Development of mediastinal lymphoma after radiotherapy for concurrent medulloblastoma and PNET in a patient with Gorlin syndrome
Jiang et al. World Journal of Surgical Oncology
Development of mediastinal lymphoma after radiotherapy for concurrent medulloblastoma and PNET in a patient with Gorlin syndrome
Tao Jiang 2 3
Junmei Wang 3
Ying Wang 0 1
Chunde Li 1 2
0 Beijing Chao-Yang Hospital, Capital Medical University , Beijing 100020 , China
1 Equal contributors
2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University , 6 Tiantan xili, Chonwen District, Beijing 100050 , China
3 Beijing Neurosurgical Institute, Capital Medical University , Beijing 100050 , China
Background: Very young children with Gorlin syndrome are at risk for developing medulloblastoma. Patients with Gorlin syndrome may have multiple system abnormalities, including basal cell carcinomas, jaw cysts, desmoplastic medulloblastoma, palmar/plantar pits, rib abnormalities, and intracranial falx calcification. The early diagnosis of Gorlin syndrome in desmoplastic medulloblastoma patients is very important because these patients should receive chemotherapy as a first-line treatment and should avoid radiotherapy as much as possible. Case presentation: In the present study, a 5-year-old male patient had a concurrent cerebellar desmoplastic medulloblastoma and temporal primitive neuroectodermal tumor. Examinations of this patient revealed multiple café-au-lait spots, a jaw cyst, and a bifid rib. A molecular classification analysis revealed that the patient's cerebellar tumor was of the sonic hedgehog subtype. Twenty-seven months after tumor resection and cerebrospinal irradiation were performed, mediastinal lymphoma was found in the patient. The patient ultimately died of lymphoma. To the best of our knowledge, this is the first report of a concurrent medulloblastoma and primitive neuroectodermal tumor and the fourth report of multiple café-au-lait spots in a patient with Gorlin syndrome. This report is also the first account of the development of mediastinal lymphoma after spinal irradiation in a patient with Gorlin syndrome. Conclusions: Chemotherapy should be the first-line treatment for medulloblastoma patients with Gorlin syndrome. Young patients with medulloblastoma of the desmoplastic subtype and multiple café-au-lait spots should be thoroughly examined for Gorlin syndrome.
Medulloblastoma; Gorlin syndrome; Chemotherapy; Café-au-lait spots; SHH subtype
Gorlin syndrome (GS), also known as basal cell nevus
syndrome (BCNS, OMIM #109400), basal cell carcinoma
nevus syndrome (BCCNS), and Gorlin-Goltz syndrome,
is an autosomal inherited syndrome that was first
described in 1963 [
]. The prevalence rates of GS range
from 1/55,600 to 1/30,827 in the UK, 1/164,000 in
Australia, and 1/235,800 in Japan [
]. GS is an
autosomal genetic disorder that is generally caused by a
mutation in the patched-1 homolog (PTCH1) gene,
which has complete penetrance and a variable
phenotype. This syndrome is characterized by the existence of
multiple basal cell carcinomas (BCCs), jaw cysts,
desmoplastic medulloblastoma, palmar/plantar pits, rib
abnormalities, and intracranial falx calcification.
The presence of desmoplastic medulloblastoma (DMB)
and a primitive neuroectodermal tumor (PNET) is
currently the major criterion for the diagnosis of GS [
However, the early diagnosis of GS in DMB patients is
difficult because the other criteria used to establish a
diagnosis of GS, such as intracranial calcification and BCC,
may not occur before the patient is 10 years old. Most
medulloblastoma patients with GS are less than three
years old, with a mean age of 2 years. Suspected DMB
patients should be screened for GS because irradiation of GS
patients may cause the development of radiation-induced
tumors, such as meningioma and ependymoma.
Chemotherapy is the first-line treatment for these patients. Here,
we report a 5-year-old boy who was diagnosed with GS
and a concurrent cerebellar medulloblastoma and
temporal PNET, as well as multiple café-au-lait spots.
Twenty-seven months after tumor resection and
radiotherapy were performed, mediastinal lymphoma was
found. To the best of our knowledge, this is the first report
of this phenomenon.
History and examination
A 5-year-old boy presented with headache, vomiting,
and vertigo with a duration of 5 months. CT and MRI
examinations revealed the presence of a right cerebellar
mass with mild enhancement and of a right temporal
mass with moderate enhancement (Figs. 1, 2, and 3).
The tumors were hypointensive in T1-weighted MRI
scans and hyperintensive in T2-weighted MRI scans. CT
examination revealed that both tumors were hyperdense.
Following these examinations, the patient was referred
to our hospital.
