RadioGraphics 2008, 10.1148/rg.

e32

© RSNA, 2008

Pictorial Review of Tuberous Sclerosis in Various Organs

Shigeaki Umeoka, MD, PhD, Takashi Koyama, MD, PhD, Yukio Miki, MD, PhD, Mikio
Akai, MD, PhD, Kazushige Tsutsui, MD, PhD, Kaori Togashi, MD, PhD

1
From the Department of Radiology, Japanese Red Cross Society, Wakayama Medical

Center, Wakayama, Japan (S.U., M.A., K.Tsutsui); Department of Radiology, Kyoto

University Hospital, 54 Kawahara-cho, Shogoin, Sakyo, Kyoto 606-8507, Japan (T.K.);
and the Department of Diagnostic Imaging and Nuclear Medicine, Graduate School
of Medicine, Kyoto University, Kyoto, Japan (Y.M., K. Togashi). Presented as an
education exhibit at the 2007 RSNA Annual Meeting. Received March 3, 2008; revision
requested April 16; revision received and accepted June 2. All authors have no financial
relationships to disclose. Address correspondence to T.K. (e-mail:
montpeti@kuhp.kyoto-u.ac.jp).

Abbreviations: AML = angiomyolipoma, CNS = central nervous system, LAM =

lymphangioleiomyomatosis, MMPH = multifocal micronodular pneumocyte
hyperplasia, SGCA = subependymal giant cell astrocytoma, TS = tuberous sclerosis
Abstract

Tuberous sclerosis is a rare autosomal dominant neurocutaneous syndrome

characterized by the presence of benign congenital tumors in multiple organs. The
diagnosis is usually established on the basis of diagnostic criteria applied to physical or
radiologic findings. Because the classical triad of epilepsy, mental retardation, and
adenoma sebaceum is uncommonly seen at clinical examination, radiologic
examinations can play an important role in the diagnosis of tuberous sclerosis and in
treatment. Cardiac rhabdomyoma, renal angiomyolipoma, and neurologic involvement
encompassing cortical or subependymal tubers and white matter abnormalities are the
common radiologic findings. Detection of these entities can be strong evidence for
suspecting tuberous sclerosis. The presence of pulmonary lymphangioleiomyomatosis,
multifocal micronodular pneumocyte hyperplasia, or multiple renal cysts also raises
suspicion of tuberous sclerosis. Moreover, tuberous sclerosis can involve bone, liver,
and the alimentary tract. The clinical course and patient prognosis depend on the sites of
manifestations. Familiarity with the clinical and radiologic findings in various organs is
crucial in diagnosis and treatment.

Learning Objectives

● Identify the radiologic features of multiorgan involvement in patients with tuberous sclerosis.

● Understand the clinical implications of various organ manifestations of tuberous sclerosis.

● Identify which organ manifestations can be a clue to suspect the presence of tuberous
sclerosis even if no clinical signs are seen and which manifestations should be carefully
evaluated in patients with clinically known tuberous sclerosis.

Introduction
Tuberous sclerosis (TS) is an autosomal dominant inherited neurocutaneous
syndrome characterized by a variety of hamartomatous lesions in various organs. TS can
affect both sexes and all ethnic groups. The estimated prevalence ranges from one in
 6000 to one in 12 000 (1), and approximately two-thirds of the cases are sporadic (2).
Classically, TS demonstrates a triad of clinical features (Vogt triad): mental retardation,
epilepsy, and adenoma sebaceum. However, it should be recognized that half of TS
patients have normal intelligence and that a quarter do not have epilepsy. The recently
advocated criteria for diagnosis of TS consist of both major and minor diagnostic
features (Table 1). Because no single clinical manifestation is diagnostic for TS
according to these diagnostic criteria, all clinical features should be evaluated.
Radiologic assessment is useful not only in diagnosis but also in determining treatment.
The presence of common manifestations, including cortical or subependymal tubers,
Teaching white matter abnormalities, cardiac rhabdomyoma, and renal AML, allows us to
Point
confirm the diagnosis in cases with characteristic symptoms or skin lesions and to
suspect TS in new cases without any clinical signs. The lungs, digestive system,
retroperitoneum, and bone, which can be less frequently involved, should also be
evaluated in patients with TS. Although recent advances in treatment have improved
morbidity, the prognosis is still quite poor and nearly 40% of patients die by the age of
35 years. The cause of death varies depending on the patient’s age (Table 2) (3).
 Table 1. Diagnostic Criteria for TS

Source.—Reference 10.
Note.—Cortical tubers together with cerebral white matter radial migration lines are
counted as one feature. In patients with LAM or renal AML, other features are required
for diagnosis.
 Table 2. Main Causes of Death Correlated with Age Group

Source.—Reference 3.

