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Teratomas in childhood: Analysis of 142 cases
Teratomas in Childhood: Analysis of 142 Cases By Deborah F. Billmire and Jay L. Grosfeld
Indianapolis, Indiana 9 This report concerns 142 infants and children with teratomas treated from 1960 to 1984. The primary site of tumor was sacrococcygeal in 84, ovarian in 15, testicular in 15, mediastinal in 14, retroperitoneal in 7, cervical in 3, and other in 4. Malignancy occurred in 40 of 142 (28%) patients. Serum for alphafetoprotein (AFP) was obtained preoperatively in 29 patients. Elevated AFP was seen in all patients with malignancy, 3 of 6 with immature lesions and 1 of 19 with a benign lesion. Postoperative rise in AFP levels was a good indicator of malignant recurrence. Beta human chronic gonadotropin (BHCG) levels w e r e only helpful in following teenage boys with testicular lesions. Benign tumors w e r e treated by complete excision alone with a 9 7 % survival. Testicular malignancies had a good prognosis with 13 of 15 surviving (87%) despite distant metastasis in four. In contrast, survival was only 3 2 % with nontesticular malignancies. Survival was 17% for resectable malignant cases treated with surgery alone compared with 1 0 0 % when operation was followed by multiagent chemotherapy. Unresectable malignant lesions w e r e usually fatal despite multiagent chemotherapy and/or second-look procedures. 9 1986 by Grune & Stratton, Inc. INDEX WORDS: Teratoma; alphafetoprotein; endodermal sinus tumor.
E R A T O M A S are the most diverse group of tumors in childhood accounting for 3% of all childhood malignancies) These tumors most often occur in a para-axial or midline location from the brain to the sacral area as well as in the gonads. This report describes a 25-year experience with 142 childhood teratomas treated at a single pediatric cancer facility. These data suggest that (1) surgical excision alone is the therapy of choice in benign cases, and (2) multiagent chemotherapy and surveillance with tumor markers have improved both recognition and survival in malignant cases.
T
PATIENTS One hundred forty-two infants and children with teratomas were evaluated and treated at the James Whitcomb Riley Hospital for
Children, Indiana University Medical Center in Indianapolis from 1960 to 1984. All sites except the central nervous system are included in this review.
Sacrococcygeal Sacrococcygeal tumors were the most frequent lesions observed in 84 cases or 59% of the total patients. The majority of these tumors were seen in girls (76%). Benign lesions occurred in 70 patients (83%), malignant lesions in 11 (13%) and 3 lesions that were initially benign later recurred as malignancies (4%). Most patients presented with an obvious sacral mass; some, however, had only asymmetry of the buttocks and seven patients had entirely presacral lesions. Prenatal ultrasound in three newborns showed polyhydramnios in all and a fetal mass in two. Age at diagnosis correlated with risk of malignancy as infants less than one month of age had a 3% incidence of malignancy compared with 38% in children over one month. It is interesting to note, however, that four patients with obvious lesions since birth had a significant delay (6 weeks, 9 months, I1 months, 2 years) in treatment. Surprisingly, all of these were found to be benign with mature histology and were resected without recurrence. Tumors ranged in size from 2.5 to 30 cm in greatest dimension (mean 13.2 cm) with most lesions having a mixture of solid and cystic components. Lumbosacral spine radiographs were obtained in 16 patients. Both patients with malignant tumors had intact sacrum as did 12 of 14 patients with benign lesions. Size and character of the tumor were unrelated to the incidence of malignancy. Fifty three of the patients had lesions that were primarily external, 24 had pelvic or abdominal extension, and 7 were entirely presacral. Benign lesions were treated with complete excision. There were three deaths from intraoperative hemorrhage early in the series with overall survival of 96%. Eight patients with malignant lesions were completely resectable at diagnosis. Of these, six received no further therapy and only one survived. Two other patients with resected lesions received adjunctive chemotherapy (Children's Cancer Study Group 861: vinblastins, bleomycin, cisplatin, cyclophosphamide, adriamycin) and both survived. Six patients with malignant teratomas were unresectable. One received no therapy and one was treated with radiation alone. Both of these children died. The remaining four patients received multiagent chemotherapy followed by second-look procedures. Despite an initial response to therapy in all, two died of recurrent disease and one died of opportunistic interstitial pneumonia but with no evidence of recurrent tumor at autopsy.
