Case series: Five pediatric germ cell/sex cord stroma tumors

Highlights • This report consists of five pediatric tumors of ovarian cell lineage.• These unusual, interesting tumors challenge both surgeon and oncologist.• Some appear malignant, seemingly require chemotherapy, but behave with benignity. Some are easily resected; others demand the utmost skill.• Complexity perplexes; elucidation is by selection – ignoring some things, attending to others.• Case studies illustrate – for good or ill – the process whereby clinical conundrums are resolved.

Interesting cases are educational; they pique our curiosity; and they are memorable! The first two cases in this series are adolescent girls with huge ovarian tumors. The resections were immensely challenging, which is unusual in itself! Salpingo-oophorectomy usually proceeds uneventfully; these tumors had parasitized the omentum, and their mobilization required division of fragile blood vessels so numerous as to resemble hydras! Both tumors appeared malignant, but the clinical outcome belied the surgeon's prognostication.
The third case is an infant who presented with a hugely distended abdomen and GI bleeding (his hemoglobin and hematocrit were 2.7 gm % and 12.2%); the etiology was a teratoma that had eroded into his stomach.
The fourth case is a newborn with an abdominal mass, diagnosed (by MR) as a mesenteric cyst. Actually, it was an Immature Teratoma arising from the small bowel mesentery.
The last case is a newborn who presented with a raised, erythematous swelling in her right cheek. Was it an abscess, a vascular malformation, or a tumor?

Ovarian tumors are complex and confusing!
They are rare; the incidence of ovarian masses is only 5/100,000 girls/year; half are neoplastic; half are cystic. Only 1% of childhood cancers are ovarian; and only 1% of ovarian malignancies occur during childhood. Ovarian tumors are less frequent in young children, but the incidence of malignancy is greater. Epithelial tumors are more common in older women, and the prognosis in adults is worse, because they present with more advanced disease, and adenocarcinoma is less responsive to chemotherapy (Tables 3, 4) [1].
• Glossary of Terms.
Syndromic Sex Cord Stroma Tumors usually occur during the first decade of life, and these tumors are benign, as in Case #2.
Ollier's Syndrome (Enchondromatosis) is a non-hereditary syndrome of mesodermal dysplasia. Fragments of the epiphyseal plate are incorporated into growing bone, forming enchondromas. The deranged cartilage may undergo a malignant transformation to chondrosarcoma (Table 7).

Materials and methods
This report was prepared in accord with the PROCESS criteria [13]; it consists of five case histories from the principal author's pediatric surgical practice; three children were treated at USA Children's and Women's Hospital, Mobile, AL; and two were treated at Palmetto Health Children's Hospital, Columbia, SC.

Case 1. Stage 3, Grade 3 Immature Teratoma
Case 1 is a 12 years old, pubertal young lady who presented with abdominal distension, so massive that her parents thought she was pregnant ( Fig. 1)! A CT scan disclosed an ovarian tumor that had areas of calcification and fat, which is consistent with a teratoma. The demarcation between the MT and IT is apparent in the operative specimen and on the CT scan. It is as if the immature component burst forth with explosive tumor growth from the confines of the well encapsulated (Fig. 2). MT. Surgery revealed widespread gliomatosis peritonei with carpeting of the pelvic peritoneum, including the serosal surface of the sigmoid colon. Pathology reported 20% Immature Teratoma (Figs. 4, 5)

Treatment milestones
Even though there was gross residual tumor, the oncologists advised a "wait and see" approach [14]. And predictably, the tumor recurred. Since Teratomas may be mixed (Table 3), careful evaluation of the reoperative specimen for possible malignant elements was advised. None were identified; however, the proportion of Immature Teratoma had diminished to 15%.
An MR was obtained four months later; and again, tumor was     present. Surprisingly though, the operative procedure was technically easier. The tumor appeared contained, less aggressive; and pathology review corroborated this impression (Fig. 3). Only 5% of the tissue was IT. The left ovary was distorted and cystic but uninvolved by tumor. The clinicians were optimistic, then baffled by the imaging studies that appeared to show "recurrent" tumor. The oncologists began chemotherapy (Bleomycin, Etoposide, and Cisplatin) hoping to hasten maturation of the teratoma. Repeat imaging was also disappointing; the tumor appeared to be enlarging, rather than diminishing in size. Why?
Had chemotherapy created a "growing teratoma?" The only hope seemed to be radical extirpation of this stubborn tumor, but the operative specimen revealed a metachronous, contralateral Mature Teratoma (Tables 8, 9) [8]!

