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Pain Medicine 2010; 11: 101–105
© American Academy of Pain Medicine
Case Report
Malignancy as a Possible Complication
of Complex Regional Pain Syndrome:
A Case Report
pme_753
101..105
Rick Kennedy, FRCA,* Joan Hester, FRCA, MSc,
FFPMRCA,* and Dominic W. N. Simon, FRCS (Tr &
Orth), BSc†
*Department of Pain Relief, King’s College Hospital,
London
†
Basingstoke and North Hampshire Hospital,
Basingstoke, Hampshire, UK
Reprint requests to: Rick Kennedy, FRCA, Anaesthetic
Department, St Thomas’ Hospital, Lambeth Palace
Road, London SE1 7EH, UK. Tel: 44-7986360997;
Fax: 00-61893463481; E-mail:
[email protected].
Sources of support: None was received.
Financial support: No funding was received for this
case report.
Conflict of interest: Nil.
Abstract
A synovial sarcoma presented in the knee of a
young woman 20 years after the onset of pain which
was attributed to complex regional pain syndrome
(CRPS). Was this a chance occurrence, or could
there be any link between the two conditions? Did
the pain itself and the persistent inflammatory and
immunological response to pain contribute to the
development of malignancy, or could the malignancy have been present subclinically for many
years and have contributed to the ongoing pain syndrome? This case report looks into the diagnosis of
synovial sarcoma and CRPS and the relationship
between the neurogenic inflammation seen in CRPS
and that seen in malignancies. The diagnosis of
CRPS is a diagnosis of exclusion. Constant vigilance of patients with this unpleasant condition is
necessary.
Key Words. CRPS;
Malignancy
Neurogenic
Inflammation;
Introduction
Asynovial sarcoma presented in the knee of a young
woman 20 years after the onset of pain which was attrib-
uted to complex regional pain syndrome (CRPS). Was this
a chance occurrence, or could there be any link between
the two conditions?
Case Description
A 28-year-old female was referred to the pain clinic at
Kings College Hospital in 2005 with a long history of
refractory left knee pain. The pain was sharp and well
localized to the supra-patellar region of the left knee. The
pain had been intermittent since the age of 7 with no
traumatic cause. A worsening of the severity of the pain
and a reduction in range of movement prompted her first
presentation to her General Practitioner in 1999 at the age
of 20.
Initially, she was referred to the Orthopedic Surgeons who
found no radiographic abnormality in the knee and treated
her with two manipulations under anesthesia over a 2-year
period. She also received two epidural infusions of local
anesthetic so that she could use a continuous passive
movement machine. None of these treatments was
effective.
In 2002, a three-phase isotope bone scan showed localized increased uptake in soft tissue at the superior aspect
of the left patella. No increased bone activity was seen
(Figure 1). A magnetic resonance scan in 2003 showed a
small supra-patellar effusion with no other abnormalities.
In 2003, she underwent arthroscopic arthrolysis followed
by physiotherapy. Over the next 2 years she received two
courses of three intravenous guanethidine leg blocks with
some temporary relief of her pain.
She was referred to pain services at her local hospital in
2005 for diagnosis and treatment of her pain. A working
diagnosis of CRPS was made. No diagnostic criteria are
available from the hospital notes. In the following 6
months, various drugs were tried. Gabapentin, reaching a
dose of 300 mg tds and tramadol 100 mg tds were moderately successful. Citalopram 30 mg daily, MST and
diclofenac had no analgesic effect.
The patient was referred to the pain relief unit at King’s
College Hospital in December 2005 for further assessment and treatment of her pain. Her pain was localized to
the anterior aspect of the left knee, which was also inappropriately cold, and the skin discolored. Sensory examination demonstrated marked allodynia over the anterior
aspect of the left knee. Flexion was limited to 45 degrees
and she was not weight bearing on the leg due to pain.
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Figure 2 Appearance of left knee, August 2007.
Figure 1 Triphasic isotope bone scan 2002, soft
tissue phase 2 showing increased tracer uptake in
the head of the left fibula.
The clinical findings were consistent with a diagnosis of
CRPS. After initial assessment, the patient’s medication
was changed to pregabalin 75 mg bd, tramadol SR
200 mg BD, and topical EMLA (a eutectic mixture of
lidocaine 2.5% and prilocaine 2.5%) cream. This combination proved to be moderately effective. Pregabalin was
titrated to 150 mg bd over the next 6 months.
A course of six guanethidine blocks in June 2006 allowed
the patient to stop her medications for 3 months. At
follow-up she was restarted on pregabalin 75 mg bd,
tramadol SR 200 mg bd, and lidocaine 5% medicated
plasters. She was referred and accepted for spinal cord
stimulation at St Thomas’ Hospital.
puted tomography (CT) chest, abdomen, and pelvis
showed mediastinal, pulmonary, and hepatic metastases.
