TITLE
Immature Teratoma in an Adolescent with Proteus Syndrome; A Novel
Association.
John S. Underwood1, Christopher
Ours2, R Cartland Burns3, Michael J
Ferguson4
1Indiana University School of Medicine, Departments of
Internal Medicine and Pediatrics
2National Human Genome Research Institute, National
Institutes of Health
3Indiana University School of Medicine, Department of
Surgery
4Indiana University School of Medicine, Department of
Pediatrics
GRANTS
Christopher Ours was supported by NIH grant HG200388
ABSTRACT
Proteus syndrome (PS) is a complex
disorder characterized by variable clinical findings of overgrowth and
tumor susceptibility. This report presents the first known association
between PS and an ovarian germ cell tumor in an adolescent with immature
teratoma. A review of the diagnosis of PS and associated tumors is
included.
KEY WORDS
Proteus syndrome, immature teratoma, abdominal mass, tumor, adolescent
PATIENT HISTORY
Our patient is a seventeen-year-old female with previously established
diagnosis of Proteus syndrome (PS). Her medical history is notable for
neuronal migration disorder, spastic quadriplegic cerebral palsy,
intellectual disability, seizures, vision impairment, scoliosis with
subsequent restrictive lung disease, leg-length discrepancy, and hepatic
steatosis. She has a history of multiple tumors and overgrowths, briefly
summarized as follows: multiple osteomas and cholesteatomas of both ear
canals requiring debridement and reconstruction; gingival hypertrophy
with biopsy-proven fibrous hyperplasia; jaw bone overgrowth requiring
partial resection; abdominal lipoma; and epidermal nevus of the anterior
neck. Biological mother and brother are healthy, paternal history is
limited, and there is no known history of consanguinity. Using the
dyadic genotype-phenotype criteria from Sapp, et al. (2019) (Sapp,
Buser, Burton-Akright, Keppler-Noreuil, & Biesecker, 2019) she meets
clinical-molecular diagnostic criteria for PS given bony overgrowth (5
points), dysregulated adipose tissue/lipoma (2 points), linear verrucous
epidermal nevi (2 points), vascular malformation (2 points), facial
phenotype (2 points) for a total score of 13 as well as a previously
identified AKT1 c.49G>A (p.E17K) variant from a skin
biopsy of affected tissue and would receive an additional 5 points forasymmetric overgrowth or cystic changes of specific organs due to
polycystic left ovary, discussed in addition to a previously identified
hemimegalencephaly, for a total score of 18. Given her score was ≥ 10,
our patient met criteria for a clinical-molecular diagnosis of PS.
CASE PRESENTATION
Our patient presented to the emergency room for acute on chronic
abdominal pain following a one-month period of weight gain and
progressive abdominal distension and discomfort. In recent weeks, she
had low-grade fevers treated unsuccessfully with a one-week course of
cefdinir. At presentation, her review of systems was positive for
fevers, fatigue, cough, and abdominal pain. She had no nausea or
vomiting and was voiding and stooling normally. She was afebrile. On
exam she was in no acute distress, but her abdomen was distended and
diffusely tender with a large mass appreciated best in the right upper
and lower quadrants. Dysmorphic features included frontal bossing,
protuberant jaw with limited mobility, depressed nasal bridge, and
macrocephaly. Eye exam was notable for bilateral exotropia and
nystagmus. On neurologic exam she had low tone with normal strength, and
she grunted or clapped to express her needs and could occasionally
follow simple commands. Musculoskeletal exam was notable for severe
thoracolumbar scoliosis.
CT of the abdomen and pelvis revealed a 35 x 23 x 16 cm mass in the
abdomen and pelvis with large cystic components, fat, calcification, and
soft tissue attenuation, which was highly suggestive of a large ovarian
teratoma (Figure 1A, Figure 1B). Marked mass effect on surrounding
organs of the abdomen and pelvis was noted as well. CBC and CMP were
unremarkable, including a normal bilirubin, AST, ALT, LDH, alkaline
phosphatase AFP, and β-hCG were also normal. A serum CA125 was elevated
at 100.2 units/mL (normal < 35.0 units/mL). A urinalysis was
unremarkable. COVID testing was not performed as this encounter took
place before the coronavirus pandemic.
She had an exploratory laparotomy and was found to have to large ovarian
masses requiring bilateral oophorectomy (Figure 2). The right ovarian
mass measured 36 x 26 x 13 cm and weighed 6,520 gm. Intraoperatively,
the capsule appeared intact with no peritoneal implants and was
considered a complete resection with no identified enlarged lymph nodes.