Ovarian From the Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine and the James Whitcomb Riley Hospital for Children, Indianapolis, Ind. Presented at the 34th Annual Meeting of the Surgical Section of the American Academy of Pediatrics. San Antonio, Texas, October 19-20, 1985. Address reprint requests to Jay L. Grosfeld, MD, Chairman. Department of Surgery, Indiana University Medical Center, 702 Barnhill Dr, Indianapolis, IN 46223. 9 1986 by Grune & Stratton. Inc. 0022-3468/86/2106-0017503.00/0 548
Teratomas of the ovary were seen in 15 girls aged 18 months to 16 years (mean 9 years). Eleven lesions were benign and four were malignant at diagnosis. Symptoms included abdominal pain in 9 patients, urinary tract complaints in 1, and I patient with an acute abdomen secondary to torsion and necrosis of a 15 cm lesion. A palpable mass was present in 12 patients with tumors ranging in size from 4.6 to 24 cm in greatest dimension. Calcification on x-ray was noted in 11 patients. All patients with benign lesions were treated with unilateral salpingo-oophorectomy. Routine bivalve and biopsy of the opposite ovary was not carried out. There have been no episodes of recurrence
Journal of Pediatric Surgery, Vol 21, No 6 (June), 1986: pp 548-551
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detected on physical examination or periodic ultrasound with followup ranging from 7 months to over 6 years. One 10-year-old girl with a mature benign lesion had associated omental and opposite ovary implants, which contained mature glial tissue on biopsy. Her AFP level was elevated preoperatively at 265 n g / m L but declined to normal levels postoperatively and she remains well at 3~/2 year follow-up. Of five patients with malignant ovarian teratomas, only one was resectable at diagnosis. This girl received both chemotherapy (VAC: vincristine, actinomycin D, cyclophosphamide) and radiation therapy successfully. The remaining four patients underwent laparotomy with biopsy or incomplete excision followed by chemotherapy. Three of these patients died of progressive disease and one of interstitial pneumonia with no evidence of residual tumor at autopsy.
Testicular All teratomas in this location were malignant and were divided into two subgroups based upon age. Six tumors were seen in young infants aged 15 months to 3 years (mean 28 months). All of these occurred on the left side and presented as a painless testicular mass of short duration. One lesion, which had been resected at an outside hospital, had been misdiagnosed preoperatively as a hydrocele. All demonstrated an infantile embryonal (yolk sac) pattern on histologic examination. None had evidence of metastatic disease at presentation. Four underwent retroperitoneal lymph node dissection with negative findings. One patient was referred from an outside hospital 14 months after diagnosis with elevated AFP, pulmonary and hepatic metastases, and massive retroperitoneal adenopathy. He was treated with four courses of cisplatin, bleomycin, and vinblastine with normalization of AFP level and resolution of the pulmonary and hepatic metastases. At anesthetic induction for his planned retroperitoneal node dissection, he developed acute respiratory failure,, which led to his death four months later. No residual tumor was noted at autopsy. The remaining patients are free of disease without further therapy with follow-up ranging from 3 months to 5 years. The nine remaining testicular tumors were seen in older boys ranging from 14 to 17 years. There was no predilection for either side. Duration of symptoms was 3 weeks to 3 months with testicular swelling in all and complaints of pain in half of the patients. Three patients had transscrotal resection of their mass done at outside hospitals and two of these boys developed wound infection. Seven of 9 underwent laparotomy for retroperitoneal lymph node dissections. Two had negative dissections, 3 had dissections with positive nodes, and 2 had massive adenopathy precluding formal node dissection. One patient without retroperitoneal node dissection early in the series received no further therapy and died of his disease. The remaining patients all underwent adjunctive chemotherapy; two with actinomycin D (one also received radiation), and the remainder with cisplatin, bleomycin, and vinblastine. Follow-up ranges from 3 months to 9 years with six patients followed over 3 years. All remain free of disease.
Mediastinal Fourteen patients presented with anterior mediastinal teratoma. Their ages covered a wide range from newborn to 18 years. The newborn presented with severe respiratory distress requiring intubation in the delivery room. One patient presented with superior vena cava syndrome and the remaining patients all presented with minor respiratory symptoms persisting over a 3-week to 6-month period including cough in 3 children, wheezing in 4, and dyspnea in 6. All tumors were located in the anterior mediastinum and five were calcified on chest x-ray. The 12 patients with benign lesions underwent excision by a right thoracotomy approach and remain free of
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recurrence from 15 months to 5 years. Two patients with malignant lesions had unresectable extension of tumor into the pericardium and epicardium and subsequently died of their disease without further therapy.
Retroperitoneal Six girls and one boy had retroperitoneal teratomas. Age ranged from newborn to 3 years with a mean of 19 months. Five had a palpable mass as the presenting complaint, one had abdominal distention, and one child with malignancy at diagnosis presented with fecal and urinary retention and right leg paralysis secondary to invasion of the spinal canal by tumor. Six of the 7 lesions were calcified on x-ray and size of the mass varied from 6 to 15 cm in greatest dimension. Five benign teratomas were completely excised without recurrence. One girl had an immature lesion associated with mature peritoneal implants of columnar epithelium. Her primary lesion was completely excised but she had a local recurrence six months later, which was malignant on histologic examination. This was treated by surgical excision followed by multiagent chemotherapy under The Children's Cancer Study Group (CCG) protocol 861 and she continues free of disease 7 months into therapy. The girl with malignancy at diagnosis had an unresectable mass, which was treated by decompressive laminectomy and biopsy followed by chemotherapy under CCG protocol 861. Although she had an initial response to therapy with a decrease in both size of the tumor mass and AFP level, progressive disease resulted in death 14 months after diagnosis.
Cervical Cervical teratomas were seen in three boys and all had benign histology. Ages were 12 months, 14 months, and 2t/2 years. Each presented with an anterior neck mass, which was easily resected without recurrence.