Surgery and diagnosis
During surgery, the two tumors were observed to have
similar appearances. Both tumors were reddish-colored
and soft, had a moderate blood supply, and were easy to
suction. The postsurgical pathology reports stated that
the tumors were a DMB (cerebellar mass) and PNET
(temporal mass) (Figs. 4 and 5).
Due to the suspicion that the boy had GS, he was
evaluated for this condition. The circumference of his head
was 48 cm. Physical examination revealed the presence
of multiple café-au-lait spots (Fig. 6). Plain film X-ray
imaging demonstrated the presence of a bifid rib and a
jaw cyst (Figs. 7 and 8). The PTCH1 gene test was
Fig. 3 Image of the right cerebellar tumor, with moderate enhancement
negative. We conducted a molecular classification of the
cerebellar tumor using the real-time polymerase chain
reaction (PCR) method [
] and the NanoString method
] and discovered that the DMB was a SHH subtype
tumor. Based on two major and one minor criteria for
GS (desmoplastic MB, bifid rib, and jaw cyst,
respectively), an unambiguous diagnosis of GS was made.
Radiotherapy and post-treatment course
After the patient was discharged, his parents refused to
allow him to receive chemotherapy, which is a treatment
that must be covered by out-of-pocket payments in
China, due to their financial difficulties. The patient
instead underwent 30.6-Gy irradiation of the entire brain
and the spinal axis and 54-Gy irradiation of the posterior
fossa. At follow-up, an MRI examination showed no
tumor recurrence. Twenty-seven months after receiving
radiotherapy, the patient experienced chest pain and had
a fever. CT examinations revealed the presence of a
mediastinal mass and chest effusion (Fig. 9). Analysis of a
biopsy performed at another hospital demonstrated that
the mass was T cell non-Hodgkin’s lymphoma (Fig. 10).
The patient’s parent refused treatment because of
financial difficulties, and the boy died 1 month later.
DMB and medulloblastoma with extensive nodularity
(MBEN) are closely associated with GS. The
development of DMB and MBEN, which are generally the first
tumoral manifestations in patients with GS, is thought
to be the major criterion for the diagnosis [
prevalence of MB in GS patients in early childhood is
difficult to estimate. The incidence of GS in MB patients
was reported to be 1–2 %, and 3–5 % of GS patients
develop medulloblastoma, generally within the first 2 years
of life [
]. In a retrospective investigation, 5 of 82
medulloblastoma patients were diagnosed with GS [
Amlashi’s cohort of 76 MB patients, the incidence of GS
among the entire cohort was 4 %, the incidence of GS in
Fig. 7 Image showing that the right fourth rib was a bifid rib
patients younger than 5 years old was 10.7 %, and the
incidence of GS in patients younger than 2 years old was
25 % [
]. In a Japanese survey, 3.3 % of 157 GS patients
had MB [
To the best of our knowledge, this is the first report of
a concurrent infratentorial medulloblastoma and a
supratentorial PNET in a GS patient. On cerebrospinal
axis MRI examination, there were no signs of CSF
seeding; two images appeared different under microscope
examination, which excluded the occurrence of tumor
metastasis. The molecular classification of the DMB as a
SHH subtype tumor was also consistent with the
diagnosis of GS. Our patient could have been diagnosed with
GS based on the presence of DMB, a PNET, a jaw cyst, a
bifid rib, and multiple café-au-lait spots, as well as the
classification of the DMB as a SHH subtype tumor. The
occurrence of multiple café-au-lait spots is associated
with many hereditary disease, including
neurofibromatosis type 1, McCune-Albright syndrome, Cowden
syndrome, and LEOPARD syndrome [
]. This is the fourth
case report of multiple café-au-lait spots in a GS patient
]. Because the clinical diagnostic criteria for GS are
continually changing, we propose that the presence of
café-au-lait spots in young DMB patients should be
considered a “trigger” for ordering a diagnostic evaluation
and a molecular blood test for GS.
GS patients are at a high risk of developing multiple
BCCs and other radiation-induced tumors, such as
meningioma, ependymoma, and fibrosarcoma, in irradiated
areas. To date, this is the first report of the development
of post-treatment non-Hodgkin’s lymphoma in a GS
patient. The hedgehog pathway regulates intrathymic T cell
development. Aberrant activation of the hedgehog
pathway is associated with the pathogenesis of malignant
]. Irradiation induces DNA damage and
genomic instability in circulating and thymic
lymphocytes, which results in apoptosis, abnormal DNA
methylation, and changes in RNA expression [
patient developed mediastinal lymphoma, which was
unequivocally diagnosed as a radiation-induced tumor.
Interestingly, we found one report of a
radiationinduced PNET that developed following treatment for
non-Hodgkin’s lymphoma . These findings may
facilitate elucidation of the molecular mechanisms
underlying tumorigenesis in GS patients.