In this article, we review the diagnosis, clinical course, and clinical and
radiologic manifestations of TS in a variety of organs. We discuss and illustrate central
nervous system (CNS), cardiovascular, pulmonary, renal, retroperitoneal, hepatic,
gastrointestinal, and skeletal involvement of TS.

Molecular Considerations
TS has been considered to be caused by mutations of two genes known as
TSC1 and TSC2. Linkage analysis in multigenerational families and positional cloning
were used to map these genes (4,5). The TSC1 gene consists of 23 exons and is
transcribed into an 8.6-kb messenger RNA. It is located on the long arm of chromosome
9 (9q34) and encodes a 130-kDa protein called hamartin. The TSC2 gene consists of 41
exons and is distributed over 44 kbp of genomic DNA. It is situated on the short arm of
chromosome 16 (16p13) and encodes a 200-kDa protein called tuberin. The location of
the TSC2 gene is contiguous with the PKD1 gene, which can explain why multiple
renal cysts are sometimes found in patients with TS (6). TSC1 and TSC2 are tumor
suppressor genes whose function is to help regulate cell growth and differentiation. If
they are altered by mutation, disturbed control of cell growth results in formation of
tumors throughout the body. A variety of mutations can occur in TS patients: More than
200 TSC1 and almost 700 TSC2 allelic variants have been reported (7,8). The frequency
of mutations in TSC2 is higher than in TSC1. There is some evidence from case series
that mutations in TSC2 tend to result in more severe disease (7). No mutation is
identifiable in 15%–20% of TS patients, and these patients generally have milder
clinical manifestations (9).
The proteins hamartin and tuberin interact with high affinity and coexist as a
complex in cells in a variety of organs, including the kidneys, brain, lungs, and pancreas.
Recent advances in cytogenetics and pathophysiology have been made toward
understanding the functions of the hamartin-tuberin complex (9). Normally, direct
phosphorylation or inactivation of tuberin regulates the Ras homologue expressed in
brain (Rheb), which is a specific GTPase downstream of tuberin. If the functions of
tuberin are altered, Rheb-GTP is excessively generated, resulting in enhanced
stimulation of the mammalian target of rapamycin (mTOR), which plays an important
role in the control of cell growth and proliferation. Although the precise role of hamartin
is not clearly known, it also has an influence on mTOR activation (9).

Dermatologic Involvement
TS can present with a variety of skin lesions, including hypopigmented
macules, facial angiofibromas, shagreen patches, and ungula fibromas. Hypopigmented
macules, which have been called “ash leaf spots” after the European mountain ash tree,
occur in more than 90% of patients with TS (10). They are generally detected in infancy
or early childhood and are typically round at one end and tapered at the other. Facial
angiofibromas, also known as “adenoma sebaceum,” are seen in approximately 75% of
patients (10). The lesions typically appear in adolescence as small red papules in the
malar area, with a so-called “butterfly distribution” (Fig 1). Shagreen patches are
typically found as grayish-green or light brown areas in the lumbosacral region in
20%–30% of patients (10). Ungula fibromas are nodular lesions located beneath the
nails of the toes or fingers. The lesions can be found in approximately 20% of patients,
especially in adolescents and adults (10). Detection of these skin lesions can be a first
step in diagnosing TS, since they are the only major diagnostic criteria that can be
evaluated at clinical examination (Table 1).