Other Sites A four-month-old girl presented with a complaint of regurgitation of feedings for 2 weeks and an episode of upper gastrointestinal bleeding shortly after birth. She was found to have a mature teratoma arising from the gastroesophageal junction, which was excised without recurrence. A 33-week gestation premature male was noted to have polyhydramnios and a midfacial mass on prenatal ultrasound. Emergency cesarian section was carried out for fetal distress and he was found to have multilobulated masses protruding from his nose and mouth. Despite emergency tracheostomy, he expired at 12 days of age from progressive respiratory failure. At autopsy, the lesion was found to be a massive benign teratoma arising from the palate. Two 12-month-old girls presented with a 2-month history of vaginal bleeding. One was found to have a malignant teratoma of yolk sac histology arising from the vagina. She was treated by vaginectomy, hysterectomy, and chemotherapy under CCG protocol 861. She remains disease free at completion of chemotherapy 2 years after diagnosis. The second child with vaginal bleeding was found to have a yolk sac malignancy arising from the cervix and was initially treated with hysterectomy but developed local recurrence within one month of operation. She then underwent radical vulvectomy and vaginectomy followed by radiation and VAC chemotherapy. She remains free of disease at 8-year follow-up.
Alpha Fetoprotein Serum alpha fetoprotein (AFP) levels were obtained preoperatively in 29 patients with teratoma including 14 sacrococcygeal, 6 ovarian, 1 testicular, 3 mediastinal, 4 retroperitoneal, and 1 vaginal.
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BILLMIRE AND GROSFELD
The normal range for age established by Tsuchida et al 2 was used to interpret the values. Of 19 patients with mature benign lesions at diagnosis, only one elevated value was seen in a girl with benign ovarian teratoma with mature glial implants. All four patients with malignancy at diagnosis (sacrococcygeal, retroperitoneal, testicular, and vagina) had AFP levels that were elevated for age. In all of these patients, AFP level correlated well with presence of active disease. Six patients with immature teratomas had preoperative AFP levels, (3 retroperitoneal, 2 ovary, 1 sacrococcygeal). Elevated values were noted in one child with sacrococcygeal and two with retroperitoneal lesions. One of these children later had a malignant recurrence, which was detected by an asymptomatic rise in AFP level. Of five patients in our series who developed malignant recurrence of previously resected benign lesions, three were detected by an asymptomatic elevation of their AFP level. Radiographic evaluation revealed the site of recurrence in two patients but use of radiolabeled antibodies to AFP was required to demonstrate the location of recurrence in the other patient, After subsequent surgical excision and chemotherapy, all of these patients are free of disease at 1 to 5 years follow-up.
Beta Human Chorionic Gonadotrophin Twenty-fourpatients had preoperativeassessment of beta human chorionic gonadotrophin (BHCG) level. Both teenage boys with malignant testicular teratoma had marked elevation (1,570 and 126,000 mlu/mL). Three other patients with malignant lesions at other sites (sacrococcygeal,retroperitoneal,vagina) all had levels less than 1.56 mlU/mL. The remaining 19 patients with benign lesions had values ranging from less than 1.56to 34 mlU/mL. All of the mildlyelevatedvalues were seen in infants less than one year of age. DISCUSSION
Teratomas are complex neoplasms composed of tissues derived from all three dermal layers: endoderm, mesoderm, and ectoderm. They may occur in many different areas of the body but are most often seen in midline and para-axial locations. The preponderance of teratomas arising in sacrococcygeal (59%) and gonadal (22%) sites observed in our series is similar to that reported in the literature. 3-5 As in most series, females accounted for approximately three fourths of the sacrococcygeal tumors. The overall incidence of malignancy was 28%. The risk of malignancy depends on the anatomic site. No malignant teratomas arising in the neck, oropharynx, or stomach have been reported in childhood, although regional lymph nodes containing glial implants have been described with benign cervical teratomas. 6'7 These tumors are remarkable not only for their histologic diversity but also for their clinical unpredictability. Multiple morphologic factors including size, cystic or solid character, and presence of calcification have been considered as possible predictors of malignant components or the potential for malignant recurrence. None of these, however, has been shown to be of significance. One consistent risk factor confirmed in several series has been the age at diagnosis for sacro-
coccygeal teratomas. In Altman's 8 survey of 405 patients, malignancy was noted in 7% of girls and 10% of boys diagnosed at less than two months of age compared with 48% of girls and 67% of boys above this age. Previous reports have suggested that this observation may be due to malignant transformation over time with continued growth of an initially benign lesion. Four of our patients had obvious sacrococcygeal teratoma from birth but did not present for excision until 6 weeks to 2 years of age and all of these were benign. Review of other series 9'~~discloses 34 similar patients with delay in excision of a recognized leesion over 5 weeks. Nine of these patients (24%) had malignancy at diagnosis, a percentage considerably less than would be predicted for infants presenting with newly recognized lesions in the age group over one month. Age at diagnosis has not been found to be predictive of malignancy for teratomas at other sites. The occurrence of gliomatosis peritonei seen in association with ovarian teratoma refers to the finding of multiple small implants of teratoma studding the peritoneal surface and was first reported by Proskauer in 1946.1~ While generally felt to be a benign phenomenon, episodes of subsequent malignancy have been reported. Our series includes two patients with gliomatosis, one with