Medical and Pediatric Oncology 7:219-224 (1979)

PROCEEDINGS OF THE TUMOR BQARD OF THE CHILDREN'S HOSPITALOF PHILADELPHIA

REVERLY RANEYJRMQ SERIES EDITOR AND GIULIO J. D W Q MD, ASSOCIATE EDITOR

Ovarian Endometrioid Carcinoma in an Eleven-Year-Old Chi Id Rebecca Byrd, MD

Key words: ovarian carcinoma, childhood

CLINICAL SUMMARY - Rebecca Byrd, MD (Oncology Fellow)

The patient is a black female who presented at age 11% years in January 1979 with a two-week history of intermittent abdominal discomfort, urinary frequency, and nocturia. There was no history of weight loss, fever, nausea, vomiting, diarrhea, or constipation. Menarche had occurred five months prior to presentation. Since then she had had menstrual bleeding every two to three weeks, with heavy flow. Review of systems was otherwise negative. There was no history of unusual maternal medications or of radiation during pregnancy.

General physical examination was normal except for a hard, irregular mass felt at the level of the umbilicus and filling the whole lower abdomen and pelvis. There was also diffuse non-pitting edema of the lower extremities. Pelvic examination under general anesthesia revealed a large pelvic mass impinging on the right side of the vaginal wall and the rectal wall.

normal limits except for three to five red blood cells per high-power field. Blood chemistries showed the following: Na, 136 mEq/liter; K, 4.7 mEq/liter; Cl, 99 mEq/liter; C 0 2 , 17 mEq/liter. The BUN was 53 mg/dl, creatinine 5.4 mg/dl, and uric acid 15 mEq/liter. Bone marrow biopsy was negative for tumor.

At presentation, the patient had a blood pressure of 120/70 and normal vital signs.

Laboratory data revealed a normal complete blood count. The urinalysis was within

RADIOGRAPHIC STUD1 ES - Spencer Borden, MD (Pediatric Radiologist)

The plain film of the abdomen shows a large mass filling the abdomen and extending up to the level of the umbilicus. The rectum is compressed. The preoperative intravenous pyelogram (IVP) shows poor excretion of the contrast material initially, but on delayed films one can see bilateral hydronephrosis and ureteral obstruction. The skeletal survey and chest roentgenograms are normal.

0098-1 532/79/0703-0219$01.40 @ 1979Alan R. Liss, Inc.

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SURGICAL REPORT - Moritz Ziegler, MD (Pediatric Surgeon)

The patient underwent exploratory laparotomy, and a mass was found arising from the left ovary and filling the entire pelvis anterior and posterior t o the uterus, depressing the bladder and compressing the rectum. The mass extended out of the pelvis t o the level of L3 and completely surrounded the aortic bifurcation. The right ovary appeared to be normal. The liver and abdominal viscera were uninvolved. There was no ascites. The kidneys were palpated and felt to be slightly larger than normal. Both ureters were identified but could not be freed from overlying tumor. Complete surgical removal was impossible, and therefore only the left ovary was removed.

PATHOLOGY REPORT - Jane Chatten, MD (Pediatric Pathologist)

All sections have a similar appearance (Fig. 1). Cystic and normal follicles are present in the attached ovarian tissue. The tumor involves the ovary and is epithelial in pattern. The nalignant cells are tall and columnar. Their arrangement is papillary. mimicking that of endometrioid carcinoma. There is no evidence for mucinous or serous differentiation, for teretoma, or for cells derived from an extra-ovarian location. This is therefore a poorly dif- ferentiated ovarian adenocarcinoma of endometrioid type.

and showed evidence of increasing renal failure. On the fourth postoperative day, the BUN value peaked at 60 mg/dl. The creatinine was 7.8 mg/dl, and the uric acid was 20.6 mg/dl with normal serum electrolytes. She then underwent cystoscopy and retrograde studies which revealed ureteral obstruction at the pelvic brim. Bilateral ureteral catheters were in- serted, and the patient had prompt diuresis with rapid return of normal renal function. Two days later the BUN was 8 mg/dl, the creatinine was 0.7 mg/dl. and the uric acid was 5.1 mg/dl. At this time the patient was begun on chemotherapy.

showed marked regression of the hydronephrosis and approximately 50% shrinkage of the mass.