Figure 1. Facial angiofibroma in a 19-year-old man. Photograph demonstrates multiple

dome-shaped papules in the malar area, with a butterfly distribution.
 Neurologic Involvement
A variety of intracranial manifestations of TS are known. Four common CNS
abnormalities are cortical tubers, subependymal nodules, subependymal giant cell
Teaching
Point
astrocytomas (SGCAs), and white matter abnormalities. Except for SGCAs, these
abnormalities can be seen in almost all patients with TS. The estimated prevalence of
cortical tuber and/or subependymal nodule is 95%–100% and that of white matter
abnormalities is 40%–90% (11). These common CNS manifestations can be an adequate
clue for suspecting TS. Other rare CNS manifestations include mild dilatation of lateral
ventricles due to atrophy or dysgenesis, cerebellar atrophy, infarction caused by
occlusive vascular disorders, cerebral aneurysm, dysgenesis of the corpus callosum,
Chiari malformation, microcephaly, macroencephaly, arachnoid cyst, neurofibromatosis,
and chordoma.

Cortical Tubers
Cortical tubers are developmental abnormalities of the cerebral cortex in
patients with TS, characterized by a loss of the normal six-layer structure of the cortex
and the presence of dysmorphic neurons and large astrocytes. They are considered to be
closely related to the neurologic manifestations of TS, including epilepsy, cognitive
disability, and neurolobehavioral abnormalities. Patients with numerous cortical tubers
tend to have more cognitive impairment and more difficulty with seizure control (12).
Autism is commonly seen in patients with frontal and parietotemporal tubers (12,13).
Approximately 50% of cortical tubers are seen in the frontal lobe, although they can
appear anywhere in the parenchyma from the cortex to white matter (1).
Magnetic resonance (MR) imaging is more applicable than computed
tomography (CT) for detection of cortical tubers (14). Usually, cortical tubers have
increased signal intensity on T2-weighted images and decreased signal intensity on
T1-weighted images. After administration of contrast material, only 10% of cortical
tubers show enhancement (15). In neonates and infants with cortical tubers, some
nodules can be missed on T2-weighted images and demonstrated only on T1-weighted
images, since they appear to have similar relaxation times to that of unmyelinated brain
(1,16,17). In older children and adults, the peripheral component of cortical tubers is
frequently isointense to normal gray matter with all pulse sequences, while the inner
component is iso- to hypointense to white matter on T1-weighted images and has high
intensity on T2 weighted images (Fig 2). Calcification and central cystic degeneration
can sometimes occur.
2a.

2b.

2c.
Figure 2. Cortical tubers in a 40-year-old woman. (a) Axial T2-weighted MR image
depicts cortical tubers as hyperintense lesions (arrows). (b) Axial fluid-attenuation
inversion-recovery MR image also demonstrates cortical tubers as hyperintense foci
(arrows). (c) On an axial T1-weighted MR image, these tubers are difficult to detect,
probably because the peripheral component is isointense to normal gray matter and the
inner component is isointense to white matter.

Subependymal Nodules and SGCAs

Subependymal nodules represent hamartomatous change in subependymal
tissue and usually occur as multiple nodules. The prevalence of patients with more than
10 subependymal nodules ranges from 12% to 57% (1,18). Leung et al revealed no
correlation between subependymal nodules and clinical severity of disease (10). Some
authors have reported that the number and location of subependymal nodules may allow
prediction of neurologic manifestations (19,20).
 CT is a useful tool for detection of subependymal nodules, since they are
associated with calcification far more commonly (88%) than are cortical tubers.
Unenhanced CT typically depicts multiple small foci with dense calcification along the
lateral ventricles bilaterally (Fig 3). At MR imaging, subependymal nodules are
hyperintense on T1-weighted images and iso- to hyperintense on T2-weighted images
(Fig 4). Subependymal nodules tend to have lower signal intensity on T2-weighted
image than do cortical tubers, probably because subependymal nodules have high water
content (14).

3.
Figure 3. Subependymal calcified tubers in a 9-month-old boy. Unenhanced CT clearly
demonstrates multiple subependymal tubers with bilateral calcification along the walls
of the lateral ventricles.

4.

Figure 4. Subependymal tubers in a 26-year-old woman. Axial T1-weighted MR image

clearly demonstrates bilateral subependymal tubers with intermediate signal intensity
(arrows).
 SGCAs are characterized by proliferative astrocytes and giant cells, with a
prevalence 1.7%–26% in patients with TS (16). The typical location of SGCAs is in the
foramen of Monro, leading to obstructive hydrocephalus (Fig 5). Typically, the initial
symptom of SGCAs is increased intracranial pressure, frequently with acute onset (21).
Different from other cerebral astrocytomas, SGCAs have benign biologic and
pathologic features (ie, slow growth, minimal or no attendant brain edema, and minimal
invasiveness). It is widely accepted that SGCAs are derived from subependymal
nodules; this is supported by the existence of intermediate cells between hamartomatous
nodules and SGCAs and by serial CT studies indicating growth of nodules into SGCAs
(22). The peak age of occurrence is 8–18 years, although SGCAs can evolve in utero
(23).

