BILATERAL RENAL ANGIOMYOLIPOMAS AND
SUBEPENDYMAL GIANT CELL ASTROCYTOMA
ASSOCIATED WITH TUBEROUS SCLEROSIS COMPLEX:
A CASE REPORT AND REVIEW OF THE LITERATURE
Rambabova Bushljetik I, Lazareska M, Barbov I, Stankov O, Filipce V, Spasovski G
*Corresponding Author: Rambabova Bushljetik I, M.D., Ph.D., University Clinic of Nephrology,
Vodnjanska 17, 1000 Skopje, Republic of North Macedonia. Tel.: +389-214-7191. Mobile: +389-72-
216-581. Fax: +389-231-1188. E-mail: irambabova@yahoo.com
page: 93
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DISCUSSION
According to the established diagnostic criteria, our
case displayed many major and two minor features for
“definitive diagnosis,” also confirmed by genetic testing.
The different disease presentation required a multi disciplinary
approach for the patient to manage the epilepsy
and renal involvement.
Our patient started with everolimus treatment in the
late phase of the disease presentation, with large AMLs in
both kidneys (>12 cm). Everolimus tablets, 10 mg/day. were
administered, with blood trough levels in the range of 5.0-
15.0 ng/mL in accordance with the guidelines. Renal AMLs
are the most frequent features of TSC as benign tumors. In
the general population the prevalence of AML is rare (0.02-
0.29%) of both males and females. Treatment of renal AML
depends on its presentation [16]. According the guidelines
for asymptomatic AMLs of >3 cm, they should be treated
with mTOR inhibitors. In our case, the reduction of AML
in the follow-up period was lower than presented literature
results, as well as the reduction of the SEGA volume was
not similar to the published studies, but still acceptable.
Phase III EXIST-1 study (NCT00789828) included 117
patients at the age of 0.8-26.6 years with TSC-associated
growing SEGA. Patients were randomly included in a 2:1
ratio to receive everolimus (n = 78) and placebo (n = 39).
The median follow-up period was 9.7 months when 35.0%
of the patients in the everolimus treatment group achieved
>50.0% reduction in size of SEGA vs. 0.0% of the patients
in the placebo group. The exploratory end points, AML re- sponse rate (>1 AML >1 cm in the longest diameter) 53.0%
achieved response rate vs. 0.0% in the placebo group [17].
The everolimus for AML associated with TSC or
sporadic lymphangiomyomatosis (EXIST-2) trial has confirmed
the previous reports. It was a multi center, randomized,
double blind, placebo-controlled, phase III trial of
118 patients with a definite TSC diagnosis and at least one
AML >3 cm that showed 42.0% reduction of AML volume
in everolimus compared to 0.0% in the placebo group [18].
After 3 years of treatment, our patient reached approximately
24.0% reduction in the longest diameter of
AML. No evidence of new AMLs or episodes of bleeding
were observed.
An extension phase of the EXIST study included 112
patients who received >1 dose of everolimus, and 58.0%
achieved AML response rate. Almost all patients (97.0%)
achieved reduction in renal lesion volumes during the
study period. Median duration of everolimus exposure
was 46.9 months. Approximately 14.3% of patients experienced
progression in AML size [19]. While previous
reports have largely assessed the effect of everolimus for
AMLs with longest diameter <10 cm, another case report
included three patients suggesting this drug might also
be effective for huge lesions of >20 cm in diameter [20].
Of note, in our case during the period of treatment,
some adverse events were registered. A few episodes of
aphthous stomatitis requiring reduction of the dose of
everolimus were observed. One febrile episode with zosterlike
cutaneous rash on the lower extremity was treated at
University Clinic of Dermatovenerology, Skopje, Republic
of North Macedonia, with temporary everolimus treatment
interruption.
Facial angiofibromas were features of the disease
with the highest response rate to treatment with good psychological
effect on the patient. In the reported studies,
proteinuria was one of the adverse events, but in our case
the patient did not experience proteinuria, and had normal
renal function for the whole period of treatment [18,19].
Due to the presence of a large brain structural manifestation,
continuous follow-up by a neurologist and a
neurosurgeon was performed. The majority of TSC patients
have neurological symptoms, ~90.0% of affected
individuals experience seizures and almost half also experience
cognitive impairments, autism, or other behavioral
disorders. Epilepsy is seen in 70.0-90.0% of patients, most
commonly presenting in the first year of life [12]. Our
patient had normal mental status without autism and/or behavioral
difficulties. However, seizures were present from
the first year of life, with prescribed therapy till 5 years.
At the age of 12 years, when the new onset of seizures
was registered, an anticonvulsive treatment was reinitiated.
After many years free of seizures, the anticonvulsive
therapy was again ceased. Thus, after 3 years undergoing
everolimus therapy, a new episode of seizure was reported
and anticonvulsive therapy was administered. The patient
was placed on lamotrigin. The MRI findings excluded
hydrocephalus without necessity of surgical treatment.
Based on the literature, surgical intervention of SEGA >3
cm has 67.0% risk of surgery-related complications and
surgery on tumors >4 cm was associated with 73.0% risk
of complications [21,22].
It is recommended that SEGAs are MRI-monitored
every 1-3 years in patients younger than 25, as these tumors
usually grow in children and young adolescents, but do
not have a tendency to grow in adulthood [21,22]. Similar
case reports are found in the literature with similar disease
presentation and medical treatment [23].
Conclusions. Tuberous sclerosis complex is a multi
systemic disorder with different symptom presentations
and the highest rate of morbidity and mortality associated
with renal and brain manifestations. Treatment with
everolimus is beneficial for even such large AMLs, and the
positive impact persisted during a long-term administration
with a low rate of adverse effects. A positive impact
of everolimus treatment was also observed on the brain
tumors, especially SEGA.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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