Ovarian adenocarcinoma in premenarchal girls

Ovarian Adenocarcinoma in Premenarchal Girls By K.R. Shankar, A. Wakhlu, G.K. Kokai, H. McDowell, and M.O. Jones Liverpool, England

Ovarian neoplasms are unusual in the paediatric age group; the majority of them are of germ cell origin. Malignant epithelial tumours of the ovary occur infrequently in adolescent girls. Ovarian carcinoma in particular is extremely rare before puberty. The authors describe 3 cases of adenocarcinoma of the ovary in premenarchal girls and highlight the

unique characteristics of this tumour in this age group. J Pediatr Surg 36:511-515. Copyright © 2001 by W.B. Saunders Company.

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omentum was excised. Peritoneal biopsies were performed from all suspicious sites, and cytologic washings were obtained from the peritoneal cavity. Histopathologic examination confirmed disseminated invasive serous papillary adenocarcinoma (Fig 1b). Postoperative chemotherapy consisted of 6 cycles of cis-diamminedichloroplatinum and cyclophosphamide at 3-week intervals. A “second look” laparotomy at the end of the chemotherapy regimen showed extensive residual seeding in the pelvic peritoneum, both ovaries and loops of intestine. Nodules also were seen on the surface of the liver. It was decided after discussion with the parents, not to offer any further treatment. She remained relatively asymptomatic for the next 9 years. At the age of 16 years she presented with right iliac fossa pain and vomiting. A clinical diagnosis of acute appendicitis was made, and a laparotomy was undertaken. At operation residual tumor was found in the peritoneal cavity with involvement of the small intestine and colon. Biopsy of tumor tissue again was that of invasive papillary adenocarcinoma of the ovary. The appendix was histologically normal. Six months later she had abdominal distension caused by ascites. A further 6 cycles of cis-diamminedichloroplatinum and paclitaxel was administered, but she did not respond to treatment. She died of metastatic disease at the age of 19 years.

VARIAN NEOPLASMS account for only 1% of all tumors in girls below the age of 17 years.1 The majority of these tumors arise from germ cells or sex cord stromal cells. Less than 20% of ovarian neoplasms arise from the surface epithelium of the ovary in children, as opposed to 70% in adults.2 Even in the paediatric age group there is a gradual increase in the incidence of epithelial neoplasms with age, most of them occurring after menarche.3 The rate of malignancy among epithelial tumors ranges from 7.5% to 30%.1,4-6 Histologically they are either serous adenocarcinoma, mucinous adenocarcinoma, or undifferentiated carcinoma.2,5,7 Ovarian adenocarcinoma may be either truly invasive or have a low malignant potential (LMP).8,9 Epithelial malignancies are detected at a relatively early stage in adolescents and, hence, patients tend to have a better prognosis than in adults.6 However, very little is known about the behavior of these neoplasms in premenarchal girls, because they are extremely rare. Management strategies are based on experiences gathered from treating similar tumors in adults with emphasis on anatomic preservation. We report 3 premenarchal girls with adenocarcinoma of the ovary and highlight their modes of presentation, treatment strategies, and outcome. To the best of our knowledge this is the largest case series of malignant epithelial ovarian tumors at such a young age. CASE REPORTS

Case 1

INDEX WORDS: Ovarian tumor, ovarian adenocarcinoma, premenarchal.

Case 2 An 11-year-old premenarchal girl presented with lower abdominal pain and a suprapubic mass. Routine blood test results were normal. Serum alpha-fetoprotein (AFP) level was normal and the ␤ human chorionic gonadotropin (HCG) level was elevated slightly. Ultrasound scans and CT scans showed a large complex solid and cystic mass occupying the whole of the pelvis. There was no evidence of metastatic disease on further imaging of the chest and abdomen. At laparotomy, a large left ovarian tumor was found, and this was excised together with the ipsilateral fallopian tube. The right ovary had a normal external appearance. Collaborative histopathologic analysis showed a poorly differentiated, partly mucus secreting cystadenocarcinoma with invasion into vascular and lymphatic spaces. Postopera-

A 7-year-old girl presented with abdominal distension and weight loss. On examination she was grossly underweight and had tense ascites. No abdominal masses were palpable. Initial laboratory test results were normal. Ultrasound scans and computed tomography (CT) scans of the abdomen showed a large cystic mass arising from the pelvis with areas of calcification within it and free peritoneal fluid (Fig 1a). Laparotomy findings showed tumour nodules studding the entire peritoneal cavity and omentum. The ovaries themselves were not enlarged. The gross tumor was removed from the pelvis, and the