5a.

5b.

Figure 5. Subependymal giant cell astrocytoma in a 24-year-old man. (a) Unenhanced

CT image demonstrates high-attenuation tumor around the foramen of Monro (arrow).
Calcified subependymal tubers are also seen. (b) Unenhanced CT image at superior
level to that in a reveals secondary hydrocephalus.
 Because surgical risk depends largely on tumor size and vascularity (22,24,25),
CT and MR imaging are useful for noninvasive evaluation. Compared with
subependymal nodules, SGCAs tend to be larger tumors (>1 cm) with more intense
enhancement. When subependymal nodules are located near the foramen of Monro and
they measure more than 5 mm in diameter, are not or are incompletely calcified, and are
enhanced by gadolinium, repeat MR imaging should be recommended (26). MR
spectroscopy of SGCAs shows high Cho/Cr and low NAA/Cr ratios, which may be
useful for distinguishing them from subependymal nodules (27).

White Matter Abnormalities

White matter abnormalities in patients with TS include (a) superficial white
matter abnormalities associated with cortical tubers, (b) radial white matter bands, and
(c) cystlike white matter lesions. Superficial white matter abnormalities are related to
almost all cortical tubers. The reported frequency of radial white matter abnormalities is
15%–27% and of cystlike lesions is 15%–44% (11,28,29). Superficial white matter
abnormalities reflect reduced myelin or increased gliotic reaction and are seen as
high-intensity areas on T2-weighted images and decreased-intensity areas on
T1-weighted images (30).
Radial white matter bands reflect altered development along the migratory
pathways of neurons and glial cells. They usually involve cerebral white matter
bilaterally (predominantly frontal lobes) and uncommonly cerebellar white matter (16).
At MR imaging, thin straight or curvilinear bands of hyperintensity on T2-weighted
images and iso- to hypointensity to normal white matter on T1-weighted images run
from ventricular or juxtaventricular white matter to the deep surface of cortical tubers or
normal-appearing cortex (Fig 6).

6.
Figure 6. Radial white matter bands in an 8-month-old boy. Axial fluid-attenuation
inversion-recovery MR image demonstrates linear radial white matter bands extending
from the cortex to the lateral ventricles (arrows). Cortical tubers are also seen
(arrowheads).
 White matter cystlike lesions are located in deep white matter, typically near
the lateral ventricles (11). These lesions are considered rare, yet they are purported to
occur in up to 44% of TS patients (11). Although the pathogenesis of cystlike lesions
remains unclear, they are considered to reflect cystic degeneration of white matter or
dilated perivascular spaces (11). At MR imaging, small well-demarcated lesions of
similar intensity to that of cerebrospinal fluid with all sequences are seen in white
matter (Fig 7).

7a.

7b.
Figure 7. Cystic white matter lesion in a 13-year-old girl. (a) Axial T2-weighted and (b)
T1-weighted MR images show a well-demarcated lesion (arrow) in the left frontal white
matter, isointense to cerebrospinal fluid.

Cardiac Involvement
Cardiac rhabdomyoma is a benign striated muscle tumor characterized by the
presence of “spider cells,” which are so named because of their radial cytoplasmic
extensions. Cardiac rhabdomyomas usually (approximately 75%) occur before the age
of 1 year and can even occur in a fetus. It is one of the common manifestations of TS,
 with a frequency of 50%–65 %; conversely, 40%–80% of patients with cardiac
rhabdomyoma have TS (31–34). Therefore, if a cardiac rhabdomyoma is found at
echocardiography, TS is highly suspected, even if there are no typical clinical symptoms
or family history of TS.
Cardiac rhabdomyomas, which may be multiple or single, are commonly
located on the ventricular septum. Most cardiac rhabdomyomas regress before birth, and
Teaching more than 80% of the tumors cause no clinical manifestations at birth (35). Moreover,
Point spontaneous regression or disappearance of the tumor can occur in 70% of children by
the age of 4 years (35). Therefore, only a minority of cases may present with
arrhythmias or heart failure. Surgical resection should be considered only if patients
present with refractory arrhythmias or hemodynamic compromise. Echocardiography is
noninvasive and can be useful in detection and follow-up of cardiac rhabdomyoma
(Movie 1 available at http://radiographics.rsnajnls.org/cgi/content/full/e32/DC1).
MR imaging can provide additional information regarding tumor extension or size,
especially in older patients or in patients with poor images at echocardiography due to
bone or lung interference (Movie 2 available at
http://radiographics.rsnajnls.org/cgi/content/full/e32/DC1) (36,37).