The patient underwent a mid-thigh amputation of the left
leg the same week. Bilateral thoracotomies were undertaken for removal of metastases. She received a course of
chemotherapy. There is no current evidence of tumor
recurrence.
The patient continues to be followed up by the pain relief
unit at King’s for phantom limb pain and neuropathic pain
around her thoracotomy scars.
By January 2007, it was noted the patient had developed
a fixed flexion deformity. The knee was intermittently
swollen with a reddish discoloration and demonstrated
marked allodynia.
At follow-up in August 2007, the knee was much more
swollen and completely fixed. The skin was erythematous,
shiny with dilated veins. The patient was noted to have lost
15 kg in weight with a body mass index of 13. However,
the appearance of her knee was alarming (Figure 2) and
was felt to be out of keeping with CRPS. Urgent radiological examination (Figure 3) and an orthopedic surgical
referral were made.
Repeat magnetic resonance imaging (MRI) (Figures 4 and
5) showed a large invasive soft tissue mass (30 ¥ 15 cm)
highly suggestive of a synovial sarcoma. The diagnosis
was confirmed by needle biopsy. Blood tests revealed
ESR 91, CRP 141, Alkaline phosphatase 188. A com102
Figure 3 Lateral X-ray of left knee, August 2007,
showing a massive soft tissue swelling with cortical
destruction of the anterior distal femur and patella,
consistent with a malignant lesion.
Malignancy in Complex Regional Pain Syndrome
symptom is of a swelling adjacent to a joint (only 10% are
intra-articular) with or without pain. The duration of symptoms ranges from 1 month to 25 years (mean 32 months).
Detection of a tumor smaller than 5 cm is associated with
a better prognosis.
Chandu de Silva et al. [1] noted that 30% of patients with
synovial sarcoma had well-localized pain at the site of the
tumor prior to development of any swelling. These
patients were 12 times more likely to have pain than
patients with other types of sarcoma. Localized pain was
the presenting complaint in 25% of patients.
The mechanism of this pain is not completely understood.
It occurs when the tumor is small and therefore pressure
effects are negligible. Hemorrhage and necrosis are also
unlikely to occur at this early stage of tumor growth.
Figure 4 Magnetic resonance imaging scan of left
knee, sagital T1 view, August 2007, showing a heterogeneous expansive soft tissue mass invading the
joint capsule.
Discussion
Synovial Sarcoma
Synovial sarcoma is a clinically and morphologically distinct neoplasm of uncertain histogenesis which mostly
affects the extremities of adolescents and young adults.
There are approximately 150 cases per year in the UK. It
is an aggressive neoplasm with 5-year survival rates
ranging from 38% to 76% [1]. The usual presenting
In animal studies, conditions resulting in exaggerated pain
states demonstrate elevated pro-inflammatory cytokines.
In addition, pro-inflammatory cytokines have been shown
to induce or increase neuropathic and inflammatory pain.
Alexander et al. [2] demonstrated significant increases in
IL-1beta and IL-6, but not TNF-alpha in the cerebral spinal
fluid of individuals afflicted with CRPS as compared with
controls.
The existence of chronic inflammatory conditions (chronic
bronchitis, esophagitis) and their links to some forms of
neoplasm strongly suggests that the inflammatory
process itself provides the prerequisite environment for the
development of malignancy. There is upregulation of
inflammatory mediators such as cyclo-oxygenase-2
leading to production of inflammatory cytokines (IL-1 a
and b, IL-2, IL-4, IL-6, IL-10 TNF-a, Interferon-g) and
prostaglandins. These may in turn suppress cell-mediated
immune responses and promote angiogenesis (IL-6, vascular endothelial growth factor). These factors may affect
cell growth resulting in cell proliferation and inhibition of
apoptosis [3,4].
When present long term, these conditions allow mutated
cells to avoid immune surveillance. A closer study of these
inflammatory pathways has shown a close interaction
between anti-apoptotic pathways, tumor suppressor
genes, as well as a number of growth factors (insulin-like
growth factor). Studying these pathways has revealed key
molecules that may provide therapeutic and antiinflammatory targets [5].
Complex Regional Pain Syndrome
Figure 5 Magnetic resonance imaging scan,
coronal T1 view, August 2007, showing a heterogeneous expansive soft tissue mass involving the distal
femur and proximal tibia.
The term CRPS describes a variety of painful conditions
with a peripheral predominance that follow injury. The
symptoms exceed in both magnitude and duration the
expected clinical course of the initial injury and often
result in significant disability. CRPS type I (reflex sympathetic dystrophy), a minor injury or fracture of a limb,
precedes the onset of symptoms. CRPS type II (causalgia) develops after damage to a peripheral nerve
(Table 1).