From the Departments of Paediatric Surgery, Paediatric Histopathology, and Paediatric Oncology, Alder Hey Children’s Hospital, Liverpool, England. Address reprint requests to M.O. Jones, Consultant Paediatric Surgeon, Department of Paediatric Surgery, Alder Hey Children’s Hospital, Eaton Rd, Liverpool L12 2AP, England. Copyright © 2001 by W.B. Saunders Company 0022-3468/01/3603-0019$35.00/0 doi:10.1053/jpsu.2001.21617

Journal of Pediatric Surgery, Vol 36, No 3 (March), 2001: pp 511-515

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crocytic hypochromic anemia, normal AFP and ␤-HCG levels. Ultrasound and CT scan of the abdomen showed a large complex cystic pelvic mass with calcification together with multiple calcified nodules throughout the abdomen and ascites (Fig 3a). Diagnostic abdominal paracentesis was performed, and the cytology of the fluid showed numerous clusters and papillary groupings of malignant epithelial cells, which were strongly positive for CA 125 on immunostaining. Frequent psammoma bodies also were identified. A provisional diagnosis of malignant epithelial tumor of the ovary was made. Further preoperative workup showed no evidence of lung metastasis on chest CT scan, but there was a suspicion of bone metastasis on the technetium Tc99 bone scan. At laparotomy, there was copious thick peritoneal fluid with granules of tumor tissue on all peritoneal surfaces. The omentum was infiltrated with tumor. The external surface of the ovaries was macroscopically normal. All gross tumor tissue was excised along with the omentum. Peritoneal washings were sent for cytology. Microscopic examination showed multiple irregular papillary projections covered by malignant columnar epithelial cells with stromal invasion. There were signs of multifocal dystrophic calcification or psammoma bodies, both in tumor cells and in the stroma. A collaborative histopathologic diagnosis of a well-differentiated serous, papillary adenocarcinoma of the ovary with extensive infiltration of the omentum, and peritoneal dissemination was made (Fig 3b). Postoperative palliative chemotherapy consisted of 3 cycles of cis-diamminedichloroplatinum at 3-week intervals. The chemotherapy was well tolerated, although the ascitis recurred. Further paracentesis again showed tumor cells. Her terminal care currently involves symptomatic treatment with analgesics, spironolactone, and occasional paracentesis.

DISCUSSION

Fig 1. (a) CT scan shows diffuse infiltrative lesion of the whole peritoneal cavity with calcification and ascites. (b) Microphotograph (original magnification ⴛ 80) shows papillary projection covered by uniform malignant epithelium with stromal invasion.

tively she received 4 cycles of etoposide, carboplatin, and bleomycin at 3-week intervals. Detailed CT scans immediately after chemotherapy and again 6 months later showed no recurrence. She underwent close follow-up in the outpatient clinic. She presented 15 months after her first laparotomy with severe abdominal pain and a recurrent suprapubic mass. Further imaging showed a large heterogenous mass arising from the pelvis (Fig 2a). At laparotomy, a solid and cystic mass was seen to arise from the right ovary. The tumor was excised together with the right fallopian tube. There was no evidence of local or distant metastasis. Omentectomy, together with iliac and paraaortic lymph node biopsies were performed. Histology confirmed a well-differentiated mucinous cystadenocarcinoma of the right ovary (Fig 2b 2c). The lymph nodes and cytologic washings from the peritoneal cavity were free of tumor cells. A further 6 cycles of cis-diamminedichloroplatinum and paclitaxel were administered. A magnetic resonance image (MRI) of the abdomen after chemotherapy showed no evidence of tumor. However, 3 months later she presented with dyspnoea, right hypochondrial pain, and skin nodules. Investigations confirmed metastatic cystadenocarcinoma. She succumbed to metastatic disease 2 years after diagnosis.

Case 3 A 5-year-old girl was admitted with gradual onset of abdominal distension and a 2-day history of lower abdominal pain. Clinical examination showed abdominal distension caused by ascites, but no masses were palpable. Initial laboratory investigations showed a mi-

Malignant epithelial tumors form a minority of childhood ovarian neoplasms and tend to occur in postmenarchal adolescent girls. Apart from the 3 cases reported here, only 2 cases of cystadenocarcinoma of the ovary in premenarchal girls have been reported previously (Table 1).10,11 Presentation All patients, including the 2 reported previously, presented with a gradual onset of abdominal distension associated with nonspecific lower abdominal pain. A majority of these children presented with ascites and quickly progressed to advance stage of the disease despite treatment. This differs from the situation in adolescents in whom the tumor tends to present at a relatively early stage (75% in stage I).7 Pathology The usual histologic types of malignant epithelial tumors of the ovary include serous, mucinous, and undifferentiated adenocarcinomas in descending order of frequency. These tumors may be either invasive or have a low malignant potential. Microscopically, serous cystadenocarcinoma shows multilayered malignant epithelium containing numerous micropapillae and areas of budding into the lumen. Some of these cells have multifocal dystrophic calcification (psammoma bodies). Un-

