Abstract
Background: The time between the initial
symptoms of osteosarcoma and Ewing sarcoma and the correct diagnosis
and treatment is long. Over the last two decades, the prognosis
for patients with these diseases has dramatically improved due to
a new chemotherapy regimen. As a consequence, a limb-sparing operation
has become an alternative to amputation. The aim of this study was
to establish the initial symptoms and physical signs of osteosarcoma
and Ewing sarcoma from the records of the first medical visit and
to identify early characteristics of the diseases to shorten the
delay to diagnosis.
Methods: A group of patients with osteosarcoma
or Ewing sarcoma was identified from the Swedish Cancer Register
of patients thirty years old and younger. Records from the first
medical visit due to symptoms related to the bone tumor were obtained
for 102 patients with osteosarcoma and forty-seven patients with
Ewing sarcoma.
Results: Pain related to strain was reported
by eighty-seven (85 percent) of the patients with osteosarcoma and thirty
(64 percent) of those with Ewing sarcoma, but only twenty-one (21
percent) of the patients with osteosarcoma and nine (19 percent)
of those with Ewing sarcoma reported pain at night. Forty-eight
(47 percent) of the patients with osteosarcoma and twelve (26 percent)
of those with Ewing sarcoma related the onset of symptoms to minor trauma
occurring around the same time. A palpable mass was noted in forty
(39 percent) of the patients with osteosarcoma and sixteen (34 percent) of
those with Ewing sarcoma at the first visit, and in most cases the
tumor diagnosis was suspected. There was a broad spectrum of misdiagnoses;
the most common was tendinitis, which was the initial diagnosis
in thirty-two (31 percent) of the patients with osteosarcoma and
ten (21 percent) of those with Ewing sarcoma. The doctor's delay
(the period from the first medical visit due to the symptoms to
the correct diagnosis) was longer for Ewing sarcoma than for osteosarcoma
(nineteen weeks and nine weeks, respectively; p < 0.0001).
Conclusions: An initial symptom of both osteosarcoma
and Ewing sarcoma was pain, which was intermittent and often related
to strain but not frequently felt at night. A history of trauma
was common, but the clinical course often diverged from what was
expected from trauma. The clinical course of osteosarcoma and particularly
of Ewing sarcoma was not steadily progressive but intermittent, which
often misled the doctor into believing that the condition was temporary.
The most important clinical feature was a palpable mass, which was noted
in more than one-third of the patients at the first visit. This
finding emphasizes that a thorough physical examination is absolutely
necessary.
Primary malignant bone tumors are rare. The two most common types,
osteosarcoma and Ewing sarcoma, have a peak incidence in the second
decade of life and an annual incidence of two and 0.8 per million
population, respectively7,13.
These tumors are so rare that most doctors will see only a few
patients with symptoms from an undiagnosed primary bone tumor during
their whole working life. Most general practitioners therefore have
little or no experience with these primary malignant bone tumors,
but they are the first doctors consulted in the initial phase of
the disease.
Numerous articles have focused on the treatment and prognosis
of primary malignant bone tumors but only a few have described the
initial symptoms of the disease. Sweden and other countries have centers
specializing in bone tumors. The physicians at these clinics meet
the patient when the tumor is diagnosed or when it is strongly suspected. The
recollection of the patient, or his or her parent, of when and under
what circumstances the disease started may at that time be influenced
by the threat of a diagnosis of cancer.
Early recognition and treatment is important in all malignant
diseases. In recent decades there has been a remarkable increase
in survival rates of both patients with osteosarcoma and those with Ewing
sarcoma1. Early diagnosis of a
bone tumor may increase not only the chance of survival but also
the possibility of performing a limb-sparing resection.
The purpose of this study was to identify the early symptoms
of osteosarcoma and Ewing sarcoma by analyzing the initial symptoms
and physical findings as described in the report from the patient's first
visit to a physician for symptoms that could be related to the bone
neoplasm. Furthermore, it was intended to establish whether something
in the patient's history or in the physical findings was characteristic
or divergent and should have made the doctors aware of a malignant
bone tumor.
