GYNECOLOGIC ONCOLOGY 35, 387-390 (1989)

CASE REPORT Hypercalcemia in Association with Mutinous Adenocarcinoma of the

Ovary: A Case Report MICHAEL BOYER, MBBS,’ MICHAEL FRIEDLANDER, PHD, FRACP, PATRICIA BANNATYNE, FRCPA,”

AND KENNETH ATKINSON, FRACOGt

Departments of Medical Oncology, *Pathology, and iGynecology, Royal Prince Alfred Hospital, Sydney, Australia

Received August 1, 1988

Hypercalcemia in association with mutinous adenocarcinoma of the ovary has not previously been reported. Such a case is presented. 0 1989 Academic Press, Inc.

Hypercalcemia is a recognized complication of ovarian carcinoma; the most common histological type is small cell undifferentiated carcinoma. A case of mutinous ad- enocarcinoma of the ovary with associated hypercal- cemia and a rapidly fatal course is presented.

CLINICAL HISTORY

A 32-year-old woman presented to the Royal Prince Alfred Hospital with a 3-week history of progressive abdominal distension, dyspnea, cough, and polydipsia. There was no past gynecological history of significance and no other medical problems.

Physical examination revealed a woman with gross abdominal distension but no obvious mass on either ab- dominal or pelvic examination. Soft end inspiratory crack- les were audible at both lung bases. The patient was dehydrated.

Serum calcium was elevated to 3.04 mmole/liter (nor- mal range 2.24-2.65 mmole/liter), while phosphate was 0.80 mmole/liter (normal range 0.60-1.30 mmole/liter) and albumin was 40 g/liter (normal range 40-52 g/liter). Other blood analytes were normal and a serum preg- nancy test was negative. The white cell count was 14.4 x log/liter (normal range 4.0-l 1.0 x log/liter), but hemoglobin and platelet count were normal. A chest X- ray revealed a diffuse reticular pattern at both bases. An

’ To whom reprint requests should be addressed at the Department of Oncology, Royal Prince Alfred Hospital, Missenden Rd., Camp- erdown 2050 N.S.W., Australia.

abdominal CT scan showed a large fluid-containing mass arising from the pelvis with multiple areas of thickening in the margins of the mass. The right ovary could not be identified.

The patient was rehydrated and the calcium fell to 2.80 mmole/liter. She underwent laparotomy the day after admission and at operation a large cystic right ovarian tumor was found. Hysterectomy, bilateral salpingo-oo- phorectomy and omentectomy were performed and en- larged para-aortic nodes were sampled.

Postoperatively the patient remained unwell and cy- tological examination of the sputum revealed adenocar- cinema cells. On the seventh postoperative day cytotoxic chemotherapy was commenced with carboplatin, 150 mg/m* intravenously, daily for 3 days. On the ninth post- operative day hypercalcemia reappeared with a calcium of 3.05 mmole/liter. The parathyroid hormone level was 17 pg/ml (normal range lo-60 pg/ml) and an isotope bone scan performed with technetium methylene di- phosphonate was normal. Calcitonin, 400 units intra- muscularly, twice daily was commenced. The calcium fell to 2.84 mmole/liter and the patient still receiving calcitonin was discharged 17 days after admission.

The patient was readmitted 4 days later with increasing dyspnea. Examination revealed her to be afebrile and drowsy. Serum calcium was 4.23 mmole/liter despite ongoing calcitonin therapy and a chest X-ray revealed a more marked reticular pattern with areas of confluence. Her condition deteriorated and she died 18 hr after ad- mission. Permission for autopsy was refused.

PATHOLOGY

The right ovarian cyst contained approximately 20 li- ters of blood-stained mucoid fluid. The cyst lining was

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388 BOYER ET AL.

FIG. 1. Cyst wall with some residual intact cytologically benign mutinous epithelial lining (arrows). The subjacent ovarian stroma is diffusely infiltrated by undifferentiated carcinoma. H & E, x56.

rough and brown and there were multiple firm, pale layer of cytologically benign mutinous epithelium which plaque-like mural nodules up to 7 cm in diameter and 2 focally became multilayered and architecturally complex cm in thickness. The serosal surface was unremarkable. with concomitant cytological atypia progressing to frank Microscopically, the cyst was lined, in part, by a single invasive carcinoma (Figs. 1 and 2). The largest mural

FIG. 2. Another part of the cyst wall showing lining of cytologically malignant, architecturally complex, mutinous epithelium at right with a transition to invasive carcinoma at left. H & E, x28.

CASE REPORT 389

FIG. 3. Mural I lodule (right) composed of closely packed hypercellular but cytologically benign mutinous glands. shows conspicuous lymphatic permeation by carcinoma cells which appear vacuolated. H & E. x90.

