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Radiological Screening
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
forHereditary Cancer
Predisposition Syndromes
GökhanKahraman , PınarÇeltikçi ,
andŞebnemKarasu
42
42.1 Introduction
Advances in cancer genetics allowed accurate
diagnosis of hereditary cancer predisposition
syndromes in the eld of medical oncology.
Hereditary cancer syndromes are characterized
by early-stage tumors that account for 3–20% of
all cancers, and most commonly demonstrate an
autosomal dominant inheritance pattern [1, 2].
Although, they constitute a small portion of all
cancers, successful diagnosis, screening, and
follow- up strategies would improve morbidity
and mortality rates in this group of patients.
American Society of Clinical Oncology (ASCO)
has published guidelines that have become the
most widely used reference sources in this eld,
which are updated with the advances in cancer
genetics [3, 4].
The diagnosis of hereditary cancer syndromes
is made by detecting the underlying gene mutation following clinical suspicion. Following diagnosis, investigating other components of the
syndrome is essential. Imaging plays an important role in the diagnosis, screening, and follow up of patients with hereditary cancer syndromes.
Early diagnosis would often lead to prophylactic
surgery, which its importance in the management
of patients with hereditary cancer syndromes is
growing [5]. Therefore, clinicians should be
aware of the current guidelines for the appropriate selection of radiological modality for screening, diagnosis, and follow-up, as well as screening
and follow-up intervals for each hereditary cancer predisposition syndrome. Also, radiologists
should be informed about the underlying genetic
condition of the patient to focus on other possible
sites for tumors. Although there are main guidelines in the literature, due to the infrequent nature
of these conditions, the choice of imaging modality and interval is still a matter of debate for most
of these syndromes. Each patient should be handled individually and should be managed in a
multidisciplinary fashion.
In this chapter, radiological imaging modalities for the diagnosis, screening, and follow-up
for the tumors caused by most common hereditary
cancer syndromes will be discussed. First, an
overview of imaging modalities will be presented,
followed by a summary of most commonly
encountered hereditary cancer predisposition syndromes with component tumors and specic
screening/follow-up recommendations.
G. Kahraman (*) · P. Çeltikçi
Faculty of Medicine, Department of Radiology,
Baskent University, Ankara, Turkey
Ş. Karasu
Department of Radiology, İzmir Katip Çelebi
University School of Medicine, İzmir, Turkey
e-mail: sebnem.karasu@ikc.edu.tr
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021
O. N. Dilek et al. (eds.), Prophylactic Surgery, https://doi.org/10.1007/978-3-030-66853-2_42
42.2 Imaging Modalities
Radiological imaging modalities are utilized for
the screening, diagnosis, staging, evaluation of
treatment response, and detection of recurrence
497
498
G. Kahraman et al.
after treatment of cancers in hereditary cancer
predisposition syndromes.
Conventional radiography (CR), ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), positron
emission tomography/CT (PET/CT), and singlephoton emission computed tomography
(SPECT) are the main imaging methods used in
the diagnosis and follow-up of patients with
these syndromes and screening of asymptomatic
mutation carriers [6, 7].
CR is an imaging technique that involves
X-rays. Chest radiography and mammography
are frequently used in cancer screening. This
modality is usually the initial imaging method
with chest and musculoskeletal systems, as it
requires exposure to relatively less amount of
ionizing radiation. However, projectional CR
image provides limited information, and if there
is accompanying clinical suspicion, further imaging is usually required.
CT is a multiplanar imaging method that provides images in three planes with excellent detail,
resolution, and three-dimensional reconstructions. On the other hand, it requires exposure to
larger doses of X-rays compared to CR, therefore, it should be reserved for further imaging.
This is the preferred modality for the imaging of
thorax, abdomen, vascular structures, and bones.
CT is commonly used in oncological imaging for
the detection, staging of cancers as well as in the
postoperative period for recurrence follow-up.
US is a radiation-free imaging method that utilizes high-frequency sound waves. They are commonly and safely employed for screening and
follow-up purposes. US is also frequently used as
a guiding imaging modality for biopsies and minimally invasive treatments. US is frequently used
for screening solid organs of the abdomen and
supercial soft tissues, such as thyroid gland,
supercial lymph nodes, breast, and testicles.
MRI is another radiation-free, multiplanar
imaging method that utilizes radiofrequency
waves. As it provides superior tissue contrast
resolution, this modality is preferred for the
imaging of the central nervous system, head and
neck, breast, abdomen, and musculoskeletal system. Whole-body MRI is a popular technique in
the diagnosis screening and follow-up of malignancies in patients with hereditary cancer syndrome due to high-resolution images acquired
without exposure to ionizing radiation [7–10].