Pulmonary and Thoracic Involvement

Pulmonary involvement of TS includes lymphangioleiomyomatosis (LAM) and
multifocal micronodular pneumocyte hyperplasia (MMPH). Pulmonary manifestations
are estimated to occur in approximately 1%–2.3% of TS patients, but recent reports
indicate that pulmonary LAM can be found radiologically in 26%–39% of female
patients with TS (38). MMPH is a rare disorder that has been described in few literature
reports. Other rare thoracic involvements include LAM involvement of the mediastinum
or thoracic duct and aortic or pulmonary artery aneurysm (39–41).

Pulmonary LAM
Pulmonary LAM is a rare entity of unknown etiology that almost exclusively
affects women and is characterized by diffuse interstitial proliferation of bundles of
smooth muscle cells and cystic change in the pulmonary parenchyma. The diagnosis in
affected patients is usually made in early adulthood, and the symptoms are commonly
dyspnea on exertion or recurrent pneumothorax. The clinical course of pulmonary LAM
is usually slow and progressive, ultimately leading to respiratory failure. The 10-year
survival rate was 79% in a study of 69 patients with pulmonary LAM (42).
Pneumothorax and chylous pleural effusion or ascites are two major complications of
 LAM. Pneumothorax can be found in 39%–53% of patients with pulmonary LAM at
presentation and in 60%–81% during the clinical course; chylothorax is found in
0%–14% of patients at presentation and in 22%–39% during the clinical course (43).
Chemical or surgical pleurodesis is performed to prevent recurrent pneumothorax, but it
sometimes results in rigid adhesion that may make lung transplantation more
problematic (44). The main mechanisms of chylothorax are (a) chyle leak, (b) general
oozing from pleural lymphatics or central vessels, and (c) transdiaphragmatic flow of
chylous ascites (43). Aggressive drainage of chylous pleural effusions should be
avoided because it may lead to protein loss.
Thin-section CT can demonstrate characteristic features of pulmonary LAM
Teaching
Point and can obviate lung biopsy. The typical CT finding is round, thin-walled cysts of
variable size and contour (Fig 8). Generally, the distribution of the cysts is symmetric
and uniform throughout the lungs. Communication between the cysts and the airway is
indicated by the fact that the size of the cysts decreases on expiratory CT images (44).
In some cases of pulmonary LAM, reticular opacities can be seen, which may reflect
interstitial edema due to obstruction of the lymphatic vessels (Fig 9). CT or MR
imaging can be helpful in detecting pneumothorax and chylous pleural effusion or
ascites (Figs 10, 11).

8.
Figure 8. Pulmonary LAM in a 29-year-old woman. Thin-section CT scan demonstrates
multiple lung cysts with well-defined thin walls. These cysts are distributed randomly
throughout the lung.
9.
Figure 9. Pulmonary LAM in a 37-year-old woman. Thin-section CT image shows
bilateral numerous cysts associated with reticular opacities.

10.
Figure 10. Pneumothorax associated with pulmonary LAM in a 37-year-old woman.
CT image of the chest demonstrates multiple lung cysts, suggesting pulmonary LAM.
Pneumothorax can be seen in the right thoracic cavity (arrows).

11.
Figure 11. Chylothorax and chylous ascites due to LAM in a 21-year old woman.
Coronal half-Fourier-acquisition single-shot turbo spin-echo (HASTE) MR image
demonstrates bilateral loculated pleural effusion and ascites. Retroperitoneal LAM is
also seen (arrows). Aspiration of the pleural effusion proved it to be a chylous effusion.