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Fig 2. (a) CT scan shows mixed solid and cystic right ovarian mass in the pelvis. (b) Cut section of the resected ovary shows multiple cysts and mucinous appearance of the stroma. (c) Microphotograph (original magnification ⴛ 80) shows mucinous, papillary, and glandular structure lined by multilayer polymorphic cells and invading stroma.

like mucinous neoplasms, serous adenocarcinomas usually are negative for staining with carcinoembryonic antigen (CEA).7 True invasive mucinous cystadenocarcinomas are notoriously difficult to distinguish from cystadenocarcinoma of low malignant potential.4,8 Invasive carcinoma is diagnosed if stromal invasion is present or if the epithelium is greater than 4 layers in thickness and exhibits severe dysplasia. In this series all the patients had invasive adenocarcinoma. This is in contrast to the adolescent population in whom tumors of low malignant potential make up 30% of all epithelial ovarian cancers.4 Diagnosis Ultrasound scan, CT, and bone scan are useful in delineating the extent of the tumor and detecting metastases. Hormonal levels and AFP levels usually are normal.7 In 2 of our patients with serous cystadenocarcinoma, immunochemical analysis of the tumors cells showed positivity for CA 125, which is a specific tumor marker of epithelial differentiation in ovarian serous carcinoma. In one of these patients a rising serum CA 125 antigen level was an indicator of tumor progression. CA 125 serology has only a 78.1% sensitivity and 76.8%

specificity in the detection of primary ovarian carcinoma.12,13 However, it may be a useful tumor marker in identifying recurrent or residual disease in malignant epithelial ovarian neoplasms. Fifteen to twenty percent of ovarian adenocarcinomas are bilateral; therefore, wedge biopsy of the contralateral ovary should be considered.5 Treatment Treatment of ovarian carcinoma is based on adult experience with an emphasis on anatomic preservation. Surgery aims to confirm the diagnosis, stage the disease, and achieve tumor clearance in early stages or cytoreduction in advanced stages. The operation involves maximum clearance of gross tumor, pelvic and paraaortic lymph node sampling, biopsies from all suspicious peritoneal surfaces including the diaphragm, multiple cytologic washing of the peritoneal cavity, and omentectomy.7 In some cases of invasive adenocarcinoma with peritoneal dissemination, the affected ovaries only may be enlarged slightly or appear “normal.” Such carcinomas probably represent multicentric tumor of the peritoneum and ovarian surface.14 Two patients in the current series presented with disseminated and invasive cancer with apparent normal-looking ovaries; metastases developed

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Another patient had contralateral ovarian mucinous cystadenocarcinoma 15 months after total excision of the left ovarian tumor. The long time gap between the first and subsequent tumor suggests that they were metachronous, and, therefore, a wedge biopsy of the contralateral ovary, if performed at the time of primary operation, may not have changed the outcome. Various adjuvant chemotherapy regimens have been tried for advanced ovarian adenocarcinoma, these includes cis-diamminedichloroplatinum, cyclophosphamide, carboplatin, bleomycin, etoposide, and paclitaxel either individually or in combination. More recently, a combination of hexamethylmelamine, doxorubicin, and cisdiamminedichloroplatinum (HAC) has been used successfully in adults with advanced ovarian carcinoma.15 However, another study advocates carboplatin as a single agent for the treatment of ovarian cancer.16 Other treatment modalities include intraperitoneal instillation of chemotherapeutic agents in patients with residual disease after debulking operation.17,18 The efficacy of this treatment has not been evaluated in children. Prognosis

Fig 3. (a) CT scan shows an infiltrative solid and cystic mass in the pelvis with calcification of the wall (white arrow). (b) Microphotograph (original magnification ⴛ 160) shows serous papillary cystic adenocarcinoma invading the omentum.

rapidly in 1 child, whereas the other child had late recurrence with metastases 9 years later. Radical abdominal hysterectomy along with bilateral salphingo oophorectomy may have improved survival in these 2 patients.

The prognosis of ovarian carcinoma depends on the stage at presentation and the histology of the tumor. A majority of adolescent girls have tumors of low malignant potential in whom the long-term survival rates are good even with more advanced disease. However, the behavior of ovarian adenocarcinoma in premenarchal girls appears to be more aggressive with no reported long-term survivors. All the patients in this series had advanced and invasive carcinoma, which has a poor prognosis in any age group. Despite advances in cancer treatment, the mortality rate in juvenile adenocarcinoma of the ovary remains

Table 1. Ovarian Adenocarcinoma in Premenarchal Girls Study

Age (yr)

Operative Treatment

Histology

Chemotherapy

Outcome

Comments

Hong et al11 (1980)

4

Right salpingooophorectomy

Papillary cystadenocarcinoma

No gross tumor 7 months after treatment. Longterm follow-up not available

Blom et al10 (1982)

4

Right salpingooophrectomy

Papillary cystadenocarcinoma

Methotrexate, cyclophosphamide, Cis-platin, Vincristine, Doxorubicin Intraperitoneal instillation of 32P

Malignant ascites at presentation. Benign transformation of tumor after chemotherapy Malignant ascites at presentation.