A listing of all patients diagnosed with osteosarcoma or Ewing
sarcoma in Sweden between the beginning of January 1983 and the
end of December 1995 was obtained from the Swedish Cancer Register
at the National Swedish Board of Health, Stockholm, Sweden. The
study was limited to patients who were thirty years old or younger,
and all tumors except those located in the skull or the ribs were
included. The Swedish Cancer Register is a population-based register
for all malignant tumors diagnosed in Sweden. A double-reporting
system is used so that every physician and pathologist has to report
all patients with a malignant tumor, and therefore almost all cases
in Sweden are reported. Each patient's data from the Swedish Cancer
Register includes information about the clinic where and the date
when the accurate diagnosis was established, the histological findings,
the location of the tumor, and the day of death.
Files from the clinic where the tumor diagnosis was initially
made were used to find information about when and where the patient
first consulted a doctor for symptoms that could be related to the primary
malignant bone tumor. Records from earlier visits were requested
until the medical file from the first visit was obtained.
The data recorded at the first medical visit included pain at
night; pain related to strain; intermittent pain at rest; swelling;
trauma; physical activity; duration of symptoms; periods of fever;
physical signs such as a palpable mass, tenderness, limping, painful
movements of the joint, restricted movements of the joint, and atrophy
of muscle; and the doctor's prescription and initial diagnosis.
Patient's delay was defined as the period from when the patient
first noted symptoms until the patient first consulted a doctor,
and doctor's delay was defined as the period from the first medical visit
for these symptoms until the date that an accurate diagnosis was
established.
The Student t test, chi-square test, and analysis of variance
were used for statistical analysis. The significance level was set
at p < 0.05.
There were 102 patients with osteosarcoma; sixty-one were male
and forty-one, female. Forty-seven patients had Ewing sarcoma; twenty-eight
were male and nineteen, female. A predilection for the male gender
of 1.5:1 was shown for both osteosarcoma and Ewing sarcoma. The
mean age of the patients with osteosarcoma was 15.8 years (range, 5.5
to 29.5 years) compared with 15.4 years (range, 2.5 to 26.0 years)
for the patients with Ewing sarcoma (Fig. 1 and Fig. 2). Seventy-five (74 percent) of
the osteosarcomas and eleven (23 percent) of the Ewing sarcomas were
located around the knee (Fig. 3).
First Medical Visit
Eighty-six (58 percent) of the patients first consulted a district
general practitioner for symptoms related to the primary malignant
bone tumor, and forty-two (28 percent) consulted a doctor at an emergency
ward. Eleven (7 percent) of the patients, who were young, saw their
school doctor, and eight (5 percent) of the patients, who were in the
military service, consulted a military doctor. Only two patients
(1 percent) consulted a private practitioner. Thus, 72 percent of
the patients first consulted a general practitioner for symptoms
related to the primary malignant disease.
Reasons for Consultation
Regional pain alone or in combination with a palpable mass were
the two main reasons that patients consulted a doctor (Table I). Seventy-one
(70 percent) of the patients with osteosarcoma and thirty-four (72
percent) of the patients with Ewing sarcoma consulted a doctor about
regional pain alone. Twenty-six (25 percent) of the patients with
osteosarcoma and seven (15 percent) of those with Ewing sarcoma
consulted a doctor about regional pain and a palpable mass. Only
four (4 percent) of the patients with osteosarcoma and five (11
percent) of those with Ewing sarcoma did not report pain at the
first medical visit; these patients all had a palpable mass only.
One patient (1 percent) with osteosarcoma and one (2 percent) with
Ewing sarcoma had regional pain and paresthesia (Table I).
Pain
Only twenty-one (21 percent) of the patients with osteosarcoma
and nine (19 percent) of those with Ewing sarcoma had pain at night;
however, eighty-seven (85 percent) of the patients with osteosarcoma
and thirty (64 percent) of those with Ewing sarcoma reported pain
related to strain. Intermittent pain at rest, which was equally
common in patients with osteosarcoma and those with Ewing sarcoma, was
reported by fifty-seven (56 percent) and twenty-seven (57 percent),
respectively.