Discussion of case 1
Principles Guiding the Treatment of Immature Teratoma [2,14]:  is not feasible. 6. The "growing teratoma syndrome" occurs when chemotherapy destroys the malignant cells (YST) while growth of immature neuroepithelial cells continues unabated. Case 2. Juvenile Germ Cell Tumor Associated with Ollier's Disease A 13 years old pubertal young lady presented with abdominal distension and discomfort, and isosexual precocious puberty. The tumor was huge (33 × 15.5 × 33 cm), and it was adherent to the surrounding structures (Figs. 6, 7). As the dissection progressed inferiorly and laterally, the operative incision was stretched open to provide better exposure. Pulling the retroperitoneum tore the tumor capsule and caused torrential hemorrhage. Fortunately, most of the omental vessels had been ligated, and the bleeding was arrested expeditiously by controlling the ovarian pedicle.
This young lady was followed post-operatively with tumor markers and imaging. Her tumor never recurred, which is consistent with the observation that syndromic patients, even those with tumor rupture, have an excellent prognosis.

Discussion of second case
What triggers tumor neovascularity, the ingrowth of omental blood vessels into certain tumors, notably ovarian tumors and uterine fibroids [15]? Perhaps rapid growth of the tumor exceeds its blood supply; the resultant ischemia causes release of angiogenic mediators.
The omentum is termed "policeman of the abdomen"! In laparoscopy, we are taught to "follow the omentum" to the pathology! It is indeed a remarkable organ, derived from mesothelial cells, consisting of adiposites and lymphoid aggregates. Omental lymphatics filter antigens and pathogens from ascitic fluid, a process vital to developing immunity and protecting the peritoneal cavity. Chemotactic stimuli lead the omentum to foci of inflammation, where recruitment of inflammatory cells (lymphocytes and phagocytes) combat infection. Stem cells promote wound healing by angiogenesis and fibrosis. Metastatic cells are filtered so effectively that omental lymphatics may be clogged by tumor cells [16].

Case 3.
A Teratoma that Eroded into the Stomach (Fig. 8) A 9 months old boy presented with abdominal distension, hematemesis, and profound anemia (HGB 2.7/HCT 12.2). He received 5 units of blood pre-operatively. He had a huge teratoma that was attached to the caudate lobe of the liver and the antrum of the stomach. The tumor had eroded through the stomach wall, causing hemorrhage and leakage of gastric contents into the tumor (Figs. 8, 9) [17][18][19].
Pathology was Mature Teratoma with islands of Yolk Sac Tumor. The child was not treated with chemotherapy in accordance with principle #3 above. The tumor did recur where it was originally attached (Fig. 10), but the histology was MT (not YST). These recurrences were excised and never recurred.

Case 4. Infant with Mesenteric Teratoma
The radiographic (MR) diagnosis in this infant was "mesenteric cyst" (Fig. 11). The excision was uneventful, but the pathology finding was unexpected: Grade I Immature teratoma without malignant elements. There was never any recurrence.

Discussion of cases 3 and 4
Retroperitoneal teratomas are notorious for distorting or obliterating the vascular anatomy. The renal vessels may be splayed apart; and/or the vena cava and/or portal vein may be encased by tumor, making resection particularly difficult [20,21]. Taking a cue from hepatoblastoma surgery, it was hoped that pre-operative chemotherapy would shrink the tumor and facilitate removal. Unfortunately the desired effect was not achieved. Chemotherapy effectively destroyed the malignant elements, but allowed unfettered growth of the immature teratoma, termed a "growing teratoma" (Principle #5, above).
The location of our tumors was intra-abdominal rather than retroperitoneal. The anatomy was distorted by their large size, but the vasculature was displaced rather than obscured, and their resection was straight-forward.