ovarian teratoma and one with a retropertioneal teratoma, an association that has not previously been reported. Progression to malignancy was seen only in the child with retroperitoneal teratoma whose initial lesion showed immature histology. The development of a malignant recurrence after excision of a benign primary tumor has also been observed. There were five such patients in our series (4.7%) with recurrence occurring 4 months to two and a half years after the initial diagnosis. Of the three sacrococcygeal teratomas, two were classified AAP Type III and one was AAP Type IV. s These categories have been reported by Altman as having an increased association with malignancy. No other risk factors for malignancy could be identified in the remaining patients. All three patients who had undergone resection of their primary tumor at our institution had their recurrence detected at an asymptomatic stage by serial monitoring of AFP level on routine follow-up. With radiologic evaluation, the site of recurrence was documented and treated with surgical excision followed by chemotherapy. All of these children are surviving free of tumor. The remaining two patients had undergone resection of their primary lesion at an outside hospital and were referred to us with symptomatic unresectable recurrence. Both were treated with chemotherapy and one survived after second-look resection. These patients emphasize the need for long-term continued follow-up with serum AFP monitoring in all patients
TERATOMAS IN CHILDHOOD
551
after excision of t e r a t o m a with good prognosis for those lesions d e t e c t e d in an a s y m p t o m a t i c phase. T h e use of a l p h a fetoprotein level m a y be a helpful indicator of the presence of m a l i g n a n c y . In interpreting these values, it is i m p o r t a n t to recognize t h a t elevated values m a y be seen in n o r m a l newborns, which decline to a d u l t values by 9 months of age. A p p l y i n g the n o r m a l curve of T s u c h i d a 2 m a k e s this s e r u m m a r k e r a helpful but not absolute d i s c r i m i n a t i v e factor. Elevated values were seen in 100% of m a l i g n a n t lesions, 50% of i m m a t u r e lesions, and 6% of m a t u r e benign lesions. In children with established m a l i g n a n cy, s e r u m A F P level has been a reliable indicator of disease activity. Prognosis for m a l i g n a n t t e r a t o m a s is r e l a t e d to stage
of disease at diagnosis r a t h e r t h a n to p r i m a r y a n a t o m i c site. T h e exception is the m a l i g n a n t t e r a t o m a of the infant testis, which has a relatively favorable prognosis c o m p a r e d with all other sites. W h e n t r e a t e d with surgical excision alone, survival is 25% to 78% 12 comp a r e d with n e a r l y universal r e c u r r e n c e and d e a t h with t e r a t o m a s at other sites. These findings a r e confirmed in our series with 100% survival in r e s e c t a b l e nontest i c u l a r patients who received a d j u n c t i v e c h e m o t h e r a p y c o m p a r e d with 17% with s u r g e r y alone. F o r patients who were u n r e s e c t a b l e at diagnosis, a p r o g r a m of c h e m o t h e r a p y followed by second-look o p e r a t i o n resulted in a survival of only 11%, although two of the deaths were r e l a t e d to opportunistic infection in patients who were free of tumor.
REFERENCES
1. Brodheur GM, Howarth CB, Pratt CB, et al: Malignant germ cell tumors in 57 children and adolescents. Cancer 48:1890-1898, 1981 2. Tsuchida Y, Endo Y, Saito S, et al: Evaluation of alphafetoprotein in early infancy. J Pediatr Surg 13:155-156, 1978 3. Berry CC, Keeling J, Hilton C: Teratomata in infancy and childhood: A review of 91 cases. J Pathol 98:241-252, 1969 4. Mahour GH, Landing BH, Woolley MM: Teratomas in children: Clinicopathologic studies in 133 patients. Z Kinderchir 23:365-380, 1978 5. Tapper D, Lack EE: Teratomas in infancy and childhood: A 54 year experience at the Children's Hospital Medical Center. Ann Surg 198:398-410, 1982 6. Watanatittan S, Othersen HB Jr, Hughson MD: Cervical teratoma in children. Prog Pediatr Surg 14:225-239, 1981
7. Gundrey SR, Wesley JR, Klein MD, et al: Cervical teratomas in the newborn. J Pediatr Surg 18:382-386, 1983 8. Altman RP, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatric Surgical Section survey. J Pediatr Surg 9:389-398, 1974 9. Donnellan WA, Swenson O: Benign and malignant sacrococcygeal teratomas. Surgery 64:834-846, 1968 10. Mahour GH, Wooley MM, Triveds SN, et al: Sacrococcygeal teratoma: A 33 year experience. J Pediatr Surg 10:183-188, 1975 11. Proskauer GG: Solid teratoma of the ovary with neurological metastases. Am J Obstet Gynecol 1:643-653, 1970 12. Green DM: The diagnosis and treatment of yolk sac tumors in infants and children. Cancer Treat Rev 10:265-288, 1983
Indianapolis, Indiana 9 This report concerns 142 infants and children with teratomas treated from 1960 to 1984. The primary site of tumor was sacrococcygeal in 84, ovarian in 15, testicular in 15, mediastinal in 14, retroperitoneal in 7, cervical in 3, and other in 4. Malignancy occurred in 40 of 142 (28%) patients. Serum for alphafetoprotein (AFP) was obtained preoperatively in 29 patients. Elevated AFP was seen in all patients with malignancy, 3 of 6 with immature lesions and 1 of 19 with a benign lesion. Postoperative rise in AFP levels was a good indicator of malignant recurrence. Beta human chronic gonadotropin (BHCG) levels w e r e only helpful in following teenage boys with testicular lesions. Benign tumors w e r e treated by complete excision alone with a 9 7 % survival. Testicular malignancies had a good prognosis with 13 of 15 surviving (87%) despite distant metastasis in four. In contrast, survival was only 3 2 % with nontesticular malignancies. Survival was 17% for resectable malignant cases treated with surgery alone compared with 1 0 0 % when operation was followed by multiagent chemotherapy. Unresectable malignant lesions w e r e usually fatal despite multiagent chemotherapy and/or second-look procedures. 9 1986 by Grune & Stratton, Inc. INDEX WORDS: Teratoma; alphafetoprotein; endodermal sinus tumor.