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Table 1 Modified IASP clinical diagnostic criteria for CRPS: Budapest Criteria, 2008 [6]
1. Continuing pain, which is disproportionate to any inciting event.
2. ⱖ1 symptom of 3 categories and ⱖ1 sign of 2 categories (Sensitivity 0.85, Specificity 0.60).
3. There is no other diagnosis that better explains the symptoms and signs.
Category 1
Category 2
Category 3
Category 4
Symptoms:
Spontaneous pain
Mechanical hyperalgesia
Thermal hyperalgesia
Deep somatic hyperalgesia
Symptoms:
Temperature asymmetry
Skin color changes
Symptoms:
Swelling
Hyperhydrosis
Hypohydrosis
Symptoms:
Motor weakness
Tremor/Dystonia
Coordination deficit
Nail/hair changes
Skin atrophy
Joint stiffness
Soft tissue changes
Signs:
Pinprick hyperalgesia
Allodynia
Signs:
Vasodilatation
Vasoconstriction
Temperature asymmetry
Skin color changes
Signs:
Swelling
Hyperhydrosis
Hypohydrosis
Signs:
Motor weakness
Tremor/Dystonia
Coordination deficit
Nail/hair changes
Skin atrophy
Joint stiffness
Soft tissue changes
Isotope bone scans are generally considered sensitive but
not specific. A triphasic bone scan may add higher degree
of specificity. The findings are suggestive of CRPS if there
is increased uptake of isotope in all three phases. The third
phase is the most important phase. The pathogenesis of
CRPS is complex. Over the last few years, knowledge of
the different mechanisms involved has grown. A complete
explanation of our understanding of its pathogenesis is
beyond the scope of this case report.
Tissue injury leads to activation of C and Ad fibres of
sensory neurons. This causes release of the inflammatory
neuropeptides substance P and calcitonin-gene-related
peptide. These neuropeptides may induce local vasodilatation and increased capillary leak, a process known as
neurogenic inflammation.
Additionally, there are raised levels of IL-6 and TNF-a,
which may remain elevated for 2–3 years. Tryptase levels
are raised in the affected limb demonstrating increased
mast cell activity. Skin biopsies show a marked increase in
the number of Langerhans cells. This has led researchers
to believe there is an immune-cell mediated component to
the inflammatory process.
Nociceptors in the dorsal horn of the spinal cord may
become sensitized by peripheral injury or inflammation
(central sensitization). This is associated with the release
neuropeptides, neurotransmitters, prostaglandin E2, and
increased expression of N-methyl D-aspartate receptors.
Thus, pain becomes chronic and non-noxious stimuli
become painful [6].
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Points of Interest
Pain may be a presenting feature of synovial sarcoma,
before swelling occurs. Calcification on plain X-rays is
often misdiagnosed as calcific tendonitis or loose bodies.
CT and MRI are useful in aiding diagnosis of synovial
sarcoma, and a triphasic isotope bone scan is useful in
aiding the diagnosis of CRPS, but none of these investigations is diagnostic.
CRPS is associated with an upregulation of proinflammatory cytokines.
Chronically increased cytokine activity may lead to cell
proliferation and tumor occurrence.
Enzyme systems and molecules in these abnormal pathways may present therapeutic targets for both cancer and
pain.
It is conjecture whether the presence of chronic inflammation and pain led to the development of malignancy, or if
the presence of subclinical malignancy could have altered
pain biology.
Conclusion
It is conjecture, in this case, if the presence of CRPS was
related to the ensuing synovial sarcoma, or if subclinical
malignancy could have contributed to the pain biology.
The diagnosisof CRPS is a diagnosis of exclusion. Chronic
Malignancy in Complex Regional Pain Syndrome
pain specialists must remain vigilant when managing
patients with this unpleasant condition and perform
repeated clinical assessment and imaging.
3 Dalgleish AG, O’Byrne KJ. Chronic immune activation
and inflammation as the cause of malignancy.
Br J Cancer 2001;85(4):473–83.
References
1 Chandu De Silva MV, Barrett A, Reid R. Premonitory
pain preceding swelling: A distinctive clinical presentation of synovial sarcoma which may prompt clinical
detection. Sarcoma 2003;7:131–5.
4 Coussens LM, Werb Z. Inflammation and cancer.
Nature 2002;420:860–7.
2 Alexander GM, van Rijn MA, van Hilten JJ, Perreault MJ,
Schwartzman RJ. Changes in cerebrospinal fluid levels
of pro-inflammatory cytokines in CRPS. Pain
2005;116:213–19.
5 Dalgleish AG, O’Byrne KJ. Inflammation and cancer:
The role of the immune response and angiogenesis.
Cancer Treat Res 2006;130:1–38.
6 Baron R. Complex Regional Pain Syndromes: Translation from Science to Clinical Practice. Seattle, WA: IASP
Press; 2008.
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