JMD 2001, Vol. 3, No. 4
Copyright © 2001 American Society for Investigative Pathology & Association for Molecular Pathology
Inheritance of Osteosarcoma and Paget’s Disease of Bone
A Familial Loss of Heterozygosity Study
Julie D. K. McNairn*,
Timothy A. Damron
,
Steve K. Landas*,
J. Lee Ambrose
and
Antony E. Shrimpton*
From the Departments of Pathology,
*
Orthopedic Surgery,
and Radiology,
SUNY Upstate Medical University, Syracuse, New York
 |
Abstract
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Pagetoid osteosarcoma is a complication of Paget’s disease of
bone. Sarcomatous transformation is most often seen in severe,
long-standing Paget’s disease. Familial clustering of Paget’s disease
has been described with apparent autosomal dominant inheritance with
high penetrance by the sixth decade. Although definitive proof of the
specific gene involved remains elusive, some researchers have
shown loss of heterozygosity in a region of chromosome 18q in a
relatively high percentage of studied patients affected with either
Paget’s disease alone, in Pagetoid osteosarcoma, and
in uncomplicated osteosarcoma. Our patient was diagnosed with Pagetoid
osteosarcoma and had a first-degree relative with history of the same.
We hypothesized that our patient’s tumor samples might contain a
similar genetic abnormality. Our analysis of several polymorphic
markers from the chromosome 18q21–22 region showed loss of maternally
inherited alleles throughout the region. This finding is similar to
those described previously4
and provides further evidence
of a susceptibility region relating to this disease. This report
describes a father and son, their young ages at diagnosis of
Pagetoid sarcoma, the identical sites of disease
involvement, and a loss of heterozygosity study illustrating
the inheritance of the presumed defective gene.
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Introduction
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Paget’s disease of bone is a disorder with a predilection for
older individuals.1, 2, 3, 4, 5, 6, 7, 8, 9
Current data suggest that the
disease affects 2 to 3% of the population over the age of fifty and
10% over the age of eighty.5
The symptoms of the disease
vary from virtually asymptomatic to widespread bone involvement with
significant morbidity.10
The most serious complication of
Paget’s disease is sarcomatous transformation of affected
bone.1
An uncoupling of bone remodeling, the underlying cause of Paget’s
disease of bone, has been explored extensively.
Somehave proposed a viral etiology given the bizarre morphology and
increased number of nuclei in giant cells.11, 12, 13
Others
have ascribed a genetic character to the
disease.3, 6, 9, 14, 15, 16
Still others have suggested a genetic
predisposition to a viral infection as a likely cause of this abnormal
bone remodeling.11, 14, 17
A combined hypothesis is a
multifactoral model, which includes both sporadic and familial forms of
the disease.9
Although Paget himself failed to recognize a familial tendency of
Paget’s disease, familial clustering has been observed. Likewise, a
familial form of osteosarcoma affecting bone involved by Paget’s
disease is documented by reports in the literature. The details of
these cases are varied; only one describes a direct lineage in which
Pagetoid osteosarcoma developed in affected family
members.15, 16, 18, 19, 20, 21, 22, 23
This genetic study describes a son and father; both affected with
Pagetoid osteosarcoma at identical anatomical sites. Both were
young men at the time of diagnosis, and both met untimely deaths from
the osteosarcoma.
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Case Presentations
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A 33-year-old man with a 9-year history of Paget’s disease
presented with a mass of the distal right femur with worsening pain, a
recent 25-pound weight loss, and drenching night sweats. Several months
before this, he had reported stiffness in his knees. The stiffness had
been attributed to chronic osteomyelitis and leg length discrepancy and
was treated with non-steroidal anti-inflammatory drugs and braces.
His past medical history was significant for multiple long bone
fractures. At age 18 he fractured his femurs bilaterally in a
motorcycle accident. At age 24 he suffered a left mid-femur fracture
while jogging. Work-up at that time led to a diagnosis of Paget’s
disease involving both femurs and proximal tibiae. Physical examination
revealed tenderness, palpable fullness, and increased warmth through
the distal right thigh.
Radiographs of the right knee and distal femur demonstrated severe bone
deformity consistent with Paget’s disease and his prior healed
fracture, but a soft tissue mass was identified posterior and medial to
the distal femur emanating from the bone (Figure 1)
. Chest radiographs identified two discrete pulmonary nodules. A bone
scan revealed markedly increased flow to the right knee and right
distal femur (Figure 2)
.