Authors’ cases

7

Cytoreductive surgery

Papillary cystadenocarcinoma

Left salpingooophorectomy

Mucinious cystadenocarcinoma

Cytoreductive surgery

Papillary cystadenocarcinoma

11

5

Cis-platin, cyclophosphamide, paclitaxel Etoposide, carboplatin, bleomycin Cisplatin

No tumor 4 months after treatment. Long-term follow-up not available Died 15 years after diagnosis Died 26 months after diagnosis In terminal care

Normal external appearance of both ovaries Metachronous tumor on contralateral ovary Normal external appearance of both ovaries

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high. It is unclear whether radical surgery provides any survival advantages. Because most patients present with disseminated disease, any improvement in outcome is likely to come as a result of research into newer chemo-

therapeutic agents and an understanding of the biology of these rare tumors. Because of the rarity of this malignancy, future collaborative studies are warranted to establish optimal management strategies.

REFERENCES 1. Abell MR, Holtz F: Ovarian neoplasm in childhood and adolescence II Tumour of non germ cell origin. Am J Obstet Gynecol 93:850-866, 1965 2. Lack EE, Yound RH, Scully RE: Pathology of ovarian neoplasms in childhood and adolescence. Pathol Ann 27:281-356, 1992 3. Breen JL, Maxson WS: Ovarian tumors in children and adolescents. Clin Obstet Gynecol 20:607-623, 1977 4. Deprest J, Moerman P, Corneillie P: Ovarian borderline mucinous tumour in a premenarchal girl: Review on ovarian epithelial cancer in young girls. Gynecol Oncol 45:219-224, 1992 5. Pfeifer SM, Gossman GG: Evaluation of adnexal masses in adolescents. Pediatr Clin North Am 46:573-592, 1999 6. Van Winter JT, Simmons PS, Podratz KC: Surgically treated adnexal masses in infancy, childhood and adolescence. Am J Obstet Gynecol 170:1780-1789, 1994 7. Morris HB, La Vecchia C, Draper GJ: Malignant epithelial tumours of the ovary in childhood: A clinicopathological study of 13 cases in Great Britain 1962-1978. Gynecol Oncol 19:290-297, 1984 8. Riopel MA, Ronnett BM, Kurman RJ: Evaluation of diagnostic criteria and behaviour of ovarian intestinal-type mucinous tumours. Am J Surg Pathol 23:617-635, 1999 9. White PF, Merino MJ, Barwick KW: Serous surface papillary carcinoma of the ovary, a clinical, pathologic, ultrastructural and immunohistochemical study of 11 cases. Pathol Ann 20:403-418, 1985 10. Blom PG, Torkildsen EM: Ovarian cystadenocarcinoma in a 4-year-old girl: Report of a case and review of the literature. Gynecol Oncol 13:242-246, 1982

11. Hong SJ, Lurain JR, Tsukada Y, et al: Cystadenocarcinoma of the ovary in a 4-year-old. Cancer 45:2227-2230, 1980 12. Bast Jr RC, Xu F, Woolas RP, et al: Complementary and coordinate markers for detection of epithelial ovarian cancers, in Sharp F, Marson P, Blackett T, et al (eds): Ovarian Cancer 3. London, England Chapman & Hall Medical, 1992, pp 189 13. Leake J, Woolas RP, Oram DH, et al: Immunocytochemical and serological expression of CA125: A clinicopathological study of 40 malignant ovarian epithelial tumours. Histopathology 24:57-64, 1984 14. Hart WR: Pathology of malignant and borderline (low malignant potential) epithelial tumors of ovary, in Coppleson M, Monaghan JM, Morrow CP, et al (eds): Gynaecologic Oncology. London, England Churchill Livingstone, 1992, pp 863-887 15. Brower MS, Coleman M, Pasmantier MW, et al: Treatment of advanced ovarian carcinoma with Hexamethylmelamine, Doxorubicin and cis-Platinum (HAC): Results in both untreated and previously treated patients. Med Pediatr Oncol 12:17-24, 1984 16. The ICON Collaborators: ICON2: Randomised trail of singleagent carboplatin against three-drug combination of CAP (cyclophosphamide, doxorubicin and cisplatin) in women with ovarian cancer. Lancet 352:1571-1576, 1998 17. Howell SB: Intraperitoneal chemotherapy for ovarian carcinoma. J Clin Oncol 6:1673-1675, 1988 18. Regelson W, Parker G: The routinization of intraperitoneal (intracavitary) chemotherapy and immunotherapy. Cancer Inv 4:29-42, 1986