The basic whole-body MRI sequence is coronal
short τ inversion recovery (STIR), in which the
majority of lesions would appear bright (hyperintense) [9]. According to indications, axial
T2-weighted, T1-weighted, diffusion-weighted,
and postcontrast T1-weighted sequences can be
added [11]. Many studies have reported that
whole-body MRI imaging detects tumors with
high sensitivity and specicity in patients with
hereditary cancer syndromes [8, 12, 13].
Molecular and nuclear imaging plays an
important role in assessing the extent of the disease and in posttreatment follow-up. Nuclear and
molecular imaging uses radioactive substances
linked to compounds used by the body’s cells or
compounds that attach to tumor cells. PET is an
imaging method using uorodeoxyglucose
(FDG), which is a radioactive glucose molecule
that accumulates in the tumor. Like PET, radioactive substances are used in SPECT. In this
method, specic tumors can be detected with
antibodies that bind to radioactive substances.
Although CT and PET are very useful modalities in the diagnosis and follow-up of oncological
diseases, repetitive imaging increases radiation
exposure and the risk of cancer development, especially in the pediatric patient group [14]. Therefore,
US and MRI are the modalities that should be preferred primarily in hereditary cancer syndromes.
42.3 Hereditary Cancer
Syndromes and Radiological
Screening
Recommendations
Syndromes of hereditary cancer predisposition
with component tumors, inheritance pattern, and
responsible genes are summarized in Table42.1.
Recommended radiological modalities and
screening/follow-up intervals are summarized in
Table42.2, based on guidelines of the American
Cancer Society (ACS), National Comprehensive
Cancer Network (NCCN), and ASCO.
42 Radiological Screening forHereditary Cancer Predisposition Syndromes
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499
(continued)
Ovarian cancer BRCA2
Prostate cancer
Pancreatic cancer
Breast cancer CHEK2
Osteosarcoma
Leukemia
Brain tumors
Adrenocortical carcinoma
Thyroid cancer
Endometrial and other cancers
Lymphoma
Endometrial cancer MSH2
Syndrome Component tumors Inheritance Genes
Hereditary breast cancer and ovarian cancer syndrome Breast cancer Dominant BRCA1
Table 42.1 Syndromes of inherited cancer predisposition in clinical oncology
Li-Fraumeni syndrome Soft tissue sarcoma Dominant p53
Cowden syndrome Breast cancer Dominant PTEN
Ataxia telangiectasia Leukemia Recessive ATM
Lynch syndrome Colon cancer Dominant MLH1
Ovarian cancer MSH6
Renal pelvis cancers
Ureteral cancers
Pancreatic cancer
Stomach and small bowel cancers
Hepatobiliary cancers
Familial adenomatous polyposis Colon cancer Dominant APC
Small bowel cancer
Peutz-Jeghers syndrome Colon cancer Dominant STK11
Breast cancer
Ovarian cancer
Pancreatic cancer
500
G. Kahraman et al.
Syndrome Component tumors Inheritance Genes
Neurobromatosis type 1 Neurobrosarcomas Dominant NF1
Table 42.1 (continued)
Pheochromocytomas
Optic gliomas
Meningiomas
Neurobromatosis type 2 Vestibular schwannomas Dominant NF2
Multiple bilateral renal angiomyolipomas TSC2
Tuberous sclerosis Myocardial rhabdomyoma Dominant TSC1
Ependymoma
Renal cancer
Giant cell astrocytoma
Von Hippel-Lindau syndrome Hemangioblastomas of retina and CNS Dominant VHL
Renal cell cancer
Pheochromocytomas
Pituitary adenomas
Parathyroid adenomas
MEN1 Pancreatic islet cell tumors Dominant MEN1
MEN2 Medullary thyroid cancers Dominant RET
Pheochromocytoma
Parathyroid hyperplasia
CNS central nervous system, MEN multiple endocrine neoplasia
42 Radiological Screening forHereditary Cancer Predisposition Syndromes
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Table 42.2 Screening recommendations for inherited cancer predisposition syndromes
Syndrome Screening
Hereditary breast
cancer and ovarian
cancer syndrome
Li-Fraumeni
syndrome (children)
Li-Fraumeni
syndrome (adults)
Cowden syndrome Annual thyroid ultrasound scan
Ataxia telangiectasia Annual breast MRI in addition to an annual mammogram
Lynch syndrome Annual pelvic ultrasound for endometrial and ovarian cancer, beginning age at 30–35 years
Familial
adenomatous
polyposis
Peutz-Jeghers
syndrome
Neurobromatosis Annual MRI, beginning in the teenage years
Tuberous sclerosis Ultrasound of the kidneys, every 1–3 years