The adjacent stt

nodule was microcystic and showed an adenoma-like or poorly formed alveolar groups. The tumor cells were arrangement of closely packed, but cytologically bland pleomorphic, with marked nuclear atypia and frequent mutinous glands (Fig. 3). The remaining solid mural nod- mitoses, up to S/high power field (Fig. 4). Many cells ules consisted of poorly differentiated adenocarcinoma displayed vacuoles or eosinophilic inclusions which con- in which the tumor cells were arranged in sheets, cords, tained mucin. Very rare tumor cells showed cytoplasmic

FIG. 4. Detail of diffuse carcinomatous infiltrate in cyst wall. Nuclear pleomorphism and mitotic activity are conspicuous. Many cells contained stainable cytoplasmic mucin. H & E, x220.

390 BOYER ET AL.

argyrophilia. Small foci of necrosis and hemorrhage were present throughout the tumor. There was very extensive lymphatic permeation by carcinoma in the cyst wall (Fig. 3) and venous permeation was noted in the medulla and hilus .

The left ovary and both fallopian tubes were within normal limits for age, with no evidence of primary or secondary neoplasia. The uterus showed widespread lymphatic permeation by adenocarcinoma, evident in the outer myometrium and cervix, but was otherwise un- remarkable. No serosal deposits of carcinoma were iden- tified in any of the organs examined. The omentum was free of tumor, other than that contained in discrete lymph nodes.

The paraaortic lymph nodes were almost replaced by metastatic poorly differentiated adenocarcinoma.

DISCUSSION

The association of hypercalcemia with carcinoma of the ovary pursuing a rapidly fatal course is well described [l]. Small cell undifferentiated carcinoma is the most common tumor to follow this pattern [I]. Other tumor types that display hypercalcemia include serous papillary cystadenocarcinoma [2], malignant lipid cell tumor [2], dysgerminoma [2], undifferentiated carcinoma [2], gran- ulosa cell carcinoma [4], undifferentiated sex cord tumor [3], and gonadal stromal sarcoma [3]. Dickersin et al. believed the cases of granulosa cell carcinoma and go- nadal stromal sarcoma and one case of undifferentiated carcinoma to most probably represent additional ex- amples of small cell carcinomas [l].

The association of ovarian mutinous adenocarcinoma with hypercalcemia and a rapidly fatal course has not previously been reported. Despite different histological tumor type, the features in this case of a young woman with a short history, hypercalcemia, and a rapidly fatal course despite surgery and chemotherapy are remarkably similar to those of cases of small cell ovarian carcinoma with hypercalcemia. Furthermore, the clinical picture in our patient is quite different from that of five older pa-

tients (three with papillary cystadenocarcinoma and two with clear cell carcinoma) reported by Allan et al. [5]. Their patients, although having hypercalcemia, had rel- atively slow progression of their underlying tumors.

The hypercalcemia that occurred was in the setting of a low-normal parathyroid hormone level and a normal bone scan. It improved transiently following removal of the tumor mass and worsened in parallel with evidence of progressive tumor growth. These findings support the hypothesis that a tumor-related humoral factor was re- sponsible for the hypercalcemia.

A variety of causes of the humoral hypercalcemia of malignancy have been investigated in the past [6]. These include ectopically produced parathyroid hormone, os- teoclast-activating factor, prostaglandins of the E series, and transforming growth factors. More recently, a para- thyroid-hormone-related protein has been described [7]. In the future, it will be of interest to search for this protein in cases such as this.

REFERENCES

1 Dickersin, G., Kline, I., and Scully, R. Small cell carcinoma of the ovary with hypercalcemic: A report of eleven cases, Cancer 49, 188-197 (1982).

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Ferenczy, A., Okagaki, T., and Richart, R. Para-endocrine hyper- calcemic in ovarian neoplasms: Report of mesonephroma with hy- percalcemic and review of literature, Cancer 27, 427-433 (1971). Holtz, G., Johnson, T., and Schrock, M. Paraneoplastic hypercal- cemic in ovarian tumours, Ubstet. Gynecol. 54, 483-487 (1979).

Cannon, P. M., Smart, C. R., Wilson, M. L., and Edwards, C. B. Hypercalcemic with ovarian granulosa cell carcinoma, Rocky. Mr. Med. J. 72, 72-74 (1977).

Allan, S. G., Lockhart, S. P., Leonard, R. C. F., and Smyth, J. F. Paraneoplastic hypercalcemia in ovarian carcinoma, hit. Med. J. 288, 1714-1715 (1984). Mundy, G. R., Ibbotson, K. J., D’Souza, S. M., Simpson, E. L., Jacobs, J. W., and Martin, T. J. Hypercalcemia of cancer: Clinical implications and pathogenic mechanisms, N. Engl. J. Med. 310, 1718-1727 (1984). Suva, L. J., et al. A parathyroid hormone-related protein implicated in malignant hypercalcemia: Cloning and expression, Science 237, 893-896 (1987).