Trauma
Forty-eight (47 percent) of the patients with osteosarcoma and
twelve (26 percent) of those with Ewing sarcoma related the onset
of symptoms to trauma occurring at about the time that the symptoms
began. Adolescents commonly engage in athletic activity; 58 percent
of the male patients and 35 percent of the female patients participated in
sports, and the majority of the traumatic incidents reported by
the patients were of a similar type and magnitude as those regularly
experienced by participants in common sports.
Physical Findings at the First Medical Visit
According to the records, none of the 149 patients had a physical
examination that revealed no remarkable findings at the first visit.
Forty (39 percent) of the patients with osteosarcoma and sixteen (34
percent) of those with Ewing sarcoma already had a palpable mass
at the tumor site at the first medical visit. As many as ninety-four
(92 percent) of the patients with osteosarcoma and thirty-three (70
percent) of those with Ewing sarcoma had tenderness at the tumor
location (Table II).
Initial Diagnosis
Osteosarcoma
At the first medical visit, a bone tumor was suspected in thirty-two
(31 percent) of the patients with osteosarcoma. There was a significant
difference, with regard to suspicion of a tumor, between male patients
(21 percent) and female patients (46 percent) (p < 0.05). Tendinitis
was the most common misdiagnosis and was the initial diagnosis for thirty-two
(31 percent) of the osteosarcomas (twenty-five [41 percent] in male
patients and seven [17 percent] in female patients). The doctor
was uncertain about the diagnosis for twelve (12 percent) of the
patients. Only two patients were initially diagnosed as having a
pathological fracture (Table III).
Ewing Sarcoma
At the first medical visit, a bone tumor was suspected in nine
patients (19 percent) who had Ewing sarcoma. Tendinitis was the
most common misdiagnosis and was the initial diagnosis for ten (21
percent) of the patients. The doctor was uncertain about the diagnosis
for nine (19 percent) of the patients. Misdiagnosis of Ewing sarcoma
of the pelvis or the proximal aspect of the femur was not uncommon.
The most frequent misdiagnoses for young patients were coxitis simplex
and osteomyelitis, whereas tendinitis and sciatica were the most
frequent misdiagnoses for older patients (Table III).
Radiographic Examination
Sixty-eight (67 percent) of the patients with osteosarcoma and
twenty-eight (60 percent) of those with Ewing sarcoma had a radiograph
made at the first medical visit. Radiographic examination was more
often carried out for young or female patients or if there was a
palpable mass or a history of limping or trauma (p < 0.05).
However, the correct diagnosis was not established for all patients
who had a radiograph. The radiograph was misinterpreted by the radiologist
as normal or inconclusive for six (9 percent) of the sixty-eight
patients with osteosarcoma and for twelve (43 percent) of the twenty-eight
patients with Ewing sarcoma.
Analgesics and Physiotherapy
Prescribed at the First Visit
Nonsteroidal anti-inflammatory drugs were prescribed for twenty
patients. Fourteen of them were diagnosed with tendinitis; two,
with sciatica; and one each, with a hematoma and a muscle rupture. The
diagnosis was uncertain for the remaining two patients. All of these
patients reported pain related to strain. Thirteen patients were
referred for physiotherapy, ten were diagnosed as having tendinitis, and
three were diagnosed as having sciatica.
Delay in Diagnosis
The patient's delay (p = 0.0002), doctor's delay (p < 0.0001),
and total delay (p < 0.0001) were all significantly longer for
the patients with Ewing sarcoma than for the patients with osteosarcoma
(Table IV).
A palpable mass, the ordering of a radiograph, and a history of
trauma were all factors that reduced the time to the correct diagnosis
significantly. When the patients had a palpable mass at the first
medical visit, the doctor's delay averaged five weeks compared with
sixteen weeks for those without a mass (p < 0.0001). When a
radiograph was made at the first visit, the doctor's delay averaged
eight weeks compared with nineteen weeks when a radiograph was not
made (p = 0.0001). Patients who reported a
traumatic incident at the onset of symptoms had a mean total delay
of sixteen weeks compared with twenty-five weeks for patients who
did not report such an incident (p < 0.01).
