FIG. 1:Large-cell variant of small-cell carcinoma.
The tumor cells have abundant eosinophilic
cytoplasm and central nuclei, many of which have prominent nucleoli.
Mitoses are readily seen. (Hematoxylin and eosin, original magnification x400.)
UTERINE AND OVARIAN CONSERVATION IN ADVANCED SMALL CELL CARCINOMA OF THE OVARY
John L. Powell, MD, Rebecca D. McAfee, MD,
Ralph C. McCoy, MD,
and Brian S. Shiro, MD
Small-cell carcinoma of the ovary is a rare and highly aggressive malignancy affecting children and young women between the ages of 9 and 42 years (average 24 years).(1,2) Since the first report by Dickersin et al,(1) 165 cases have been reported in the world's literature, 123 patients (75%) have died of their tumors, generally within 1-2 years.(1-8) Almost all patients with tumors of a stage higher than Ia have died of disease. Benrubi et al in 1993(5) and Young et al in 1994(7) reported one patient each with stage IIb disease who received surgery, intensive multi-agent chemotherapy, and radiation therapy and were alive and apparently free of disease at 4 and 7 years, respectively. Young et al(7) also reported a 19-year-old with a stage III disease who was alive and well 2.5 years following hysterectomy, bilateral salpingo-oophorectomy, and chemotherapy with cisplatin, etoposide, doxorubicin, and vincristine. In 1997, Tewari et al(8) reported the 5-year survival of a 26-year-old woman treated by total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and debulking at 14 weeks gestation followed by multi-agent chemotherapy with vinblastine, cisplatin, cyclophosphamide, bleomycin, doxorubicin, and etoposide.
This report describes the apparent successful treatment of a young woman with stage IIIc disease who underwent optimal debulking surgery followed by induction chemotherapy with bleomycin, etoposide, and cisplatin and consolidation chemotherapy with vincristine, dactinomycin, and cyclophosphamide.
In 1987, Ulbright et al(9) provided histologic, immuno-histochemical, and ultrastructural evidence suggesting a germ-cell origin for small-cell carcinoma of the ovary. On this basis we decided to treat this patient with a chemotherapy regimen used for patients with advanced germ-cell tumors.
The patient was a 21-year-old white female, gravida 0, para 0, who presented with right lower quadrant abdominal pain of 2 weeks duration. A sonogram revealed a 12-cm solid right ovarian neoplasm. On March 23, 1995, she underwent a right oophorectomy at Onslow County Hospital for a 12.0 cm x 12.5 cm x 6.5 cm solid right ovarian neoplasm that was classified as malignant. The mass was ruptured in the process of removal through a Pfannenstiel incision. Tumor markers drawn 4 days postoperatively were alpha-fetoprotein 2.2 ng/mL, carcinoembryonic antigen 1.6 ng/mL, CA 125 28.1 U/mL, and hCG less than 5 mIU/mL. Chest x-ray was normal. The patient was referred to the Gynecologic Oncology Service at New Hanover Regional Medical Center, where a serum calcium level was normal.
On April 18, 1995, she underwent exploratory laparotomy, right salpingectomy, omentectomy, lysis of adhesions, appendectomy, bilateral pelvic lymphadenectomy, periaortic lymphadenectomy, excision of intra-abdominal tumor implants from the pelvic peritoneum, anterior abdominal wall, serosa of small bowel, serosa of the sigmoid, small bowel mesentery, and peritoneal cytology. The serosa and mesentery of the vermiform appendix were involved with tumor. She was found to have a stage IIIc large-cell variant of a small-cell carcinoma of the ovary with extensive periaortic lymph node metastasis. Lymph nodes in the periaortic area extended from the bifurcation of the aorta up the level of renal vessels and were the size of golf balls and largely replaced by metastatic tumor. She had numerous 1-cm implants of tumor on the pelvic peritoneum, anterior abdominal wall peritoneum, serosa of the right fallopian tube, serosa of small bowel, sigmoid serosa, and small bowel mesentery. The liver, gallbladder, pancreas, diaphragm, uterus, left fallopian tube, and left ovary were all normal. At the end of the operative procedure, all gross tumor had been removed.
