3. DiGeorge AM. Hyperparathyroidism. In: Behrman RE, Kliegman RM, Arvin AM, eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, Pa: WB Saunders Co; 1996:1609-1611.
4. Grill V, Rankin W, Martin TJ. Parathyroid hormone–related protein (PTHrP) and hypercalcemia. Eur J Cancer. 1998;34:222-229.
5. Matias-Guiu X, Prat J, Young R, et al. Human parathyroid hormone–related protein in ovarian small-cell carcinoma: an immunohistochemical study. Cancer. 1994;73:1878-1881.
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6. Young RH, Oliva E, Scully RE. Small-cell carcinoma of the ovary, hypercalcemic type: a clinicopathological analysis of 150 cases. Am J Surg Pathol. 1994;18:1102-1116.
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7. Scully RE. Small-cell carcinoma of hypercalcemic type. Int J Gynecol Pathol. 1993;12:148-152.
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8. Scully RE, ed, Young RH, ed, Clement PB, ed. General features of ovarian tumors; miscellaneous primary tumors. In: Tumors of the Ovary, Maldeveloped Gonads, Fallopian Tube, and Broad Ligament. Washington, DC: Armed Forces Institute of Pathology; 1998. Atlas of Tumor Pathology; 3rd ser, pt 23:27-50; 316-320.
SECTION EDITOR: ENID GILBERT-BARNESS, MD
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