Von Hippel-Lindau
syndrome
MEN1 MRI of the brain, every 3–5 years, beginning between ages 5 and 10 years
MEN2 MRI or CT scan of the abdomen, every 4–5 years
CT computed tomography, MRI magnetic resonance imaging, MEN multiple endocrine neoplasia
Annual MRI scans of both breasts, between ages 25 and 29 years
Annual mammogram and breast MRI scans of both breasts, between ages 30 and 75 years
Transvaginal ultrasound, every 6 months, beginning at age 30–35 years
Ultrasound of abdomen and pelvis, every 3–4 months for adrenocortical carcinoma
Annual brain MRI for brain tumor
Annual whole-body MRI for soft tissue and bone sarcoma
Annual MRI scans of both breasts, beginning at age 20–25 years
Annual mammogram; an annual breast MRI, beginning at age 30 years
Annual transvaginal ultrasound, beginning at age 30 years (or from 5 years before age of
earliest uterine cancer in the family)
Kidney ultrasound scan or MRI, every 2 years, beginning at age 40 years
Colonoscopy, every 5 years starting at age 35 years
Annual/biannual colonoscopy starting at age 20–25 years
Annual ultrasound of the thyroid gland, beginning at age 25–30
Annual colonoscopy starting at age 10–12 years
Upper gastrointestinal endoscopy starting at age 25–30 years with an interval of 6 months
to 4 years
CT enterography or MR enterography, upper GI endoscopy, and colonoscopy at age 8
years; if no polyps, repeat at age 18 years; then every 3 years
MRI with MR cholangiopancreatography of pancreas and/or endoscopic US, every 1–2
years beginning at age 30 years
Annual pelvic examination, Papanicolaou test, and pelvic US beginning at age 25 years
Annual breast MRI and/or mammography starting at age 25 years
Annual testicular examination from birth to teenage years and annual testicular US starting
at:
MRI or CT scan of brain and abdomen, every 1–3 years, usually until the teenage years
Chest CT scan, if symptoms suggest a need
Echocardiography, every 1–3 years from birth
Annual abdominal ultrasound, beginning in the teenage years
Annual abdominal CT scan or MRI in adulthood
MRI of the brain and spine, every 2 years beginning in the teenage years
MRI or CT scan of the chest and abdomen, every 2–4 years, beginning at age 20 years
Annual ultrasound of thyroid beginning at age 5 years or after thyroidectomy
501
42.3.1 Hereditary Breast andOvarian
Cancer Syndromes
and 44% for ovarian cancer in BRCA1 and 69%
for breast cancer and 17% for ovarian cancer in
BRCA2 [16]. In most series, BRCA2-associated
Hereditary predisposition is seen in 5–10% of all
breast cancers, and most of them are associated
with genetic mutations of BRCA1 and BRCA2
[15] (Fig. 42.1). The cumulative cancer risk in
BRCA mutation carriers is 72% for breast cancer
breast cancers do not differ from sporadic breast
cancers in terms of phenotype and behavior [17].
BRCA1-associated breast cancers are generally
high grade, poorly differentiated, inltrating ductal carcinomas [18]. Most BRCA1-associated
502
Fig. 42.1 Invasive
ductal carcinoma with
BRCA1 mutation in a 38
years old woman. Her
sister also had a history
of breast cancer when
she was 28 years old. On
transverse fat-saturated
T1W breast MR image,
a malignant nodule,
which is enhancing in
the early arterial phase,
is seen in the left breast
(arrow)
G. Kahraman et al.
breast cancers are triple-negative (estrogen, progesterone, and human epidermal growth factor 2
receptor-negative) [16]. Breast and ovarian cancer risk increase are more prominent in BRCA1
carriers. Pancreatic, prostate, and other cancers
risks are higher in BRCA2 carriers [19].
Prophylactic mastectomy may be able to reduce
the risk of developing breast cancer by 95% in
women who carry a BRCA1 or BRCA2 gene
mutation. Moreover, bilateral prophylactic
salpingo- oophorectomy in BRCA1 and BRCA2
mutation carriers may reduce ovarian cancer risk
by about 80% [20]. ACS and ASCO screening
guidelines for individuals with BRCA mutations
are summarized in Table42.2 [21].
42.3.2 Li-Fraumeni Syndrome
Li-Fraumeni syndrome is an autosomal dominant
disease caused by mutations in TP53 gene and
characterized by the development of multiple
tumors. In one analysis, the lifetime risk of developing cancer in carriers was estimated to be 73%
in men and approximately 100% in women [22].