MMPH
MMPH is a rare pulmonary disorder that can be associated with TS. It is
characterized by multicentric, well-demarcated nodular proliferation of type II
pneumocytes along alveolar septa. Since the hamartomatous nature of micronodular
epithelial proliferations has been emphasized, the terms multiple adenomatoid tumors,
 acinar atypical adenomatoid proliferation of epithelium, and micronodular hyperplasia
of type II pneumocytes have been proposed as being more descriptive names. Recently,
these lesions have come to be commonly called MMPH, taking their pathogenesis and
locations into account. MMPH can occur in patients with or without LAM,
predominantly in female patients. Clinically, patients with MMPH may present with
dyspnea, cough, and mild to moderate hypoxemia. Unlike with pulmonary LAM,
treatment is usually unnecessary because MMPH does not appear to be fatal and
progressive.
At thin-section CT, multiple tiny nodules (1–8 mm in diameter) are diffusely
scattered throughout the lung in a random distribution (Fig 12). Although differentiation
of MMPH from miliary metastatic or granulomatous disease is difficult, MMPH should
be considered in the differential diagnosis when multiple tiny pulmonary nodules are
present in patients with TS (38).

12.
Figure 12. MMPH in a 19-year-old man. CT scan demonstrates multiple tiny nodules
(arrows), with random distribution in the lungs.

Renal and Retroperitoneal Involvement

Teaching Renal involvement of TS includes renal angiomyolipoma (AML), renal cysts,
Point and renal cell carcinoma. Renal AML is one of the common manifestations, with a
frequency of 55%–75% in patients with TS (9); conversely, approximately 20% of
patients with AML have TS (45). The second most common renal manifestation of TS is
renal cysts. Although their exact frequency is unknown, that estimated by Stillwell et al
is 18%–53% (46). Rarely, renal cell carcinoma and oncocytoma may also occur in
patients with TS (9). Reteroperitoneal LAM can occur in up to 20% of patients with
LAM.

Renal AML
AMLs are the most common benign tumors of the kidney, characterized by
variable amounts of abnormal vessels, immature smooth-muscle and fat cells. Although
 renal AMLs are sometimes asymptomatic and are incidentally discovered, they may
cause variable symptoms in as many as 87% of patients, including abdominal pain,
nausea, vomiting, palpable mass, hematuria, anemia, and hypertension. Compared with
sporadic lesions, AMLs seen in patients with TS tend to manifest at a younger age and
to be multiple, larger, and bilateral and to grow (47). The most alarming complication of
renal AMLs is rupture due to their abnormal vasculature, frequently associated with
aneurysms. Patients with a ruptured renal AML often present with pain or shock at acute
onset. The probability of rupture depends on the formation of an aneurysm, which is
related to the size of the renal AML (48). Although most asymptomatic renal AMLs do
not require treatment, symptomatic lesions (especially a ruptured AML) may be treated
by surgical or interventional procedures.
Teaching CT can permit specific diagnosis of a renal AML by demonstrating the
Point
presence of intratumoral fat. Typical CT findings of renal AMLs are noncalcified
cortical tumors containing fat of less than –20 HU (Fig 13) (45). Although unenhanced
CT with thin sections is useful for detecting small amounts of fat, intratumoral fat
cannot be detected in approximately 4.5% of all renal AMLs (49). These tumors
frequently become clinically problematic because differentiating them from renal cell
carcinomas is difficult. Jinzaki et al suggested that AMLs with minimal fat should be
considered when the tumor demonstrates (a) hyperattenuation at unenhanced CT, (b)
homogeneous enhancement, (c) hypointensity on T2-weighted MR images, and (d)
homogeneous isoechogenicity at ultrasonography (Fig 14) (50,51). When intrarenal,
perinephric, or retroperitoneal hemorrhage is seen, a ruptured AML should be suspected
(Fig 15). If the bleeding masks the fat component of the tumor, it may be difficult to
differentiate it from a ruptured renal cell carcinoma. In such cases, biphasic
contrast-enhanced CT may be useful for differentiating these two entities (49).

13.
Figure 13. Renal AMLs in a 38-year-old woman. Axial unenhanced CT image
demonstrates multiple fat-containing tumors in the kidneys.
14a.