E R A T O M A S are the most diverse group of tumors in childhood accounting for 3% of all childhood malignancies) These tumors most often occur in a para-axial or midline location from the brain to the sacral area as well as in the gonads. This report describes a 25-year experience with 142 childhood teratomas treated at a single pediatric cancer facility. These data suggest that (1) surgical excision alone is the therapy of choice in benign cases, and (2) multiagent chemotherapy and surveillance with tumor markers have improved both recognition and survival in malignant cases.
T
PATIENTS One hundred forty-two infants and children with teratomas were evaluated and treated at the James Whitcomb Riley Hospital for
Children, Indiana University Medical Center in Indianapolis from 1960 to 1984. All sites except the central nervous system are included in this review.
Sacrococcygeal Sacrococcygeal tumors were the most frequent lesions observed in 84 cases or 59% of the total patients. The majority of these tumors were seen in girls (76%). Benign lesions occurred in 70 patients (83%), malignant lesions in 11 (13%) and 3 lesions that were initially benign later recurred as malignancies (4%). Most patients presented with an obvious sacral mass; some, however, had only asymmetry of the buttocks and seven patients had entirely presacral lesions. Prenatal ultrasound in three newborns showed polyhydramnios in all and a fetal mass in two. Age at diagnosis correlated with risk of malignancy as infants less than one month of age had a 3% incidence of malignancy compared with 38% in children over one month. It is interesting to note, however, that four patients with obvious lesions since birth had a significant delay (6 weeks, 9 months, I1 months, 2 years) in treatment. Surprisingly, all of these were found to be benign with mature histology and were resected without recurrence. Tumors ranged in size from 2.5 to 30 cm in greatest dimension (mean 13.2 cm) with most lesions having a mixture of solid and cystic components. Lumbosacral spine radiographs were obtained in 16 patients. Both patients with malignant tumors had intact sacrum as did 12 of 14 patients with benign lesions. Size and character of the tumor were unrelated to the incidence of malignancy. Fifty three of the patients had lesions that were primarily external, 24 had pelvic or abdominal extension, and 7 were entirely presacral. Benign lesions were treated with complete excision. There were three deaths from intraoperative hemorrhage early in the series with overall survival of 96%. Eight patients with malignant lesions were completely resectable at diagnosis. Of these, six received no further therapy and only one survived. Two other patients with resected lesions received adjunctive chemotherapy (Children's Cancer Study Group 861: vinblastins, bleomycin, cisplatin, cyclophosphamide, adriamycin) and both survived. Six patients with malignant teratomas were unresectable. One received no therapy and one was treated with radiation alone. Both of these children died. The remaining four patients received multiagent chemotherapy followed by second-look procedures. Despite an initial response to therapy in all, two died of recurrent disease and one died of opportunistic interstitial pneumonia but with no evidence of recurrent tumor at autopsy.