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Figure 1. Anteroposterior radiograph of the right distal femur shows severe
deformity due both to the underlying Paget’s disease and a healed
distal femoral fracture. A soft tissue mass is shown extending
posteromedially
(arrows).
Pagetoid involvement of the adjoining proximal tibia is also seen.
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Figure 2. Total skeleton bone scan shows increased uptake in the medial and
lateral condyles and distal medial cortex of the right femur, with a
negative image created by the tumor mass
(arrow).
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A magnetic resonance imaging study demonstrated Paget’s disease
involving the epiphysis and distal diametaphyseal region of the right
femur. A large soft tissue mass was appreciated posteromedially
adjacent to the thickened periosteum and cortex of the distal
diametaphysis with distal extension (Figure 3)
. The soft tissue mass was approximated to be 10 centimeters in
greatest dimension.
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Figure 3. Magnetic resonance imaging coronal T1 weighted spin echo
(A) and
coronal T2 weighted fast spin echo
(B) show a
large lobulated tumor mass arising from the epiphysis and distal
diametaphysis. The mass
(arrows) shows
low signal on T1-weighted images and hyperintensity on T2-weighted
images.
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The clinical and radiological data supported a presumptive diagnosis of
Pagetoid osteosarcoma. An open biopsy of the right distal thigh mass
showed a storiform, collagenized neoplasm with focal osteoid
production. The cells were very pleomorphic, forming sheets in several
foci. There were scattered tumor giant cells with a semicircular
configuration of nuclei at the cell periphery. Mitotic figures were
seen at a rate of approximately 60/10 high power field. The diagnosis
of Grade 4 osteosarcoma, fibroblastic type, was made (Figure 4)
.
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Figure 4. Histological sections of the tumor mass
(A, B)
demonstrate the hypercellular storiform tumor mass. Mitotic figures are
extensive. Focal scant osteoid production is identified in A
(arrows)
diagnostic of osteosarcoma. Histological sections of bone away from the
sarcoma within the resected distal femoral specimen
(C) illustrate
haphazardly organized, thickened trabeculae and irregular cement lines
consistent with bone involved by Paget’s disease after neoadjuvant
chemotherapy. A: Trichrome stain, x20; B:
Hematoxylin and eosin, x40; C: Hematoxylin and eosin,
x20).
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The patient was treated with neoadjuvant chemotherapy, including high
dose methotrexate, as per modified POG protocol 9450. A magnetic
resonance imaging study performed following the neoadjuvant therapy
showed a large, lobulated mass of the distal femur with soft tissue
extension. The mass was similar to, but slightly larger than that
described in previous studies. Additional lung nodules were identified
at this time.
The patient underwent a right above-the-knee amputation, as the tumor
involvement was too extensive to consider limb-sparing surgery.
Examination of the amputation specimen showed Grade 4 osteosarcoma
similar to that in the biopsy specimen. Gross examination of the
specimen showed destruction of the metaphysis and tibial plateau. The
tumor mass was thirteen by nine by eight centimeters and appeared to
enter the knee joint space. Microscopic examination showed marginal
necrotic bone and approximately 50% tumor necrosis identified. The
resection margins were free from tumor, as confirmed by frozen section.
Despite additional chemotherapy, including high-dose methotrexate,
etoposide, ifosfamide, adriamycin, and platinum, with resection of
multiple lung nodules, the patient succumbed to his disease almost 2
years following diagnosis.
The father of our patient presented at age 39 to Roswell Park Cancer
Center in Buffalo, NY in early 1962 with abnormal x-ray findings of
both distal femurs. A presumptive diagnosis of osteogenic sarcoma of
both femurs was rendered. He underwent biopsies of both right and left
femurs to confirm this presumptive diagnosis. Both biopsies illustrated
Paget’s disease of bone. However, only the specimen from the right
femur contained osteogenic sarcoma arising in the Paget’s disease. He
underwent a right hip disarticulation. Nearly one year later, severe
pain prompted x-rays of the chest, pelvis, and left leg. These all
failed to demonstrate metastases or disease progression. Approximately
six months later, the patient presented again with lesions of the left
femur and tibia including a pathological fracture through the upper
left tibia. An open biopsy performed at this time showed osteogenic
sarcoma of the left leg. X-rays of the chest demonstrated two discreet
pulmonary nodules, believed to be metastatic involvement. The patient
was treated with BCNU (bis-chloronitrosourea, carmustine) for 3 days
but suffered severe toxicity. No further chemotherapy or surgery was
initiated. The patient succumbed to his osteosarcoma 3 months later,
less than 2 years after his initial diagnosis.