14b.
Figure 14. Renal AMLs with minimal fat in a 19-year-old man. (a) Unenhanced CT
image demonstrates multiple high-attenuation tumors in the kidneys. (b)
Contrast-enhanced CT image shows homogeneous enhancement of the tumors.

15a.

15b.
15c.
Figure 15. Ruptured renal AML in a 35-year-old woman. (a) Unenhanced CT image
shows a fat-containing tumor in the left kidney. Hyperattenuating material suggestive of
hemorrhage is also seen in and around the tumor. (b) Contrast-enhanced CT image
demonstrates an aneurysm in the tumor (arrow). (c) Selective left renal arteriogram
shows multiple aneurysms in the tumor.

Other Renal Lesions

Renal cysts or polycystic kidney disease can develop in patients with TS. As
opposed to renal AMLs, renal cysts occur in younger children (10). Although renal cysts
are generally asymptomatic, they can more frequently cause subsequent hypertension or
renal failure than can renal AMLs (9). A typical CT finding is bilateral multiple renal
cysts in younger patients (Fig 16).
16.
Figure 16. Renal cysts in a 10-month-old girl. Contrast-enhanced CT image shows
multiple renal cysts bilaterally.

It had been purported that there is a significant association between renal cel
carcinomas and TS, since renal malignant tumors can occur in young patients with TS.
However, recent meta-analysis has shown that the overall incidence of renal cell
carcinomas in patients with TS is identical to that in the general population (52).
Although no significant difference in incidence has been found, renal cell carcinomas
associated with TS tend to occur in younger patients and to grow more slowly (10). The
average age of TS patients with renal call carcinoma is 28 years, 25 years younger than
the average age in the general population (53). A variety of subtypes of renal call
carcinoma, including clear cell, papillary, and chromophobe carcinoma have been
reported in patients with TS (9). CT findings in renal call carcinomas depend on their
subtypes, owing to microvessel density or the presence of intratumoral necrosis or
hemorrhage. Clear cell carcinoma, which is the most common subtype of renal call
carcinoma, typically demonstrates heterogeneous enhancement and early washout at
biphasic contrast-enhanced CT. Chromophobe renal call carcinomas frequently
demonstrate early weak enhancement and early washout (Fig 17). Papillary carcinomas
tend to exhibit gradual enhancement, which is sometimes difficult to differentiate from
that of AMLs with minimal fat (54).
 17a.

17b.
Figure 17. Renal cell carcinoma in a 52-year-old woman. (a) Biphasic
contrast-enhanced CT image during the corticomedullary phase demonstrates a
well-defined tumor with nonhomogeneous enhancement in the left kidney. (b) During
the early excretory phase, the tumor shows an early washout pattern. It was surgically
proved to be a chromophobe renal cell carcinoma.

Retroperitoneal LAM
Retroperitoneal LAM is histologically identical to its pulmonary counterpart.
Related symptoms include abdominal bloating or discomfort, lymphedema of the lower
extremities, paresthesia of the lower extremities, nocturia, incontinence, perineal
swelling, chylous vaginal discharge, and palpitation. Chylous ascites can occur when
overdistended lymphatic cysts rupture in the intraperitoneal cavity (44). Radiologically,
thick- or thin-walled cystic lesions can be found in the retroperitoneum, which may
reflect dilatation of lymph vessels due to obstruction (Fig 18). Enlarged lymph nodes,
dilatation of the thoracic duct, ascites, and pleural effusion can be associated with
retroperitoneal LAM. Although other retroperitoneal cystic tumors such as
Teaching lymphangioma can be considered as differential diagnoses, when retroperitoneal cystic
Point
masses are found in patients with TS, retroperitoneal LAM should be suspected, unless
a retroperitoneal abscess or tumor is clinically suggested.
18.
Figure 18. Retroperitoneal LAM in a 37-year-old woman (same patient as in Fig 9).
HASTE MR image demonstrates multiple high-intensity cystic lesions along the aorta
and bilateral iliac arteries. Right renal AML is also seen.