Ovarian From the Department of Surgery, Section of Pediatric Surgery, Indiana University School of Medicine and the James Whitcomb Riley Hospital for Children, Indianapolis, Ind. Presented at the 34th Annual Meeting of the Surgical Section of the American Academy of Pediatrics. San Antonio, Texas, October 19-20, 1985. Address reprint requests to Jay L. Grosfeld, MD, Chairman. Department of Surgery, Indiana University Medical Center, 702 Barnhill Dr, Indianapolis, IN 46223. 9 1986 by Grune & Stratton. Inc. 0022-3468/86/2106-0017503.00/0 548
Teratomas of the ovary were seen in 15 girls aged 18 months to 16 years (mean 9 years). Eleven lesions were benign and four were malignant at diagnosis. Symptoms included abdominal pain in 9 patients, urinary tract complaints in 1, and I patient with an acute abdomen secondary to torsion and necrosis of a 15 cm lesion. A palpable mass was present in 12 patients with tumors ranging in size from 4.6 to 24 cm in greatest dimension. Calcification on x-ray was noted in 11 patients. All patients with benign lesions were treated with unilateral salpingo-oophorectomy. Routine bivalve and biopsy of the opposite ovary was not carried out. There have been no episodes of recurrence
Journal of Pediatric Surgery, Vol 21, No 6 (June), 1986: pp 548-551
TERATOMAS IN CHILDHOOD
detected on physical examination or periodic ultrasound with followup ranging from 7 months to over 6 years. One 10-year-old girl with a mature benign lesion had associated omental and opposite ovary implants, which contained mature glial tissue on biopsy. Her AFP level was elevated preoperatively at 265 n g / m L but declined to normal levels postoperatively and she remains well at 3~/2 year follow-up. Of five patients with malignant ovarian teratomas, only one was resectable at diagnosis. This girl received both chemotherapy (VAC: vincristine, actinomycin D, cyclophosphamide) and radiation therapy successfully. The remaining four patients underwent laparotomy with biopsy or incomplete excision followed by chemotherapy. Three of these patients died of progressive disease and one of interstitial pneumonia with no evidence of residual tumor at autopsy.
Testicular All teratomas in this location were malignant and were divided into two subgroups based upon age. Six tumors were seen in young infants aged 15 months to 3 years (mean 28 months). All of these occurred on the left side and presented as a painless testicular mass of short duration. One lesion, which had been resected at an outside hospital, had been misdiagnosed preoperatively as a hydrocele. All demonstrated an infantile embryonal (yolk sac) pattern on histologic examination. None had evidence of metastatic disease at presentation. Four underwent retroperitoneal lymph node dissection with negative findings. One patient was referred from an outside hospital 14 months after diagnosis with elevated AFP, pulmonary and hepatic metastases, and massive retroperitoneal adenopathy. He was treated with four courses of cisplatin, bleomycin, and vinblastine with normalization of AFP level and resolution of the pulmonary and hepatic metastases. At anesthetic induction for his planned retroperitoneal node dissection, he developed acute respiratory failure,, which led to his death four months later. No residual tumor was noted at autopsy. The remaining patients are free of disease without further therapy with follow-up ranging from 3 months to 5 years. The nine remaining testicular tumors were seen in older boys ranging from 14 to 17 years. There was no predilection for either side. Duration of symptoms was 3 weeks to 3 months with testicular swelling in all and complaints of pain in half of the patients. Three patients had transscrotal resection of their mass done at outside hospitals and two of these boys developed wound infection. Seven of 9 underwent laparotomy for retroperitoneal lymph node dissections. Two had negative dissections, 3 had dissections with positive nodes, and 2 had massive adenopathy precluding formal node dissection. One patient without retroperitoneal node dissection early in the series received no further therapy and died of his disease. The remaining patients all underwent adjunctive chemotherapy; two with actinomycin D (one also received radiation), and the remainder with cisplatin, bleomycin, and vinblastine. Follow-up ranges from 3 months to 9 years with six patients followed over 3 years. All remain free of disease.
Mediastinal Fourteen patients presented with anterior mediastinal teratoma. Their ages covered a wide range from newborn to 18 years. The newborn presented with severe respiratory distress requiring intubation in the delivery room. One patient presented with superior vena cava syndrome and the remaining patients all presented with minor respiratory symptoms persisting over a 3-week to 6-month period including cough in 3 children, wheezing in 4, and dyspnea in 6. All tumors were located in the anterior mediastinum and five were calcified on chest x-ray. The 12 patients with benign lesions underwent excision by a right thoracotomy approach and remain free of
549
recurrence from 15 months to 5 years. Two patients with malignant lesions had unresectable extension of tumor into the pericardium and epicardium and subsequently died of their disease without further therapy.
Retroperitoneal Six girls and one boy had retroperitoneal teratomas. Age ranged from newborn to 3 years with a mean of 19 months. Five had a palpable mass as the presenting complaint, one had abdominal distention, and one child with malignancy at diagnosis presented with fecal and urinary retention and right leg paralysis secondary to invasion of the spinal canal by tumor. Six of the 7 lesions were calcified on x-ray and size of the mass varied from 6 to 15 cm in greatest dimension. Five benign teratomas were completely excised without recurrence. One girl had an immature lesion associated with mature peritoneal implants of columnar epithelium. Her primary lesion was completely excised but she had a local recurrence six months later, which was malignant on histologic examination. This was treated by surgical excision followed by multiagent chemotherapy under The Children's Cancer Study Group (CCG) protocol 861 and she continues free of disease 7 months into therapy. The girl with malignancy at diagnosis had an unresectable mass, which was treated by decompressive laminectomy and biopsy followed by chemotherapy under CCG protocol 861. Although she had an initial response to therapy with a decrease in both size of the tumor mass and AFP level, progressive disease resulted in death 14 months after diagnosis.
Cervical Cervical teratomas were seen in three boys and all had benign histology. Ages were 12 months, 14 months, and 2t/2 years. Each presented with an anterior neck mass, which was easily resected without recurrence.