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Materials and Methods
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Linkage Analysis
Microsatellite markers located in 18q21.2–18q23 were selected for
polymerase chain reaction, based on their heterozygosity. Primers were
obtained from Research Genetics (Huntsville, AL) and amplified using
the manufacturer’s conditions. DNA isolated from peripheral blood and
tumor samples were genotyped at these markers by running PCR products
on 8% polyacrylamide gels.
Patient Samples
Formalin-fixed post-surgical osteosarcoma samples were obtained
from the primary and metastatic tumor sites from our patient. A matched
control sample was obtained as adjacent normal tissue from the
post-surgical specimen. Tumor samples from the father of our patient
were unavailable. A blood sample was obtained from the mother and
siblings of our patient to better elucidate the inheritance at the 18q
loci in question. This research was done under the approval of the
Institutional Review Board, and informed consent was obtained before
sample acquisition.
DNA Isolation
DNA was isolated from the formalin-fixed post-surgical
specimens as described previously.24
DNA was isolated from
the peripheral blood sample of the living relatives using a non-organic
extraction kit, Intergen Company, (Q-Biogene, Carlsbad, CA) catalog
number S4520.
Loss of Heterozygosity Analysis
Several polymorphic microsatellite loci were used in this
analysis, including D18S858, D18S1144, D18S1129, D18S38,
D18S1147, D18S60, D18S68, D18S1142, D18S42, D18S55, D18S1113, D18S878,
D18S43, D18S844, and myelin basic protein. Additional tumor markers in
the 18q region were uninformative. PCR amplified products from the
unaffected mother (I:2), three unaffected siblings (II:1, II:2, II:3),
the affected son (II:4), and his tumor (II:5) were run on
polyacrylamide gels and detected by silver staining.25
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Results
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Results from the 18q microsatellite
markergenotyping are shown in Figures 5
and 6
. Unfortunately no material was available from the affected father
(I:1), though his genotype could be partially reconstructed from his
offspring. Loss of heterozygosity involving the maternally inherited
alleles was detected in the tumor (II:5) as compared to the blood
(II:4). Markers in 18q21.2 (D18S858), 18q22.1(D18S68, D18S1113,
D18S878) were detected in reduced amounts indicating a chromosomal
deletion. The reduced amounts rather than complete absence of the
maternal allele indicated that the tumor sample included non-tumor
tissue. The maternally inherited MBP microsatellite allele in 18q23 did
not appear to be deleted in the tumor. Thus the distal breakpoint
appears to lie between D18S878 and MBP. The proximal breakpoint was not
defined but appears to lie proximal to D18S858. All other markers were
uninformative.
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Figure 5. Pedigree microsatellite genotype results. The index case is represented
by post-surgical non-tumor specimen
(II:4) and post-surgical
tumor specimen (II:5).
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Figure 6. A: D18S858 PCR product from blood (lane 1) and
from tumor of the index case (lane 2). Run on an 8%
polyacrylamide gel for 11,000- volt hours. Note that allele 1 (•) of
the tumor is present in reduced amounts compared to allele 1 in blood
(x). B: In contrast, in lane 3, MBP PCR product
from blood, and lane 4, from tumor of the index case show no
evidence of loss of heterozygosity.
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This result is consistent with the paternal transmission of a mutation
in a putative tumor suppressor gene that is uncovered by an acquired
"second hit" deletion including 18q22.1 in the tumor. The carrier
status of this putative tumor suppressor mutation in the three
unaffected siblings is uncertain given the lack of an exact location of
the tumor suppressor and the lack of a paternal sample to genotype.
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Discussion
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Worsening pain, pain resistant to analgesics, or changes in the
pain pattern often signals the development of osteosarcoma in Paget’s
disease.26, 27
Swelling, fracture, weight loss, night
sweats, and neurological complaints may accompany these
symptoms.2, 28
The typical presentation of an affected
patient with sarcomatous transformation is a 65-to-70 year-old man with
a 15-to-25 year history of polyostotic Paget’s
disease.2, 27, 28, 29
The sarcoma itself is usually high grade
with a poor prognosis.29
Some researchers have attributed
the low survival in Pagetoid osteosarcoma to effects of advanced age: a
weakened immune system, a decreased ability to battle the disease, and
decreased tolerance of treatment,27
for example. Other
factors, such as environmental exposure, may also prove significant
though proof is lacking. However, both patients described here were
significantly younger than those typically affected by these disease
processes, though they did exhibit some of the classic symptoms. The
x-ray findings in our patient clearly show involvement by the sclerotic
phase of Paget’s disease, suggesting a long disease course.