Case 5. Metastatic Gestational Choriocarcinoma
This baby's mother brought her to the emergency department, because of the growth on her cheek. (Fig. 12). Surgery was consulted for drainage of an "abscess". The photos were taken for consultation with an oncologist and otolaryngologist. An MR was obtained and the mass was thought to be a "vascular malformation". She was admitted and treated with propranolol and prednisone, and the lump transiently diminished in size; however, the mass ulcerated and bled, leading to readmission and transfusion; ultimately, she was referred to another institution for embolization. Unfortunately, she was lost to follow-up for a time; and when she reappeared, the tumor had grown to monstrous proportions (Fig. 13). Obviously, the initial diagnosis of vascular anomaly was erroneous. Biopsy revealed choriocarcinoma, and an elevated HCG and pulmonary metastasis. Her mother's HCG, also, was elevated, presumably from uterine involvement. Both mother and child responded well to chemotherapy and are disease free.

Discussion
This is a case of gestational choriocarcinoma arising in the mother's placenta, metastatic to the infant. Newborns with this disease usually present with anemia, hepatomegaly, and precocious puberty. Metastatic disease may involve the liver, lungs, brain, and skin [22].
Gestational choriocarcinoma occurs in 1/50,000 pregnancies. Nongestational choriocarcinoma is even rarer; it arises from malignant degeneration of extra-embryonic germ cells in the brain, mediastinum, or gonads.

Conclusion
We learn from interesting cases, and Case 1 is illustrative of two errors that clinicians are especially prone to make: 1. Allowing emotion (rather than reason) to dictate therapeutic decisions 2. Jumping to conclusions (Cognitive Bias) The oncologic data is ambiguous: adults with IT routinely receive chemotherapy, but children do not. Should an adolescent (a pubertal young lady) be treated as an adult or a child? Yet there is no evidence that IT responds to chemotherapy in either case. That conviction initially guided therapy; it was the best "evidence based treatment". But the young lady's clinical course confounded the expectations of her physicians, causing them to question their initial decision. Considering her multiple recurrences, should not chemotherapy be tried?
The quandary for clinicians is that sometimes reappraisal and change is necessary; in other instances, the correct posture is to stay the course! Clinicians are like detectives. What makes Sherlock Holms the master sleuth? His perception is more acute, and his conclusions are more accurate. A less competent detective jumps to conclusions, which inevitably do not take into account all of the facts. Once a theory is  [11][12][13][14][15][16][17][18][19][20] embraced, clues that contradict it are overlooked. Clinicians do the same thing, as is demonstrated in Case 1. By (almost) all measures, the teratoma was becoming more mature (pathology, AFP levels, and gross appearance); however, this evidence was seemingly contradicted by the radiographs, which showed "persistent" or "recurrent" Immature Teratoma.
Choosing one explanation (assigning a label) obfuscates other possibilities. 1 Our sure convictions cause us to overlook crucial bits of information. The evidence of increasing benignity was ignored, and a therapeutic approach was tailored to rid the patient -once and for allof tumor. Teratomas may be metachronous and bilateral [17]. Sherlock Holms would have considered this fact and chosen a more nuanced surgical approach.
Mark Twain, "It's not what we don't know that gets us into trouble. It's what we know for sure that just ain't so." Our certain conclusions may be "dead wrong" and cause us "double trouble". The error is compounded by delayed recognition.
Case 5 reinforces the lesson that interpretations of radiographs may be flawed. No one wants to biopsy a vascular malformation, but correct diagnosis precedes appropriate therapy.
Interesting cases are engaging and memorable, and they illustrate important lessons: • Once the best evidence based therapy is determined, "Stay the course!" • Don't jump to conclusions. Make sure your solution to diagnostic dilemmas take into account all the facts.
• Don't take short cuts. Correct diagnosis always precedes effective therapy.  1 Einstein famously introduced a "fudge factor" into his gravitational equations to prevent the universe from imploding! The facts were made to conform to the theory rather than vice versa.    [11][12][13][14][15][16][17][18][19][20] Ethical approval I have obtained IRB approval from both institutions in which these children were cared: University of South Alabama, Mobile AL and Palmetto Health Children's Hospital, Columbia, SC.

Sources of funding
Myself.

Author contribution
Dr. Nottingham was the sponsoring author in Columbia. He enabled me to access patient information.

Conflicts of interest
None.

Trial registry number
None.
Guarantor I do. James G. Glasser, MD.