The tumor was predominantly solid with microcystic areas. Cells were large with abundant cytoplasm and large pleomorphic nuclei, many of which showed central nuclei (Figure 1). The mitotic rate was high. Both intracellular and extracellular hyaline globules were present, and these globules were negative for alpha-fetoprotein. Schiller-Duval bodies were not identified. Peritoneal washings were negative for malignant cells. Immunohistochemical stains were positive for cytokeratins, epithelial membrane antigen, and vimentin. The tumor showed negative results with carcinoembryonic antigen, placental alkaline phosphatase, alpha-fetoprotein, hCG, and human placental lactogen. Given the morphologic features combined with the immunohistochemical features, the tumor was categorized as a large-cell variant of a small-cell carcinoma.
Seven days following surgery she was started on a combination chemotherapy regimen consisting of three monthly intravenous cycles of bleomycin 30 units day 1, etoposide 100 mg/m2 days 1-5, and cisplatin 20 mg/m2 days 1-5 followed by three monthly intravenous cycles of vincristine 1.5 mg/m2 day 1, dactinomycin 350 ug/m2 days 1-5, and cyclophosphamide 150 mg/m2 days 1-5. She completed all of her chemotherapy in September 1995.
In January of 1997, the patient was asymptomatic, but an 8 cm left ovarian cystic mass was detected on routine examination. Vaginal probe ultrasound revealed an 81 mm x 42 mm complex left ovarian cystic mass. She underwent left ovarian cystectomy February 4, 1997, for a benign ovarian cyst. Exploration, peritoneal biopsies, and peritoneal washings for cytology were all negative for malignancy.
The patient is menstruating normally and is free of disease, more than 2 years since completion of chemotherapy. A serum FSH level is 9.2 mIU/mL.
The decision to recommend removal or conservation of a normal ovary and uterus in a young woman with advanced ovarian cancer is controversial and presents a difficult choice for the thoughtful gynecologic surgeon. The golden rule of pelvic surgery is the conservation of useful organ function provided it does not compromise the patient's survival. Historically, this approach was considered only in young women with stage I invasive epithelial, borderline, and stromal- and germ-cell tumors with the recommendation for removal of the remaining uterus and adnexa when childbearing is complete because of the potential for development of carcinoma in the remaining ovary. The high incidence of unilaterality (159 of 165 cases, 96.4%) in small-cell carcinoma of the ovary should make it more amenable to conservative surgery. Selection criteria should include a young woman who desires to preserve fertility, who is willing to risk secondary surgery, in whom the uterus and opposite ovary appear normal, and in whom, in the opinion of the surgeon, removal of all gross tumor can be achieved.
Patients with advanced small-cell carcinoma of the ovary should undergo cytoreductive surgery to remove as much of the tumor and its metastasis as possible. The staging operation should include unilateral oophorectomy or salpingo-oophorectomy, total omentectomy, resection of any metastatic lesions from the peritoneal surfaces or the intestines, pelvic and periaortic lymphadectomy, and peritoneal cytology. Because of the low incidence of bilateral ovarian involvement and the risk of adhesions that may compromise future fertility, biopsy of the contralateral normal appearing ovary is unwarranted. Pathological review is recommended to ensure the correct diagnosis of this rarelv encountered neoplasm. Combination chemotherapy should be initiated promptly postoperatively. Adequate follow-up is mandatory to detect recurrences as soon as possible. Because total abdominal hysterectomy and bilateral salpingo-oophorectomy are the standard surgical procedures in patients with advanced ovarian cancer, physicians should understand that the conservative approach should be considered only in selected cases, after proper assessment of the risks and benefits and thorough counseling of the patient. Nevertheless, cure without deformity or loss of function must ever be surgerys highest ideal.
REFERENCES
Address reprint requests to:
John L. Powell, MD
Director of Gynecology Oncology
Coastal Area Health Education Center
PO Box 9025
Wilmington, NC 28402-9025