Dr. Byrd: Postoperatively the patient had a low urine output of 500-700 cc/34 hours

Dr. Borden: A repeat IVP was performed after the first cycle of chemotherapy and

DISCUSSION - Dr. Byrd

Malignant ovarian neoplasms in childhood and adolescence are rare. It has been esti- mated that they comprise approximately 1% of all pediatric cancers [ I ] . Of the malignant ovarian tumors in children, approximately 60% are classified as germ-cell, 70% as epithelial, and 20% as stromal cell tumors [2-71. The epithelial tumors almost never occur in the pre- pubertal child but increase in frequency with advancing age. In a literature review by Breen and Maxson, there were 1,002 cases of ovarian neoplasms in children reported between 1963 and 1975. There were no reports of endometrial carcinoma in this group [8] .

Ovarian carcinoma is the fourth leading cause of death from cancer in adult American females, and much of the information concerning this tumor comes from the literature con- cerning these patients. In adults, approximately 60% of all ovarian carcinomas are stage I11 or IV (FIG0 staging) a t the time of diagnosis [ 101 . Five-year survival rates reported range from 0 to 10% for these stages; with all stages considered together, the overall survival is 25% [l 11 . Well-differentiated endometrioid carcinoma has a five-year survival of 62%, and the poorly differentiated carcinoma has only a 23% five-year survival [ I ? ] .

Childhood Ovarian Carcinoma 22 1

Fig. 1. The frond-like papillary arrangement of tall, columnar epithelium is characteristic of endometrioid carcinoma (hematoxylin and eosin; original magnification, X 125).

A combination of therapies has been used for treatment of ovarian carcinoma. Surgery is important for diagnosis, staging, and if possible, tumor removal. Since the majority of patients present with unresectable stage 111 or IV disease, complete surgical removal is often impossible, and other therapeutic measures are needed.

However, controlled clinical trials examining the use and effectiveness of radiation therapy alone or in combination with chemotherapy are inconclusive [13,14].

of the ovary. Approximately 50% of patients respond favorably, but the complete response rate is only 10-15% [ lo] . The median duration of survival after single-agent therapy is only 10-1 2 months [ 1 1 ] . Recent chemotherapy trials have identified nonalkylating agents with activity against ovarian carcinoma [9, 15, 161 . 'Ihese include 5-fluorouracil, methotrexate, adriamycin, cyclophosphamide, cis-dichlorodiammineplatinum, and hexamethylmelamine. Combinations of adriamycin and cis-dichlorodiammineplatinum with and without cyclo- phosphamide have produced tumor responses in patients failing treatment with alkylating agents alone [17, 181 . More encouraging, however, are the results of Young and co-workers

Radiation therapy is the other traditional method used to treat ovarian carcinoma.

The alkylating agents were the first single chemotherapeutic agents treating carcinoma

222 Byrd

[l 11 , who treated adults with ovarian adenocarcinoma with a combination of hexamethyl- melamine, methotrexate, cyclophosphamide, and 5-fluorouracil. Compared to L-phenylal- anine mustard alone, the combination produced a significant increase in response rate (75% vs 54%), complete remissions (33% vs 16%), and median duration of survival (29 months vs 17 months) [ 1 11.

ovary in children is limited. A review of the literature reveals that only nine patients have been reported since 1963 with unspecified or poorly differentiated adenocarcinoma. None were reported as having endometrioid carcinoma [5, 7,8, 19,201 . One of the patients was six years old; all the others were 14-19 years old at diagnosis. Although staging, treatment plans, and outcome are not described in detail, only one of five was known to be alive at the time of the reports [7].

she had surgically unresectable stage I11 disease. Information derived from adults indicates that multiple-agent chemotherapy is preferable to any single agent, so that we elected t o use a four-drug regimen of intravenous cyclophosphamide, adriamycin, cis-dianimindei- chloroplatinum, and oral hexamethylmelamine. The therapy required the patient to be hospitalized for approximately 72 hours every four weeks. During her first six courses she had only mild nausea and vomiting, alopecia, and transient neutropenia and thrombocyto- penia. She has continued full time in school and enjoys peer- and family-related activities.