Seventy-six (75 percent) of the patients with osteosarcoma had
a doctor's delay that was shorter than two months, and only ten
(10 percent) had a doctor's delay exceeding six months. However, nineteen
(40 percent) of the patients with Ewing sarcoma had a doctor's delay
of less than two months, and thirteen (28 percent) had a doctor's delay
exceeding six months.
There were only small differences in delay between male and female
patients. Female patients with osteosarcoma had a longer mean patient's
delay (eight weeks compared with five weeks for male patients; p < 0.05),
but the doctor's delay did not differ between the sexes.
In this investigation, we intended to establish the initial symptoms
and physical signs of osteosarcoma and Ewing sarcoma by analyzing
the records from the first visit to a physician for symptoms that
could be related to the bone neoplasm. No previous studies on this
subject have, to our knowledge, utilized this source of information;
instead, investigators have relied upon data given at admission
to the tumor clinic, when the diagnosis was known or strongly suspected10,15. We compared the patient history
that was recorded at the first visit with that recorded at admission to
the tumor center. The discrepancy between the data in those files
demonstrated how vital it is to use primary medical records in a
study on the initial symptoms of bone tumors. All but three of the records
used in the present study were typewritten, and nearly all had a
clear description of symptoms and physical signs at the first medical
visit.
The predilection for the male gender (1.5:1) and the anatomical
distribution of the osteosarcomas (distal aspect of the femur, forty-five
patients; proximal aspect of the tibia, twenty-five; and proximal
aspect of the humerus, ten) observed in the present study are characteristic
of and in accordance with previous findings in large studies of primary
bone tumors1-3. The present series
is therefore representative of these neoplasms.
As expected, most patients first sought medical attention from
the district general practitioner. Most general practitioners presumably
had little experience with bone tumors and not infrequently described
the clinical picture as unfamiliar. They were often doubtful about
the diagnosis and ordered an early check-up. Many patients attributed the
onset of symptoms to a traumatic incident and therefore went to
the emergency ward, as would be expected. Most patients who visit
an emergency room after a traumatic episode expect a radiograph to
be made, and radiographs were made for twenty-three (79 percent)
of the twenty-nine patients with osteosarcoma and ten (77 percent)
of the thirteen with Ewing sarcoma who visited an emergency room
in our study.
Symptoms and Physical Findings
Pain that is more severe at night than during the day is generally
accepted as a typical symptom of a primary malignant bone tumor.
Letson et al.8 stated: "In contrast,
pain from a musculoskeletal malignancy is often continuous and dull.
It is usually severe at rest and is characteristically worse at night."
Simon and Finn9 stated that "unremitting
pain or pain that is more severe at rest or at night than during
the day is often considered as a symptom of a malignant disease."
The present study showed that pain at night was not a dominant initial
symptom of malignant bone tumors as only twenty-one (21 percent)
of the osteosarcomas and nine (19 percent) of the Ewing sarcomas
caused pain at night. However, pain related to strain and intermittent
pain at rest were frequent; as these symptoms are also common in several
benign musculoskeletal disorders, they can easily lead to an inaccurate
diagnosis.
Consistent with previous studies6,13,
fourteen (30 percent) of the patients with Ewing sarcoma had unexplained
periods of fever. A combination of this fever with pain and an inconclusive
radiograph led the doctor to suspect osteomyelitis, which has also
been reported earlier5,14. This
initial misdiagnosis delayed correct treatment for several months.
A palpable mass, the physical finding that most strongly indicates
a bone tumor, was reported, at the first visit, in forty (39 percent)
of the patients with osteosarcoma and sixteen (34 percent) of those
with Ewing sarcoma. Vlasak and Sim13 reported
that approximately 70 percent of patients with Ewing sarcoma had
a palpable mass at the time of diagnosis, but they made those observations
at a later stage of the disease. In the present study, not all patients
with a palpable mass were suspected to have a malignant bone tumor
but they had a significantly shorter doctor's delay. Twenty-three
(72 percent) of the thirty-two patients with osteosarcoma and all
nine of the patients with Ewing sarcoma who had a preliminary diagnosis
of a bone tumor at the first visit had a palpable mass. This prevalence
emphasizes both that a palpable mass is one of the strongest indications
of a primary malignant bone tumor and that a thorough and extensive
physical examination of every patient is very important.
