Pediatr Blood 2014;61:363–365

BRIEF REPORT Increased Incidence of Retroperitoneal and Decreased Incidence of Sacrococcygeal Teratomas in With Down Syndrome

Tetsuko Kobayashi, MD,* Yoshihiro Sakemi, MD, and Hironori Yamashita, MD, PhD

Individuals with Down syndrome (DS) have a unique profile of found that the incidence of retroperitoneal teratomas was higher and , with a higher incidence of and a lower the incidence of sacrococcygeal teratomas was lower in infants with incidence of solid tumors than seen in the general population. We DS than in the general population. Pediatr Blood Cancer 2014;61: recently encountered two cases of infants with DS with retroperito- 363–365. # 2013 Wiley Periodicals, Inc. neal . After reviewing the literature on teratomas in DS, we

Key words: Down syndrome; ; retroperitoneal teratoma; sacrococcygeal teratoma

INTRODUCTION showed calcification in the left upper . Abdominal ultrasonography showed a 6-cm mass in the RP area. Magnetic Down syndrome (DS) has a unique profile of neoplasms, with a resonance imaging showed a 6.3 cm  6.2 cm  4.9 cm multi- higher incidence of and a lower incidence of solid tumors, lobular cystic mass in the RP area, compressing the pancreas and except for testicular tumors, than the general population [1–4]. The splenic artery and vein. Serum AFP and NSE levels were 16.6 and decreased incidence of most solid tumors in DS has been associated 64.8 ng/ml, respectively. During surgery, a 6-cm tumor was found at with specific chromosome 21 genes [5,6]. the upper side of the left kidney. The caudal part of the tumor Teratoma is the most common histologic subtype of childhood adhered tightly to the left adrenal . The tumor was removed germ cell tumors arising in gonadal and extragonadal locations [7]. surgically, along with part of the left adrenal gland. Histopatholog- During infancy, most germ cell tumors are extragonadal ical examination revealed a 7.5 cm  7.0 cm solid, partly cystic teratomas [8]: sacrococcygeal (SC) teratomas are the largest mass composed of cells with skin and its appendages, bronchial subgroup and retroperitoneal (RP) and mediastinal teratomas are tissue, choroid plexus and neural tissue (cerebrum and cerebellum), minor subgroups [8,9]. A previous literature review showed that, of adipose tissue, partly immature foci, smooth muscle elements, seven infants with DS with teratomas, five were RP and only two adrenal tissue, bone, and bone marrow. Compact growth foci of were at other locations [1]. We also encountered two cases of RP small round cells with vacuolated cytoplasm were present. teratomas in infants with DS. Our experience and the literature Immature teratoma was diagnosed. Relapse or recurrence has not review together suggest that RP teratomas occur more frequently occurred for 4 years. and that SC teratomas occur less frequently in infants with DS than in the general population. We compare the clinical features of two DISCUSSION infants with DS with RP teratoma with those previously described. Including the two patients described here, 11 infants with DS Patient 1 teratomas have been identified in the literature (Table I) 8 with RP and 3 with cranial teratomas, but none with SC teratomas by At the age of 6 months, a palpable mass was detected in the searching PubMed using the search terms (germ cell tumors OR upper abdomen of a female infant with DS, born at gestational age teratoma) and DS, which showed 46 original articles that included 9 36 weeks, 4 days, weighing 2,550 g. Abdominal ultrasonography pediatric teratomas. showed a 5-cm mass in the RP area; computed tomography showed The eight patients with DS with RP teratoma (Patients 1, 3, 5–8, a 5.5-cm mass with calcification adjacent to the right kidney and 10, and 11) included three male and five female patients. Female right side . Serum a-fetoprotein (AFP) and neuron- predominance was in agreement with surveys of teratomas in the specific enolase (NSE) levels were 42.8 and 13.0 ng/ml, respectively. general infant population [8]. Birth weights ranged from 2,100 to At surgery, a round 7.5-cm tumor was found in the RP area and was 5,100 g (mean Æ SD, 2,898 Æ 889.3 g). Ages at diagnosis ranged exfoliated from the surrounding tissues and excised en bloc. from 34 weeks of gestation to 5 years (median age, 5.5 months), in Histopathological examination showed the presence of multilobular agreement with findings showing that most RP teratomas are lined by ciliated columnar, respiratory-type pseudostratified diagnosed during the first year of life [17]. Five tumors were columnar or squamous . Lymphoid follicles, peripheral discovered by palpation, and 2 by calcified images on radiography. nerves, and cartilaginous and adipose tissue including benign lipoblasts, smooth muscle cells, and neural tissue with choroid plexus were also noted. Mature cystic teratoma was diagnosed. One Department of Pediatrics, National Hospital Organization Kokura year later, the tumor has not recurred. Medical Center, Fukuokashi, Fukuokaken ÃCorrespondence to: T. Kobayashi, Department of Pediatrics, Kyushu Patient 2 University Hospital Maidashi, 3-1-1, Higashiku, Fukuokashi, Fukuokaken. Patient 2 was a female infant with DS, born at gestational age E-mail: [email protected] 37 weeks, 3 days, weighing 2,216 g. At 1 year, chest radiography Received 20 April 2013; Accepted 19 June 2013

