Hypercalcemia

Small cell carcinoma of the ovary is a rare malignant tumor of the ovary. It is the most common undifferentiated ovarian carcinoma in young women. Approximately two thirds of patients with ovarian small cell carcinoma have hypercalcemia. The mechanism of development of hypercalcemia is unclear, although parathyroid hormone-related protein has been found in some of the cases. Parathormone expression in tumor cells, rarely reported, was seen in this case, suggesting that ectopic parathyroid hormone production by the tumor cells may be the cause of hypercalcemia.

(Arch Pathol Lab Med. 2005;129:531-533)

Small cell carcinoma of the hypercalcemic type is a rare malignant tumor of the ovary. It is the most common form of undifferentiated ovarian carcinoma in young women younger than 40 years of age. Since the first case report by Dickersin et al1 in 1982, several cases have been reported.2-9 In one large series, most of the patients presented with a unilateral tumor and nonspecific clinical manifestations such as abdominal pain and swelling, pelvic pain, or mass.2 Approximately 66% of patients in this series presented with hypercalcemia, and its associated manifestations included fatigue, lethargy, polydypsia, and polyuria.2 The mechanism of development of hypercalcemia associated with this tumor is not clear. Some studies have documented serologically the presence of parathyroid hormone (PTH)-related protein (PTHrp), but the ectopic production of PTH is rarely reported.7-10 Small cell carcinoma is characterized histologically by sheets of closely packed small tumor cells, with scattered follicle-like structures in approximately 80% of the cases.2 The prognosis of small cell carcinoma of ovary is poor, even if diagnosed in the early stage. Patients with stage I disease have an average survival of 5.7 years.2 Currently, bilateral salpingo-oophorectomy with hysterectomy is the standard treatment in the early-stage patients.11 For the higher stage or recurrent tumor, chemotherapy, radiotherapy, or both may improve survival.2

REPORT OF A CASE

The University of Texas Medical Branch's Surgical Pathology Database from 1993 to 2003 was used to identify 2 patients with the diagnosis of small cell carcinoma of ovary. We report the case of one patient who had symptomatic hypercalcemia as a presenting manifestation of her cancer. A 37-year-old white woman, gravida 2, para 1, presented with a 3-week history of nausea, vomiting, and abdominal pain. Physical examination revealed a soft abdomen, with tenderness and fullness in the right lower quadrant. Pelvic examination revealed a 6- to 8-week-sized uterus and a right adnexal mass. Pelvic ultrasound and computed tomographic scan of the abdomen and pelvis confirmed the presence of a complex adnexal mass arising from the right ovary, measuring 14 × 12 × 9 cm. There was no radiographie evidence of metastatic disease. Electrolytes were all within normal limits except for an elevated serum calcium level of 13 mg/dL. The patient underwent exploratory laparotomy with total abdominal hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic and para-aortic lymph node dissection, and omentectomy. Preoperatively, the serum CA 125 level was 73.4 U/mL. The resected right ovarian mass measured 11.0 cm in maximum dimension and weighed 510 g. Grossly, the tumor had a tan-white to redbrown, lobulated external surface and solid and cystic areas with focal necrosis and hemorrhage on cut surface (Figure 1, A). Representative sections of the tumor were fixed in formalin, embedded in paraffin, sectioned serially at 4 µm, and stained with hematoxylin-eosin. Immunohistochemical stains were performed on selected sections. Cytogenetic analysis of the tumor was also performed. The patient was diagnosed with stage IC disease because of the presence of peritoneal washings positive for carcinoma. Intraoperatively, there was also rupture of the tumor capsule. At the conclusion of surgery, there was no visible evidence of metastasis.