Limping by children is in most cases a self-limiting, benign
condition; however, some rare serious conditions must be excluded11, as limping has been reported as
a symptom of primary malignant bone tumors. Our study showed that
it was common, with twenty-eight of the patients with osteosarcoma
and nineteen of the patients with Ewing sarcoma limping in the initial phase
of the disease (Table II).
Initial Diagnosis
A history of minor trauma, pain related to strain, and regional
tenderness generated a broad spectrum of possible diagnoses (Table III). Although
tendinitis is an uncommon condition in such a young population,
it was the most frequent misdiagnosis in this study. In many cases, both
the history and the physical signs were inconsistent with this diagnosis.
These patients were ordered to refrain from physical activity for
two to three weeks. During this period, the pain subsided and both
the patient and the doctor were led to believe that the condition
was temporary and would resolve spontaneously. However, when the
patient resumed physical activity, the pain returned and often became
more severe.
Age naturally had an influence on the possible misdiagnoses:
children with hip pain were diagnosed as having coxitis, osteomyelitis,
or Legg-Calvç¬erthes disease, but young adults with the same symptoms
and physical findings were diagnosed as having tendinitis and sciatica.
Radiographs
As many as sixty-eight (67 percent) of the patients with osteosarcoma
and twenty-eight (60 percent) of those with Ewing sarcoma had a
radiograph made at the first medical visit. This high proportion
of the patients who were examined radiographically might be explained
by the fact that many patients related the onset of symptoms to
a traumatic episode; a radiograph was made to exclude the possibility
of a fracture. The initial radiographs were misinterpreted by the
radiologist as normal or inconclusive for six (9 percent) of the sixty-eight
patients with osteosarcoma and twelve (43 percent) of the twenty-eight
patients with Ewing sarcoma. Amazingly, radiographs were not made
at the first visit for ten patients who had a palpable mass. Five
of these patients had a misdiagnosis of tendinitis; one each, a
misdiagnosis of muscle rupture, sciatica, and hematoma; and two, an
uncertain diagnosis.
Delay in Diagnosis
Sneppen and Hansen10 reported
a mean total delay in the diagnosis of osteosarcoma of twenty-eight
weeks compared with fifteen weeks in the present study. This discrepancy
in delay has two possible explanations. First, Sneppen and Hansen
calculated the total delay on the basis of information given at
the time of the patient's admission to the tumor center, whereas
in the present study we used the records from the first medical
visit. The difference in population between the studies is also
important. The present study was limited to patients who were no
older than thirty years of age because osteosarcoma has a different
etiology and pattern in older patients. In contrast, Sneppen and
Hansen included patients of all ages.
Frassica et al.6 reported a
mean total delay in diagnosis of thirty-two weeks for patients with
Ewing sarcoma of the pelvis, and Damron et al.4 reported
a mean total delay in diagnosis of thirty-seven weeks for patients
with Ewing sarcoma of the proximal aspect of the femur. This data
is in accordance with that in the present study, in which the mean
total delay in the diagnosis of Ewing sarcoma was thirty-four weeks.
There might be several different reasons why the patient's and
doctor's delays in the diagnosis of Ewing sarcoma were longer than
the delays in the diagnosis of osteosarcoma. First, malignant diseases
are generally believed to have a steadily progressive course. However,
patients with Ewing sarcoma often reported relapsing fever and periods of
pain that were followed by periods with no or only few symptoms.