No peritoneal washings were obtained. The left ovarian mass measured 14
x 11 x 5 cm and weighed 380 mg. The patient tolerated the procedure well
and had an unremarkable post-operative course, during which she was
placed on prophylactic enoxaparin given the increased risk of venous
thromboembolism in Proteus syndrome (Keppler-Noreuil et al., 2019). She
was discharged after four days and evaluated one month later in oncology
clinic, where repeat CT abdomen/pelvis showed no residual disease. Final
pathology of the right ovarian mass indicated Grade III immature
teratoma based on the extent of primitive neuroepithelial elements
(Figures 3A-C). Due to complete resection, she was considered stage I,
per Children’s Oncology Group (COG) staging, and stage IA by the
Fédération Internationale de Gynécologie et d’Obstétrique (FIGO)
classification (Prat, 2014). Final pathology of the left ovarian mass
revealed polycystic ovary.
DISCUSSION
Proteus syndrome is an uncommon and complex disorder characterized by
variable clinical findings of overgrowth and tumor susceptibility. It
was first described by Cohen and Hayden in 1979 (Cohen & Hayden, 1979)
and later termed Proteus syndrome by Wiedemann et al in 1983 (Wiedemann
et al., 1983) due to its phenotypic heterogeneity. Correct diagnosis is
paramount in PS and can be difficult due to the diversity of
presentations (L. Biesecker, 2006; L. G. Biesecker, 2001). Since the
publication of a revised diagnostic criteria in 2006 (L. Biesecker,
2006), an activating mutation in AKT1 c.49G>A p.E17K
of the PI3K-AKT pathway has been associated with PS (Carpten et al.,
2007; Lindhurst et al., 2011). In order to include genotype in the
diagnostic criteria a dyadic genotype-phenotype approach has been
proposed (Sapp et al., 2019). Our patient meets genotype and phenotype
diagnostic criteria, as described previously. In a 2004 review of 205
reported cases of PS, less than half of published cases of PS (47%) met
diagnostic criteria, and importantly reported cases in this study that
met the PS criteria had a higher incidence of morbidity and mortality
compared to those in the non-Proteus group (Turner, Cohen, & Biesecker,
2004). The need for molecular testing is further highlighted by
phenotypic overlap with similar but distinct syndromes such as PTEN
hamartoma tumor syndrome and PIK3CA related overgrowth spectrum (PROS)
(Barker et al., 2001; Caux et al., 2007; Cohen, Turner, & Biesecker,
2003; Smith et al., 2002; X. Zhou et al., 2001; X. P. Zhou et al.,
2000).
Tumors usually associated with PS have been reviewed elsewhere (L.
Biesecker, 2006; L. G. Biesecker et al., 1999; Gordon, Wilroy, Lasater,
& Cohen, 1995; Turner et al., 2004) and include cerebriform connective
tissue nevi, bilateral ovarian cystadenomas, parotid gland monomorphic
adenomas, lipomas, regional lipohypoplasia, and vascular malformations,
all of which are considered in the diagnostic criteria (Cohen, 2014;
Nelson & Ruben, 2008). In regards to an association with germ cell
tumors, Hong et al. (2010) (Hong et al., 2010) described a girl with PS
found to have a pelvic mass at 21 months of age that was later resected
at 5 years of age and found to be a mature cystic teratoma of the left
ovary. Another case report by Zacharious and Krug, et al (1996)
(Zachariou, Krug, Benz, & Daum, 1996) described a young boy with PS and
a mature sacrococcygeal teratoma, however a panel of experts later
reviewed this case, among others, and determined that this patient did
not meet diagnostic criteria for PS and likely had a non-Proteus
condition (Turner et al., 2004). Our case describes an adolescent female
with PS who developed a massive immature teratoma, which represents an
association between PS and an ovarian germ cell tumor not previously
described in PS.
Recommendations from Children’s Oncology Group (Billmire et al., 2014)
and the National Comprehensive Cancer Network (Network, 2020) support
surgery-only in stage I patient with periodic surveillance thereafter.
There has been debate between adult and pediatric providers regarding
the value of chemotherapy should this tumor relapse. Given the
activating AKT1 mutations found in PS, there are reports of AKT1
variants in testicular germ cell tumors (GCT) (Feldman et al., 2014),
but not ovarian GCT. Though not AKT1 activating mutations, similar
pathway proteins, PIK3CA and PTEN, have shown mutations in ovarian GCTs
and AKT1 amplification was additionally noted (Van Nieuwenhuysen et al.,
2018). Additionally, there is a recent case report in Proteus syndrome
with different ovarian tumor pathology, low grade serous ovarian
carcinoma, that showed response to the AKT inhibitor, miransertib (Leoni
et al., 2019). These findings collectively argue that treatment with an
AKT inhibitor should be explored in ovarian immature teratomas,
especially ones associated with Proteus syndrome.
In summary, we report the first known association with PS and
development of an immature teratoma. Given the germline AKT1 variant in
this case and the lack of chemotherapy response usually observed in
pediatric immature teratomas, treatment with an inhibitor of
PI3K-AKT-MTOR pathway makes an intriguing option should recurrence
occur.
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