Microscopically, the tumor showed closely packed, small, monomorphic, round to oval cells with hyperchromatic nuclei, small nucleoli, high nuclear-cytoplasmic ratio, numerous mitoses, and pseudofollicles filled with periodic acid-Schiff-positive eosinophilic material (Figure 1, B and C). Immunohistochemical stains showed strong and diffuse staining of tumor cells with antibodies to CD15 and vimentin and focal staining with cytokeratin AE1/3, epithelial membrane antigen, CD30, and synaptophysin (Figure 1, D). In addition, approximately 30% of tumor cells were stained with antibody to PTH (Figure 1, E), and 5% of tumor cells stained with c-Kit (CD117) (photo not shown). Cytogenetic analysis of the tumor showed a normal female karyotype, 46,XX. A diagnosis of stage IC small cell carcinoma of hypercalcemic type was rendered. The patient's serum calcium decreased to normal after surgery (Figure 2). The patient did not have an elevated PTHrp level during her hospitalization. Her serum PTH level was normal prior to surgery, surged postoperatively, then dropped to the normal range almost immediately (Figure 2). After optimal cytoreductive surgery, the patient received adjuvant chemotherapy with 6 cycles of paclitaxel and carboplatin. Subsequently, she completed another 6 cycles of consolidation single-agent paclitaxel chemotherapy. She is without evidence of disease at 27 months from initial diagnosis.

COMMENT

Ovarian small cell carcinoma of the hypercalcemic type, a rare malignant tumor of ovary, was first reported in 1982.1 It is the most common undifferentiated ovarian carcinoma in young women younger than 40 years of age, with an average age at presentation of 24 years.2 Fewer than 200 cases have been reported in the literature.2-9 Although approximately 66% of the patients presented with hypercalcemia in one large series, however, parathormone expression was rarely seen. In our study, parathormone expression in tumor cells was demonstrated using immunohistochemistry. Although the serum PTH level did not correlate with the serum calcium level prior to surgery, a significant, brief surge of the PTH level was seen immediately after surgery. This increase may have been caused by PTH release from the tumor cells during surgical manipulation. On the other hand, the patient's PTHrp was never elevated. This finding does not support the PTHrp-mediated calcium release from the bone in this case.

As one of the paraneoplastic disorders, the humoral hypercalcemia of malignancy presents in a variety of cancers, for example, squamous cell carcinoma of lung, adenocarcinoma of gastrointestinal tract, and small cell carcinoma of ovary. Hypercalcemia is reportedly caused by a circulating factor that mediates calcium release from bone. Most studies have demonstrated that PTHrp secreted by tumor cells acting through PTH receptor mediates the calcium release.5,11,12,13 Recently, Tsunematsu et al6 reported PTHrp mRNA expression in tumor cells. Thus, the common belief is that PTHrp plays an important role in the development of hypercalcemia. Some investigators have suggested that PTHrp can be used as a clinical marker of hypercalcemia, in addition to serum calcium level.5 However, not all cases of small cell carcinoma of ovary, hypercalcemic type, have evidence of elevated serum PTHrp or expression of tumor PTHrp, as was seen in our case. In such cases, ectopic hormone production may be one of the considerations. A review of literature indicates that there are only 4 reports of ectopic production of PTH of ovarian tumors.7-10 These reports documented ectopic parathormone production by gene rearrangement or immunohistochemistry.

In our case, there was no elevation of serum PTHrp, but approximately 30% of tumor cells expressed PTH by immunohistochemical stain (Figure 1, E). However, there was no correlation seen among immunoexpression, serum levels of parathormone, and calcium prior to surgery in our case. The sharp, brief surge of the serum PTH level seen immediately after surgery may be explained by tumor release of PTH during surgical manipulation (Figure 2). Therefore, we postulate that ectopic production of PTH was the cause of this patient's hypercalcemia.

The histogenesis of small cell carcinoma of ovary is unknown. The tumor cells cannot be subtyped as surface epithelial, germ cell, sex-cord, or neuroendocrine cells.14 An animal model used to investigate the histogenesis did not find a histogenetic relationship with either the germ cell tumor or epithelial tumor of ovary.15 In terms of oncogenesis, approximately 80% of small cell carcinomas of ovary overexpress p53 protein, suggesting that a p53 mutation may be an underlying cause.3 In our case, approximately 30% of tumor cells expressed p53 by immunohistochemistry (photo not shown). Similar to other malignancies, in ovarian small cell carcinoma, overexpression of p53 may not explain entirely the origin of tumorigenesis, and further investigation is needed.