Early and prompt diagnosis is important in patients
suspected to have GS, as chemotherapy is the first-line
treatment for tumors in GS patients. The desmoplastic
variant of MB and MBEN in GS generally occur in
children who are 2 years of age or younger. Most of the
main criteria for GS, such as intracranial calcification,
jaw cysts, and BCC, do not appear until the second
decade of life, which makes early diagnosis of GS in very
young patients difficult [
]. Medulloblastoma patients
with GS generally have a promising survival rate due to
recent advancements made in chemotherapy [
detection rate of a mutated PTCH 1 gene is only 50–
85 % [
], which makes early diagnosis more difficult.
Amlashi et al. have even suggested avoiding radiotherapy
in DMB patients who are less than 5 years old [
The overexpression of the members of the canonical
hedgehog signaling pathway plays an important role in
tumorigenesis in GS patients. In the majority of GS
patients, the loss of function of PTCH1 has been found,
which causes the reduction of the inhibition of the
smoothened (SMO) oncogene and the subsequent
aberrant activation of the glioma-associated oncogene
homolog (GLI) family members. It is possible that SMO
inhibitors, such as vismodegib, may serve as new
therapeutics for the treatment of tumors in GS patients.
Vismodegib has proven to be effective in the treatment
of GS-related BCC and keratocystic odontogenic tumors
]. Robinson et al. reported that vismodegib
exhibited activity against adult recurrent or refractory
SHHMB . However, the response to SMO inhibitors of
medulloblastoma patients was variable and transient,
and this drug was most effective in treating tumors with
upstream activating aberrations in the SHH pathway.
The existence of a PTCH1 mutation was correlated with
a positive response to the drug, and aberrations in GIL2
and SUFU were found in the nonresponders [
The lack of efficacy of SMO inhibitors and the
acquired resistance to these inhibitors in medulloblastoma
patients argues for the use of GLI-specific inhibitors.
GLI1 is the most significant member of the hedgehog
pathway and plays a role in promoting carcinogenesis.
Several studies have shown that aberrant GLI1 expression
occurred independently from the signaling of the
canonical HH pathway through PTCH and SMO [
was responsible for the development of radioresistance
and chemoresistance in tumors . The aberrant
expression of GLI1 was closely linked to the activity of several
non-canonical signaling pathways, such as the Kirsten rat
sarcoma viral oncogene homolog (KRAS) pathway, the
avian myelocytomatosis virus oncogene cellular homolog
(C-MYC) pathway, the transforming growth factor β
(TGFβ) pathway, the wingless-type MMTV integration
site family (WNT) pathway, and the β-catenin pathway.
Together, these data suggest that administering specific
inhibitors of the final step in the hedgehog pathway may
be the most effective treatment option and the ideal
approach to use in future studies. Currently, there are
several agents (HPT, GANT58, GANT61, and arsenic
trioxide) that are known to inhibit the transcriptional activity
of GLI [
]. Although GLI1-specific inhibitors are still
in the preclinical stage of testing, studies in which
combinations of GLI1 inhibitors and chemotherapeutic agents
were used to treat other types of tumors have been
To the best of our knowledge, this is the first report of a
concurrent medulloblastoma and PNET and the fourth
report of multiple café-au-lait spots in a patient with GS.
This is also the first report of mediastinal lymphoma
developing after spinal irradiation for the treatment of GS.
Chemotherapy should be the first-line treatment for
medulloblastoma patients with GS. We propose that young
patients with the desmoplastic subtype of
medulloblastoma and multiple café-au-lait spots should be
thoroughly examined for the existence of GS.
BCC: basal cell carcinoma; CSI: cerebrospinal axis irradiation; DMB:
desmoplastic medulloblastoma; GLI: glioma-associated oncogene homolog;
GS: Gorlin syndrome; MBEN: medulloblastoma with extensive nodularity;
PNET: primitive neuroectodermal tumor; SMO: smoothened
The National Key Technology Research and Development Program of the
Ministry of Science and Technology of China (2013BAI09B03) supported the
molecular subgroups of medulloblastoma specimens.
Availability of data and materials
TJ drafted the manuscript and monitored the patient. JW participated in
conducting the pathological examinations. YW conducted the molecular
genetic studies and contributed to the study design. CL conceived the
study, participated in its design and coordination, and helped draft the
manuscript. CL and YW contributed equally to this study. All of the authors
read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patient for the publication
of this case report and any accompanying images. Written informed consent
for publication of their clinical details and clinical images was obtained from
the parent of the patient. A copy of the consent form is available for review
by the editor of this journal.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Beijing Tian Tan
Hospital, Capital Medical University (reference number: KY2014-021-02).
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