Other Sites A four-month-old girl presented with a complaint of regurgitation of feedings for 2 weeks and an episode of upper gastrointestinal bleeding shortly after birth. She was found to have a mature teratoma arising from the gastroesophageal junction, which was excised without recurrence. A 33-week gestation premature male was noted to have polyhydramnios and a midfacial mass on prenatal ultrasound. Emergency cesarian section was carried out for fetal distress and he was found to have multilobulated masses protruding from his nose and mouth. Despite emergency tracheostomy, he expired at 12 days of age from progressive respiratory failure. At autopsy, the lesion was found to be a massive benign teratoma arising from the palate. Two 12-month-old girls presented with a 2-month history of vaginal bleeding. One was found to have a malignant teratoma of yolk sac histology arising from the vagina. She was treated by vaginectomy, hysterectomy, and chemotherapy under CCG protocol 861. She remains disease free at completion of chemotherapy 2 years after diagnosis. The second child with vaginal bleeding was found to have a yolk sac malignancy arising from the cervix and was initially treated with hysterectomy but developed local recurrence within one month of operation. She then underwent radical vulvectomy and vaginectomy followed by radiation and VAC chemotherapy. She remains free of disease at 8-year follow-up.
Alpha Fetoprotein Serum alpha fetoprotein (AFP) levels were obtained preoperatively in 29 patients with teratoma including 14 sacrococcygeal, 6 ovarian, 1 testicular, 3 mediastinal, 4 retroperitoneal, and 1 vaginal.
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BILLMIRE AND GROSFELD
The normal range for age established by Tsuchida et al 2 was used to interpret the values. Of 19 patients with mature benign lesions at diagnosis, only one elevated value was seen in a girl with benign ovarian teratoma with mature glial implants. All four patients with malignancy at diagnosis (sacrococcygeal, retroperitoneal, testicular, and vagina) had AFP levels that were elevated for age. In all of these patients, AFP level correlated well with presence of active disease. Six patients with immature teratomas had preoperative AFP levels, (3 retroperitoneal, 2 ovary, 1 sacrococcygeal). Elevated values were noted in one child with sacrococcygeal and two with retroperitoneal lesions. One of these children later had a malignant recurrence, which was detected by an asymptomatic rise in AFP level. Of five patients in our series who developed malignant recurrence of previously resected benign lesions, three were detected by an asymptomatic elevation of their AFP level. Radiographic evaluation revealed the site of recurrence in two patients but use of radiolabeled antibodies to AFP was required to demonstrate the location of recurrence in the other patient, After subsequent surgical excision and chemotherapy, all of these patients are free of disease at 1 to 5 years follow-up.
Beta Human Chorionic Gonadotrophin Twenty-fourpatients had preoperativeassessment of beta human chorionic gonadotrophin (BHCG) level. Both teenage boys with malignant testicular teratoma had marked elevation (1,570 and 126,000 mlu/mL). Three other patients with malignant lesions at other sites (sacrococcygeal,retroperitoneal,vagina) all had levels less than 1.56 mlU/mL. The remaining 19 patients with benign lesions had values ranging from less than 1.56to 34 mlU/mL. All of the mildlyelevatedvalues were seen in infants less than one year of age. DISCUSSION
Teratomas are complex neoplasms composed of tissues derived from all three dermal layers: endoderm, mesoderm, and ectoderm. They may occur in many different areas of the body but are most often seen in midline and para-axial locations. The preponderance of teratomas arising in sacrococcygeal (59%) and gonadal (22%) sites observed in our series is similar to that reported in the literature. 3-5 As in most series, females accounted for approximately three fourths of the sacrococcygeal tumors. The overall incidence of malignancy was 28%. The risk of malignancy depends on the anatomic site. No malignant teratomas arising in the neck, oropharynx, or stomach have been reported in childhood, although regional lymph nodes containing glial implants have been described with benign cervical teratomas. 6'7 These tumors are remarkable not only for their histologic diversity but also for their clinical unpredictability. Multiple morphologic factors including size, cystic or solid character, and presence of calcification have been considered as possible predictors of malignant components or the potential for malignant recurrence. None of these, however, has been shown to be of significance. One consistent risk factor confirmed in several series has been the age at diagnosis for sacro-