The most common cancers in Li-Fraumeni syndrome are sarcomas, brain tumors, breast cancers, adrenocortical carcinomas, and leukemia
[22]. The incidence of all sarcomas is increased,
except for Ewing sarcoma. Osteosarcoma is the
most common sarcoma in Li-Fraumeni
syndrome.
Adrenocortical carcinoma is seen in 10–14%
of TP53 mutation carriers [23]. Moreover, the
incidence of several brain tumors, including
astrocytoma, medulloblastoma, ependymoma,
and choroid plexus carcinoma, is increased in
TP53 mutation carriers [24]. ACS and ASCO
screening guidelines for patients with TP53
mutations are summarized in Table42.2 [11].
42.3.3 Cowden Syndrome
Cowden syndrome is an autosomal dominant disease characterized by the development of multiple
hamartomas and malignancies. It is caused by
PTEN gene mutation. Risks of breast, colon, brain,
endometrium, and thyroid malignancy are
increased in Cowden syndrome [25]. Breast cancer is the most common malignancy in Cowden
syndrome [26]. In addition to breast cancer, the
incidence of benign breast pathologies, such as
broadenoma, brocystic changes, and ductal
hyperplasia, is also increased [25]. Thyroid cancers are the second most common malignancy in
Cowden syndrome with papillary carcinoma being
the most common type. The risk of benign pathol-
42 Radiological Screening forHereditary Cancer Predisposition Syndromes
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ogies, such as multinodular goiter, adenomas, and
Hashimoto thyroiditis, is also increased. The incidence of papillary renal cell carcinoma, endometrial cancers, and colorectal carcinoma is increased
in Cowden syndrome [27]. NCCN and ASCO
screening guidelines for patients with PTEN mutations are summarized in Table42.2 [28].
42.3.4 Lynch Syndrome
Hereditary colorectal cancer syndromes account
for 5–10% of all colorectal cancers. Most hereditary colorectal cancer syndromes are hereditary
nonpolyposis colorectal carcinoma (Lynch syndrome) and familial adenomatous polyposis
(FAP). Lynch syndrome is caused by a mutation
in a mismatch repair gene (MLH1, MSH2, MSH6)
[
29]. Lynch syndrome is the most common
hereditary colorectal carcinoma syndrome [30].
Colorectal carcinomas occur at an early age in
patients with Lynch syndrome (50% before the
age of 50) and the risk of synchronous and metachronous cancers is increased [31]. In addition to
colorectal carcinomas, the risks of endometrial
cancer, ovarian carcinoma, small intestine and
gastric adenocarcinoma, ureter and renal pelvis
transitional cell carcinoma, and glioblastoma are
increased [32]. Endometrial cancer is the most
common extracolonic malignancy in Lynch syndrome [33]. The US Multi-society Task Force on
Colorectal Cancer and ASCO screening guidelines for patients with Lynch syndrome are summarized in Table42.2 [30].
42.3.5 Familial Adenomatous
Polyposis
Familial adenomatous polyposis (FAP) is an
autosomal dominant disease characterized by the
development of multiple colorectal adenomas
and caused by APC gene mutation [34]
(Fig.42.2). The lifetime risk of colorectal carcinoma is 100% in these patients [35]. Therefore,
prophylactic proctocolectomy is essential [36].
The risks of extracolonic malignancy, such as
papillary thyroid carcinoma, duodenal adenocar-
Fig. 42.2 Thirty-one years old man with familial adenomatous polyposis. He had a history of total colectomy
because of numerous colonic polyps. A smooth contoured,
homogenous polypoid soft tissue is seen in the jejunum
lumen on transverse abdominal CT image (arrow). It was
hystopathologically diagnosed as tubulovillous adenoma
with high-grade dysplasia
cinoma, brain tumors, hepatoblastoma, are also
increased. Moreover, the incidence of osteoma,
gastric fundic gland, and duodenal polyps and
congenital hypertrophy of the retinal pigment
epithelium are increased [
of Gastroenterology and ASCO guidelines for
screening patients with APC mutations are summarized in Table42.2 [37].
42.3.6 Von Hippel-Lindau Disease
Von Hippel-Lindau disease (VHL) is an autosomal dominant disease characterized by the development of many malignant and benign tumors
and is caused by VHL gene mutation [38]. Central
nervous system hemangioblastoma is the most
common tumor in VHL and most commonly
occurs in the retina, cerebellum, and spinal cord
[39] (Fig.42.3). Endolymphatic sac tumor, clear
cell renal cell carcinoma and renal cysts, pheochromocytomas, papillary cystadenoma of the
epididymis, pancreatic cysts, serous cystadenoma, and neuroendocrine tumors of the pancreas are other manifestations seen in VHL
[40–44] (Figs.42.3 and 42.4). ASCO screening
guidelines for patients with VHL mutations are
summarized in Table42.2 [45].