The intermittent clinical course misled the doctor into believing
that the patient's symptoms were temporary and that the condition
was resolving spontaneously. Furthermore, it was not uncommon for
the initial radiograph to be inconclusive or normal. It often takes
a long time before a doctor will reconsider a diagnosis when the
radiograph is normal. Thus, the doctor's delay exceeded five months
for nine of twelve patients with Ewing sarcoma who had a normal
or inconclusive initial radiograph. Finally, only eleven (23 percent)
of the Ewing sarcomas were located around the knee compared with
seventy-five (74 percent) of the osteosarcomas. Tumors located in the
spinal and pelvic regions are more difficult to diagnose because
they must grow larger before they are palpable and are visible on
plain radiographs15.
Patient's delay differed according to gender; female patients
with osteosarcoma waited for a longer period of time before consulting
a doctor. However, the doctor already suspected a bone tumor at
the first visit in 46 percent of the female patients compared with
21 percent of the male patients. The fact that male patients more
often participate in sports gave both the doctor and the patient
a conceivable explanation for the symptoms. The fact that female
patients waited for a longer period before consulting a doctor and
the fact that they were less muscular made it easier for the doctor
to notice a palpable mass. These factors may explain the observed
difference between the sexes with regard to the delay in diagnosis.
The delay between the time when the patient first noted symptoms
and the first medical visit (the patient's delay) may be impossible
to change, as in the present study there were no evident obstacles that
prevented the patient from seeing a doctor. The only way to reduce
the total delay may be to shorten the period from the first medical
visit to the establishment of the accurate diagnosis (the doctor's
delay). In this study, the doctor's delay in the diagnosis of osteosarcoma
was generally short; it did not exceed two months for seventy-six
(75 percent) of the osteosarcomas. The patients with Ewing sarcoma
generally had a long doctor's delay; thirteen patients (28 percent)
had a delay that was longer than six months. All except one of the thirteen
patients consulted a doctor more than six times before the tumor
was diagnosed, and one patient visited the hospital sixteen times
and the district general practitioner seven times about symptoms
related to the bone tumor. Three patients with Ewing sarcoma of
the pelvis had intermittent low-back pain. After several weeks of conservative
treatment with analgesics and physiotherapy, a radiograph of the
lumbar spine was ordered. However, the correct diagnosis was further
delayed because the radiograph did not include the pelvis.
Our data showed that a long doctor's delay was due to three main
factors. First, tumors of the spinal and pelvic regions were difficult
to visualize on the plain radiographs. Second, a radiograph showing
normal findings was believed to exclude a diagnosis of a malignant
tumor and the interpretation was accepted for too long before repeat
radiographs were made. Finally, treatment for other diagnoses proceeded
for too long despite the divergence of the clinical picture from
what could be expected from the original (incorrect) diagnosis.
Three factors were associated with a short doctor's delay: the
presence of a palpable mass, which emphasizes the importance of
a thorough and extensive physical examination; the ordering of a radiograph,
although in most cases the radiographic examination was conducted
to exclude the possibility of a fracture without any suspicion of
a bone neoplasm; and the age of the patient, with children having
a shorter doctor's delay because the doctor's uncertainty concerning
the diagnosis resulted in an early check-up and more frequent radiographs.
Another factor that should raise the doctor's suspicion of a
malignant tumor is the clinical course after a minor traumatic episode.
Forty-eight (47 percent) of the patients with osteosarcoma and twelve
(26 percent) of those with Ewing sarcoma related the onset of symptoms
to a traumatic incident occurring at a similar time, findings that
are consistent with those of previous reports10,12.
Primary malignant bone tumors are rare, whereas children and young
adults are frequently seen by a doctor after minor trauma. However,
the clinical course of the patients in our study often diverged from
what is expected after minor trauma. The patients had temporary
pain connected to the trauma, but the symptoms resolved in a day
or two. After a short period (days or weeks) of little or no pain,
the pain returned and became more intense and severe with time.
In conclusion, an initial symptom of the primary bone tumors
was intermittent pain that was often related to strain but was not
frequently felt at night. A history of trauma was common, but the
clinical course often diverged from what should be expected from
such an etiology. The clinical course was not always steadily progressive
but was often intermittent, misleading the doctor to believe that
the condition was temporary. The most important clinical feature
was a palpable mass, which was noted at the first visit in more
than one-third of the patients. This finding emphasizes that a thorough physical
examination is absolutely necessary.
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