C 2013 Wiley Periodicals, Inc. DOI 10.1002/pbc.24693 Published online 31 July 2013 in Wiley Online Library (wileyonlinelibrary.com). 364 Kobayashi et al.

Since infants undergo regular well-baby examinations, tumors can be detected before symptoms develop. Delayed discovery can result in larger tumors and more advanced [17]. Patient 8 experienced rupture of a huge tumor, and, in patients 10 and 11, pressure from other organs resulted in hydronephrosis and a pressed pancreas. Histologically, of the 11 teratomas, 9 were mature, and 2 were immature (all benign). This predominance of benign teratomas is also observed in general infant populations in other studies [8,17]. Despite being benign, these tumors may cause death

shortly after hospitalization 56 days of hospitalization by rupture, as in Patient 8.

Died a few hours after birth We also compared tumor locations in infants with and without DS. In the latter, SC teratomas were the most common and RP teratomas, the least common. The percentages of patients with SC and RP teratomas were 41.7% and 4.4%, respectively, in a German study [8], and 88% and 12%, respectively, in an Italian study [9]. A literature review of all tumors in patients with DS showed a

grade II–III predominance of RP teratomas [1]. Among infants with DS with Matura teratoma Tumor completely resected Mature teratoma Disease free for 56 months teratomas, six had RP but none had SC teratomas, possibly providing further evidence of the predominance of RP teratomas in infants with DS. However, this is difficult to confirm because of insufficient numbers of tumors for study as the frequency of infants with DS with teratomas is very low and performance of cohort studies is difficult. Therefore, we believe that the evidence presented here is necessary and sufficient. The increased incidence of RP teratomas in infants with DS decreased tone radiograph may be due to the pathologic association between RP teratomas and fetus-in-fetu (FIF) [18]. FIF, regarded as a malformed parasitic monozygotic diamniotic twin found inside the body of a living child or adult, is distinguished from teratoma by the presence of a spinal axis [19]. However, whether FIF is a malformation or a tumor (i.e., a highly differentiated teratoma) is uncertain [18]. The most frequent site of FIF is the RP area [19]. Thus, some infants with DS with RP teratomas may actually have FIFs, which would be confirmed by the presence of an axial skeleton within the supposed RP teratoma. The lack of SC teratomas in DS may be due to the activation of genes specifically in patients with DS. Comparisons of genetic expression profiles in infants with SC and RP teratomas may elucidate the mechanism of origin of these tumors. Extragonadal teratomas are thought to arise from germ cells that migrate aberrantly [7], whereas SC teratomas may arise from totipotent cells derived from the remnant of Hensen’s knot located at the

Duration of [20]. Some genes in individuals with DS may inhibit the (wk) Birth weight (g) Age at diagnosis Symptoms Histology Outcome generation and/or growth of tumors originating from the remnant of Hensen’s knot. We suggest careful abdominal palpation and radiograph examination for abdominal calcification for infants with DS during medical checkups. Since benign teratomas can be life-threatening given their size and location, early detection is important. From the viewpoint of basic research, elucidation of the possible reasons for the increased number of RP teratomas and the decreased number of SC teratomas in infants with DS will contribute to understanding the function of some chromosome 21 genes.

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Pediatr Blood Cancer DOI 10.1002/pbc