503
35]. American College
504
de
hi
G. Kahraman et al.
a
bc
f
g
Fig. 42.3 Thirty-eight years old man with von HippelLindau syndrome. (a–c) On fat-saturated contrastenhanced T1W transverse MR images, bilateral enhancing
cerebellar hemangioblastomas are seen (arrows). There is
also a large parenchymal defect in the left cerebellar
hemisphere due to previous surgical resection. (d–e)
Transverse fat-saturated T2W (d) and postcontrast T1W
abdomen MR images show a cystic lesion in the pancreatic tail (short arrows). (f–i) There are renal cell carcinomas seen in both kidneys as heterogeneously enhancing
solid masses in transverse postcontrast fat-saturated T1W
MR images (arrowheads)
42 Radiological Screening forHereditary Cancer Predisposition Syndromes
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505
ab
Fig. 42.4 Transverse CT (a) and T2W MR (b) images of a 38 years old woman with von Hippel-Lindau syndrome.
Diffuse distribution of multiple small cysts in pancreas parenchyma (arrows)
42.3.7 Tuberous Sclerosis
Tuberous sclerosis (TSC) is a neurocutaneous
syndrome characterized by the development of
multiple hamartomas, benign and malignant
lesions, and caused by autosomal dominant TSC
gene mutations [46]. The most common cutaneous ndings are angiobromas and hypomelanotic macules. In the brain, cortical tubers,
subependymal nodules, subependymal giant cell
astrocytoma (SEGA), and dysplastic white matter lesions can be encountered [47] (Fig.42.5).
Seizures are seen in 80–90% of patients with
TSC [48]. Multiple renal angiomyolipomas can
be present in 80% of patients with TSC [49]
(Fig. 42.5). The incidence of renal cell carcinoma is slightly increased (4%) [50]. Retinal
hamartoma, pulmonary lymphangioleiomyomatosis, cardiac rhabdomyoma, sclerotic bone
lesions, and hepatic angiomyolipoma are other
lesions accompanying TSC [47] (Fig. 42.5).
International Tuberous Sclerosis Complex
Consensus Group and ASCO screening guidelines for patients with TSC mutations are summarized in Table42.2 [51].
42.3.8 Multiple Endocrine Neoplasia
Type 1 (MEN1)
Multiple endocrine neoplasia type 1 (MEN1) is
an autosomal dominant disease characterized by
the parathyroid gland, pancreas, and pituitary
gland tumors (Fig.
42.6). It is caused by MEN1
gene mutation [52]. Primary hyperparathyroidism is the most common abnormality (90–100%).
Preoperative imaging allows a more focused surgical approach. Pancreatic and duodenal neuroendocrine tumors are seen in 30–75% of MEN1
patients, and most of them are functional.
Gastrinoma is the most common type, which may
present with Zollinger-Ellison syndrome [53].
Pituitary tumors are seen in 30% of MEN1
patients, with prolactinoma being the most common type. Carcinoids of thymus, bronchus, stomach, duodenum, and adrenal gland are other
tumors associated with MEN1. Endocrine
Society and ASCO screening guidelines for
patients with MEN1 mutations are summarized in
Table42.2 [54].
42.3.9 Multiple Endocrine Neoplasia
Type 2 (MEN2)
Multiple endocrine neoplasia type 2 (MEN2) is
divided into three groups: MEN2A, MEN2B, and
familial medullary thyroid carcinoma (MTC).
MTC is the most common malignancy seen in
MEN2 syndrome. MEN2A is associated with
MTC, pheochromocytoma, and parathyroid
tumors. MEN2B is characterized by marfanoid
appearance and development of MTC, mucosal
neuroma, and intestinal ganglioneuromas. The
gene associated with MEN2 is RET [55]. In MEN2
syndrome, MTCs usually present at an earlier age
506
G. Kahraman et al.
a
c d
b
e f
Fig. 42.5 Twenty-one years old woman with tuberous
sclerosis. (a, b) Transverse FLAIR images of brain MRI
show subependymal nodules (black arrows) and cortical
tubers (white arrows). (c–f) A small hepatic angiomyolipoma (AML) is seen as a hypodense lesion in the right
liver lobe (black arrow—c). Multiple renal AMLs in both
kidneys (long white arrows—d and a hematoma in the left
perirenal space due to an AML rupture (short white
arrows—e). (f) On transverse CT images, there are multiple sclerotic hyperdense lesions seen in iliac bones
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