Miscellaneous Abdominal Involvement

A variety of digestive organs have been reported to be involved in patients with
TS, including the alimentary tract, hepatobiliary system, and pancreas. The most
common manifestation of gastrointestinal involvement is polyps, which are frequently
multiple and can occur anywhere from the esophagus to the rectum (Fig 19). The
prevalence of gastrointestinal polyps is unknown but may be underestimated because
they are usually asymptomatic. Gould et al documented that 14 of 18 (78%) patients
with TS had intestinal polyps (55). Some reports described that some gastrointestinal
polyps show early malignant change (56). Rarely, ulceration, fibrous tumors, vascular
malformations, adenocarcinomas, and leiomyomas (Fig 20) have been reported to be
associated with TS (56,57).

19a.
19b.

19c.

19d.
Figure 19. Intestinal polyposis in a 33-year-old man. (a, b) Contrast-enhanced CT
images of different levels demonstrate multiple high-attenuation polypoid lesions
(arrows) in the small intestine. Left renal AML is also seen (arrowheads). (c) Upper
gastrointestinal endoscopy demonstrates multiple gastric polyps. (d) Colonoscopy
reveals multiple polyps in the colon.

20.
Figure 20. Intestinal leiomyoma in a 52-year-old woman (same patient as in Fig 17).
Contrast-enhanced CT image demonstrates well-defined tumor in the mesentery,
attached to the small intestine (arrow). The tumor was surgically proved to be
leiomyoma of the jejunum.
 A variety of hepatobiliary lesions have been described in patients with TS,
including hepatomegaly, AMLs, lipomas, hamartomas, and fibromas. Most hepatic
AMLs are sporadic, and only 5.8% of hepatic AMLs has been reported to associated
with TS (58). When both hepatic and renal AMLs are incidentally found, TS should be
considered in the differential diagnosis. Although most patients with hepatic AMLs are
asymptomatic, some may present with abdominal pain, general malaise, abdominal
discomfort, and upper-abdominal mass. As is the case with their renal counterparts,
intratumoral fat content disclosed with CT or MR imaging can be a diagnostic clue for
hepatic AMLs (Fig 21). Although the pancreas is a rare organ for manifestations of TS,
hypoplasia, islet-cell tumor, hamartoma, and mucoviscidosis have been reported (56).

21.
Figure 21. Renal and hepatic AMLs in a 56-year-old woman. Coronally reformatted
unenhanced CT image demonstrates fat-containing tumors in the liver and right kidney
(arrows).

Skeletal Involvement
Osseous manifestations of TS include cystlike lesions, hyperostosis of the inner
table of the calvaria (Fig 22), osteoblastic changes, periosteal new bone formation, and
scoliosis. These osseous lesions can occur anywhere in bone, commonly in the calvaria,
short tubular bones of the hand or foot, spine, and pelvis. The cystlike lesions are
usually irregularly circumscribed and have a sclerotic appearance peripherally. Some
lesions gradually increase in size and number over many years. The frequency of
abnormal sclerotic islands in the calvaria is approximately 40% and of definite
radiographic changes in the hands or feet is approximately 66% (59). On skeletal
radiographs or CT images, cortical or medullary cystlike radiolucent areas or sclerotic
deposits are found focally or diffusely. Cortical lesions are sometimes associated with
subperitoneal new bone deposition. The prevalence of scoliosis is also unclear. Madigan
et al reported that six of 12 patients with TS showed radiologic evidence of scoliosis
(60). Although most patients with scoliosis are asymptomatic, one-third had spastic
quadriplegia (60).
22.
Figure 22. Multiple sclerotic bones in the calvaria of an 11-year-old boy. Coronally
reformatted unenhanced CT image demonstrates multiple islands of increased
attenuation within the calvaria.

Conclusions
TS has a wide variety of clinical and radiologic manifestations. It should be
suspected when some of the common manifestations are found, including CNS
involvement, renal AML, and cardiac rhabdomyoma, even if clinical signs are not
obvious. Familiarity with the clinical course, sites of potential involvement, and
frequency of involvement can allow correct treatment and improvement in quality of
life. Recognition of radiologic features of various organ manifestations is essential for
making the correct diagnosis and is helpful for detecting additional abnormalities.

Acknowledgments: We sincerely acknowledge Kyo Itoh, MD, PhD, Toyomichi Shibata,

MD, Chikara Maeda, MD, and Yo Kajiyama, MD, PhD, for their contributions of
materials used in this review.
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