coccygeal teratomas. In Altman's 8 survey of 405 patients, malignancy was noted in 7% of girls and 10% of boys diagnosed at less than two months of age compared with 48% of girls and 67% of boys above this age. Previous reports have suggested that this observation may be due to malignant transformation over time with continued growth of an initially benign lesion. Four of our patients had obvious sacrococcygeal teratoma from birth but did not present for excision until 6 weeks to 2 years of age and all of these were benign. Review of other series 9'~~discloses 34 similar patients with delay in excision of a recognized leesion over 5 weeks. Nine of these patients (24%) had malignancy at diagnosis, a percentage considerably less than would be predicted for infants presenting with newly recognized lesions in the age group over one month. Age at diagnosis has not been found to be predictive of malignancy for teratomas at other sites. The occurrence of gliomatosis peritonei seen in association with ovarian teratoma refers to the finding of multiple small implants of teratoma studding the peritoneal surface and was first reported by Proskauer in 1946.1~ While generally felt to be a benign phenomenon, episodes of subsequent malignancy have been reported. Our series includes two patients with gliomatosis, one with ovarian teratoma and one with a retropertioneal teratoma, an association that has not previously been reported. Progression to malignancy was seen only in the child with retroperitoneal teratoma whose initial lesion showed immature histology. The development of a malignant recurrence after excision of a benign primary tumor has also been observed. There were five such patients in our series (4.7%) with recurrence occurring 4 months to two and a half years after the initial diagnosis. Of the three sacrococcygeal teratomas, two were classified AAP Type III and one was AAP Type IV. s These categories have been reported by Altman as having an increased association with malignancy. No other risk factors for malignancy could be identified in the remaining patients. All three patients who had undergone resection of their primary tumor at our institution had their recurrence detected at an asymptomatic stage by serial monitoring of AFP level on routine follow-up. With radiologic evaluation, the site of recurrence was documented and treated with surgical excision followed by chemotherapy. All of these children are surviving free of tumor. The remaining two patients had undergone resection of their primary lesion at an outside hospital and were referred to us with symptomatic unresectable recurrence. Both were treated with chemotherapy and one survived after second-look resection. These patients emphasize the need for long-term continued follow-up with serum AFP monitoring in all patients
TERATOMAS IN CHILDHOOD
551
after excision of t e r a t o m a with good prognosis for those lesions d e t e c t e d in an a s y m p t o m a t i c phase. T h e use of a l p h a fetoprotein level m a y be a helpful indicator of the presence of m a l i g n a n c y . In interpreting these values, it is i m p o r t a n t to recognize t h a t elevated values m a y be seen in n o r m a l newborns, which decline to a d u l t values by 9 months of age. A p p l y i n g the n o r m a l curve of T s u c h i d a 2 m a k e s this s e r u m m a r k e r a helpful but not absolute d i s c r i m i n a t i v e factor. Elevated values were seen in 100% of m a l i g n a n t lesions, 50% of i m m a t u r e lesions, and 6% of m a t u r e benign lesions. In children with established m a l i g n a n cy, s e r u m A F P level has been a reliable indicator of disease activity. Prognosis for m a l i g n a n t t e r a t o m a s is r e l a t e d to stage
of disease at diagnosis r a t h e r t h a n to p r i m a r y a n a t o m i c site. T h e exception is the m a l i g n a n t t e r a t o m a of the infant testis, which has a relatively favorable prognosis c o m p a r e d with all other sites. W h e n t r e a t e d with surgical excision alone, survival is 25% to 78% 12 comp a r e d with n e a r l y universal r e c u r r e n c e and d e a t h with t e r a t o m a s at other sites. These findings a r e confirmed in our series with 100% survival in r e s e c t a b l e nontest i c u l a r patients who received a d j u n c t i v e c h e m o t h e r a p y c o m p a r e d with 17% with s u r g e r y alone. F o r patients who were u n r e s e c t a b l e at diagnosis, a p r o g r a m of c h e m o t h e r a p y followed by second-look o p e r a t i o n resulted in a survival of only 11%, although two of the deaths were r e l a t e d to opportunistic infection in patients who were free of tumor.
REFERENCES
1. Brodheur GM, Howarth CB, Pratt CB, et al: Malignant germ cell tumors in 57 children and adolescents. Cancer 48:1890-1898, 1981 2. Tsuchida Y, Endo Y, Saito S, et al: Evaluation of alphafetoprotein in early infancy. J Pediatr Surg 13:155-156, 1978 3. Berry CC, Keeling J, Hilton C: Teratomata in infancy and childhood: A review of 91 cases. J Pathol 98:241-252, 1969 4. Mahour GH, Landing BH, Woolley MM: Teratomas in children: Clinicopathologic studies in 133 patients. Z Kinderchir 23:365-380, 1978 5. Tapper D, Lack EE: Teratomas in infancy and childhood: A 54 year experience at the Children's Hospital Medical Center. Ann Surg 198:398-410, 1982 6. Watanatittan S, Othersen HB Jr, Hughson MD: Cervical teratoma in children. Prog Pediatr Surg 14:225-239, 1981
7. Gundrey SR, Wesley JR, Klein MD, et al: Cervical teratomas in the newborn. J Pediatr Surg 18:382-386, 1983 8. Altman RP, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatric Surgical Section survey. J Pediatr Surg 9:389-398, 1974 9. Donnellan WA, Swenson O: Benign and malignant sacrococcygeal teratomas. Surgery 64:834-846, 1968 10. Mahour GH, Wooley MM, Triveds SN, et al: Sacrococcygeal teratoma: A 33 year experience. J Pediatr Surg 10:183-188, 1975 11. Proskauer GG: Solid teratoma of the ovary with neurological metastases. Am J Obstet Gynecol 1:643-653, 1970 12. Green DM: The diagnosis and treatment of yolk sac tumors in infants and children. Cancer Treat Rev 10:265-288, 1983