Both of these patients had involvement of the distal femur, a common
site of involvement for both the diseases.2, 27, 30, 31
One
previous report of a father and son affected in identical locations
describes a father, affected at age 78, and son, affected at age 60,
with Pagetoid osteosarcoma. Both men were affected at the proximal
tibia, had long histories of Paget’s disease leading up to the
sarcomatous transformation, and died of their disease within months of
diagnosis with evidence of pulmonary metastases.18
Previous to that report, Paget’s disease was considered to be
transmitted as an incompletely dominant X-linked gene. That case was
the first to give credence to male-to-male transmission, initiating
research to explore the possibility of involvement of an autosomal
gene. Since this time, evidence has pointed to several genes linked to
Paget’s disease, some as yet unidentified. Linkage analysis studies
first uncovered an apparent link to the HLA locus on chromosome 6, now
termed PDB1.11
Further study provided evidence of linkage between Paget’s disease and
a susceptibility locus on chromosome 18q21–22. This locus harbors the
gene identified in a family afflicted with familial expansile
osteolysis, a rare bone disorder with features very similar to Paget’s
disease.6, 13
A subsequent study has also identified a
putative tumor suppressor gene on chromosome 18q. In that study, all
tumor samples examined from individuals affected with Pagetoid
osteosarcoma showed some loss of heterozygosity in the 18q21–22 region
studied. A lower percentage of tumor samples from sporadic
osteosarcoma, those not superimposed on Paget’s disease, also showed
loss of heterozygosity in this same region.4
This is in
contrast to the more conventional high-grade osteosarcomas occurring in
children affected with retinoblastoma, as part of the Li-Fraumeni
syndrome, or in so-called cancer families.32, 33, 34
Another
study used seven polymorphic loci in this region of chromosome
18q21–22 in eight genetically diverse families affected by Paget’s
disease only. Five of eight showed linkage to the region, while two
showed no linkage and the last family was inconclusive. Interestingly,
three of the families were of Spanish decent, yet one showed linkage to
this region.5
Our genetic analysis does support the idea of a susceptibility region
on chromosome 18 in the region described previously.4, 5, 6
Work to definitively determine the associated gene would potentially be
helpful in further understanding the disease etiology. The gene
encoding the receptor activator of nuclear factor-
B
(RANK, TNFRSF11A) lies within the critical region of
18q that has been deleted. The RANK gene represents a strong
candidate gene since it has been found to be mutated in familial
expansile osteolysis.35
Although thus far the
RANK gene has not been found to be mutated in Paget’s
disease of bone, Wuyts did find a statistical association between a
RANK polymorphism and Paget’s disease of bone, indicating that it may
represent a susceptibility factor36, 37
Sequencing of this
gene in the presented family, as well as examination of other regions,
including the PDB1 locus may uncover more information.
Other siblings within this family may have inherited the same alleles
as our patient. However, these siblings, ranging in age from 39 to 44,
do not show any signs of Paget’s disease or Pagetoid osteosarcoma to
this point. Although they are younger than the typical age for
diagnosis with either disease, they are both older than their family
members were at initial presentation. Why only one offspring was
affected by severe Paget’s disease and Pagetoid osteosarcoma is not
easily explained. The similarity of his disease to that of his father
is curious. Perhaps elucidation of the gene involved will clarify the
mechanism. This may be the key to improving the dismal prognosis
associated with this disease.
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Acknowledgments
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The authors are grateful for the consultative input of Dr.
Krishnan Unni of the Mayo Clinic, Rochester, Minnesota. We thank S.O.
Sanderson, M.D. for his assistance in photographing the histological
sections.
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Footnotes
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Address reprint requests to Timothy A. Damron, M.D., Department of Orthopedics, Suite 100, 550 Harrison Center, Syracuse, NY 13202. E-mail: damront{at}mailbox.upstate.edu
Supported by funding from the Pathology Medical Service Group
and the Marvin A. Damron Memorial Cancer Research Fund.
Accepted for publication July 27, 2001.
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Abstract
Introduction