In summary, we report a case of small cell carcinoma of ovary with hypercalcemia and intratumoral ectopic PTH expression. Small cell carcinoma of ovary has a poor prognosis, with the most important prognostic factor being the stage at the time of diagnosis.2 More than 50% of stage IA patients die within 2 years, and 33% have an average 6-year disease-free survival.2 Among the stage IA group, patients with tumor size less than 10 cm have a better prognosis, compared with those with larger tumors.1 Therapy is primarily surgical, with adjuvant treatment reserved for advanced-stage disease.

References

1. Dickersin GR, Klinc IW, Scully RE. Small cell carcinoma of the ovary with hypercalcemia: a report of eleven cases. Cancer. 1982;49:188-197.

2. Young R, Oliva E, Scully RE. Small cell carcinoma of the ovary, hypercalcemic type: a clinicopathological analysis of 150 cases. Am I Surg Pathol. 1994; 18:1102-1116.

3. Seidman J. Small cell carcinoma of the ovary of the hypercalcemic type: p53 protein accumulation and clinicopathologic features. Cynecot Oncol. 1995; 59:283-287.

4. Matias-Guiu X, Prat J, Young RH, et al. Human parathyroid hormone-related protein in ovarian small cell carcinoma: an immunohistochemical study. Cancer. 1994:73:1878-1881.

5. Nagasaki K, Otsubo K, Kajimura N, et al. Circulating parathyroid hormone-related protein (109-141) in malignancy-associated hypercalcemia. lpn J Clin Oncol. 1996:26:6-11.

6. Tsunematsu T, Saito T, lguchi H, Fukuda T, Tsukamoto N. Hypercalcemia due to parathyroid hormone-related protein produced by primary ovarian clear cell adenocarcinoma: case report. Gynecol Oncol. 2000;76:218-222.

7. Nussbaum SR, Gaz RD, Arnold A. Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone. N Engl I Med. 1990;323:1 324-1328.

8. Abeler V, Kjorstad KE, Nesland JM. Small cell carcinoma of the ovary: a report of 6 cases, /ni/ Gynecol Pathol. 1988;7:31 5-329.

9. Aguirre P, Thor AD, Scully RE. Ovarian small cell carcinoma: histogenetic considerations based on immunohistochemical and other findings: ovarian small cell carcinoma. Am I Clin Pathol. 1989:92:140-149.

10. Holtz G, lohnson TR Jr, Schrock ME. Paraneoplastic hypercalcemia in ovarian tumors. Obstet Gynecol. 1979:54:483-487.

11. Fletcher CM. Diagnostic Histopathology of Tumors. 2nd ed. New York, NY: Churchill Livingstone; 2000.

12. Suva L|, Winslow GA, Wettenhall RE, et al. A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science. 1987;237:893-896.

13. Mangin M, Webb AC, Dreyer BE, et al. Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy. Proc Natl Acad Sd USA. 1988;85:597601.

14. Dickersin GR. The role of electron microscopy in gynecological pathology. (n( I Gynecol Pathol. 2000;! 9:56-66.

15. Walt H, Hornung R, Fink D, et al. Hypercalcemic-type of small cell carcinoma of the ovary: characterization of a new tumor line. Anticancer Res. 2001 ; 21:3253-3259.

Lei Chen, MD; Tri A. Dinh, MD; Abida Haque, MD

Accepted lor publication October 13, 2004.

From the Departments of Pathology (Drs Chen and Haque) and Obstetrics and Gynecology (Dr Dinh), The University of Texas Medical Branch, Galveston.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Abida Haque, MD, Department of Pathology, 2.190 John Sealy Annex, 301 University Blvd, Galveston, TX 77555-0588 (e-mail: ahaque@utmb.edu).

Copyright College of American Pathologists Apr 2005
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