The duration of clinical responses in adults varies with drug regimen and staging, but the overall prognosis in all carcinomas of the ovary is poor. It is too early to predict the duration of clinical remission in this patient. but we are encouraged that she has had such a prompt and dramatic tumor response.

pose a young girl to the development of ovarian carcinoma?

anomalies in seven patients with various ovarian tumors. but there are no consistent fami- lial aggregations or congenital defects in this tumor type [4] .

effective agent in testicular carcinoma as well as in ovarian carcinoma.

was not simple. On initial evaluation, in the emergency room, this patient was thought to be pregnant and was referred to our service. When we felt the mass and found a negative ilrine pregnancy test. we arranged a n immediate IVP and admission for laparotomy. Ob- vlously, the tumor was quite advanced at diagnosis.

address at this point. This first is, how likely is it that this patient’s clinical response will be permanent? Second, should she have radiation therapy? Third. should she have a ”second- look” operation now? The completeness of response could be assessed at the time of surgery and the right ovary, tube, and uterus could be removed.

is any evidence for hormonal influences on the development of this tumor?

cycles and thus has not had much estrogen stimulation. Her type of tumor usually spreads quickly and often involves the peritoneum. Over the last five years, management of ovarian

In contrast t o the extensive experience in adults, information on carcinoma of the

Our patient has a tumor that is rarely seen in childhood and adolescence. At diagnosis

Dr. Anna Meadows (Pediatric Oncologist): Are there any conditions known to predis-

Dr. Byrd: There are none cited in the literature. I have seen a summary of congenital

Dr. Donald Norris (Pediatric Oncologist): I t is interesting that cis-platinum is an

Dr. Gertrude Frishmuth (Gynecologist): I want to state that arriving at this diagnosis

Dr. Beverly Raney (Pediatric Oncologist): There are three questions that we need to

Dr. Borden: Dr. Mikuta, could you tell me in your reply to Dr. Raney whether there

Dr. John Mikuta (Gynecologic Oncologist): This girl has had only a few menstrual

Childhood Ovarian Carcinoma 22 3

carcinoma has become increasingly the province of the chemotherapist. We do not think an operation is indicated now, because six months of chemotherapy is not enough for this girl’s tumor, despite its good response so far. Her treatment should continue for 18 months, at which time a complete hysterectomy and right salpingo-oophorectomy should be per- formed in order t o remove any possible microscopic residual disease. Then chemotherapy could be stopped. Here at the University of Pennsylvania, “second-look” operations were performed on women with stage 111 and IV ovarian carcinoma as soon as they had a com- plete clinical response. Eight of 11 such recent patients still had residual disease at operation, and therefore we think the second operation was performed prematurely. The three others who had no disease at early second-look surgery are all well, one at six years after presenting with a stage I11 tumor. There does not seem to be any therapeutic advantage for early hys- terectomy in these patients.

is found at 18 months? Dr. Littman (Pediatric Radiotherapist): What about radiation therapy if residual disease

Dr. Mikuta: I think that radiotherapy (RT) might be useful then.

Dr. Raney: Would RT be helpful now?

Dr. Littman: RT is of doubtful efficacy in this disease. Also, the volume that would have to be irradiated now is large, possibly leading to curtailment of chemotherapy because of marrow suppression due to pelvic RT.

ectomy now, why should it be done a year from now?

we sometimes find microscopic foci of tumor in them. In addition, older women have a risk, perhaps as high as 3076, of having endometrial carcinoma of the uterus after having had ovarian carcinoma. We think all the tissue at risk should be removed, including the omentum, if the patient is well 18 months after starting treatment.

Dr. Raney: In summary, we have decided to continue the multiple-agent chemotherapy regimen that so far has been effective, to re-evaluate the patient frequently, and to perform a right salpingo-oophorectomy, hysterectomy, and omentectomy at 18 months if she re- mains healthy. If she has regrowth of tumor in the pelvis prior to 18 months, radiation and different drugs could be used to control recurrent disease, perhaps coupled with an explor- atory laporatomy. l’he latter would be performed to determine whether the previously in- operable tumor had been rendered resectable by therapy up to that point.

Dr. Raney: If there is no strong reason to do a hysterectomy and right salpingo-oophor-

Dr. Mikuta: There are two reasons for removing these tissues later. The first is that

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