INTRODUCTION
Pancreatic endocrine tumors (PETs) are relatively rare, having a clinical detection
rate of 1:100,000 which comprise 1%–2% of all pancreatic tumors [1], [2]. PETs are considered functional or nonfunctional and may be
sporadic or inherited but little is known about their molecular pathogenesis [1], [2], [3]. There is currently no formal classification system
for PETs. Their clinical presentation varies depending on whether the tumor is
functional [1]. It is believed that 20%–25% of gastrinoma
is due an inherited disorder termed multiple endocrine neoplasia type 1 (MEN1) [1], [4]. Gastrinomas are gastrin-secreting functional PETs
and cause increased acid secretion resulting in peptic ulcer formation, known as the
Zollinger-Ellison syndrome (ZES [1], [5]. There are two
major treatment goals for ZES: (1) to control the acid hypersecretion so that the
ulcer can heal and (2) to remove the gastrinoma itself. With administration of
proton pump inhibitors, acid secretion can be controlled in almost all patients
[6], [7].
Most PETs are relatively indolent but ultimately malignant [1], [8], and surgical removal of a gastrinoma is the only modality that offers
the possibility of cure. Debulking surgery is often considered useful in
unresectable patients [1], and since many patients with
MEN-1 or sporadic gastrinomas have multifocal or microscopic lesions, debulking may
be the only surgical option and is considered by some to be controversial [6], [9].
Bone metastases occur in 7% of patients with gastrinomas and only when there are
concurrent liver metastases, do bone metastases occur in 31% [10], [11]. The axial skeleton is the most frequent site of bone
metastases in patients with gastrinomas, although more distal metastases can occur
early in up to 15%–30% of patients [10]. We report
successful surgical therapy for spinal cord compression performed three times within
4 years in a patient with spinal metastases due to metastatic pancreatic
gastrinoma.
CASE REPORT
In October 2007, a 42-year-old man presented for evaluation of back pain of 4 months’
duration ([Fig 1]). His history included symptomatic
treatment in 2001 for diarrhea and abdominal pain. Three years later in 2004 the
patient had imaging studies that showed multiple liver lesions and a mass in the
pancreas. The gastrin level was elevated at 23,000 pg/mL. The patient was diagnosed
with ZES and metastatic gastrinoma. He received three treatments of
chemoembolization, octreotide, and high doses of nexium at that facility. One year
later, he presented to another facility with back pain, and imaging revealed a tumor
at T11. He underwent resection of the tumor and fusion of T9–L1, followed by
radiation. A few months later in October 2005 the patient complained of left hip
pain and was found to have another metastasis. He underwent stereotactic radiation
therapy to the left hip, L4, and coccyx at that facility in January 2006, and was
administered 1000 mg streptozocin and 1500 mg fluorouracil (5-FU) for approximately
6 months. The maintenance therapy of capecitabine [Xeloda®] was not well tolerated
and was discontinued.
At the time of his visit in October 2007, computed tomography demonstrated a large
metastasis to the left pedicle, vertebral body, and left lamina of T3 causing
lateral compression of the spinal cord ([Fig 2]). The
patient described intermittent numbness over the left side of his chest that
disappeared when he was able to move his arms and mild tenderness to palpation over
his upper thoracic spine. He was otherwise neurologically intact with normal motor,
sensory, and deep tendon reflexes on detailed neurological examination. He underwent
tumor debulking with removal of the rib head on the left with spinal cord
decompression, instrumented fixation, and posterolateral fusion with allograft from
T1–T5. The patient’s symptoms improved. Pathological examination revealed metastatic
gastrinoma. Immunohistochemical stains showed the tumor cells were positive for
synaptophysin, chromogranin, pan-cytokeratin and gastrin, supporting the diagnosis
([Fig 3]). He was discharged home 3 days
postoperatively; his pain was controlled with oral medications, and was instructed
to wear the thoracolumbosacral orthosis when out of bed. He then underwent radiation
from T2–T4, which was completed end of November 2007. The patient received 4 mg
zoledronic acid [Zometa®] intravenously for bone protection every 4 weeks. In
January 2008 he underwent SIR-spheres to the hepatic artery via interventional
radiology.
Eighteen months later, in May 2009, he again presented to the hospital with left arm
numbness and tingling of approximately 3 weeks’ duration, as well as onset of
numbness and tingling below T4 of 2 days’ duration. His symptoms did not improve
with dexamethasone therapy [Decadron®]. He was currently receiving radiation therapy
to a mass surrounding C7. On examination he was neurologically intact with the
exception of 4/5 strength to left finger extension, and hyperreflexia in the
bilateral upper extremities and lower extremities. Magnetic resonance imaging of the
C-spine showed a diffuse cervical metastatic lesion centered at the C7 vertebral
body with central canal and left neuroforaminal stenosis ([Fig 4]). Computed tomography of the T-spine was somewhat limited
secondary to previous hardware placement; however, it revealed a metastatic lesion
at the T3 level as well as metastasis to several ribs.
Fig 1
Patient sampling and selection.
Fig 2
Computed tomographic scan shows tumor destruction of body, pedicle, and
lamina of T3 with spinal cord compression.
Fig 3a–e
A pathological specimen shows positive staining for (a)
hematoxylin-eosin x200; (b) synaptophysin x200; (c) chromogranin x200; (d)
pan-cytokeratin x400; and (e) gastrin x280.
Fig 4
Magnetic resonance imaging reveals circumferential compression of the
spinal cord at C7.
The patient underwent a C7 corpectomy with placement of a cage from C6–T1 and
posterior fusion of C2–C7. The patient was able to ambulate with walker before
discharge.
Pathological examination revealed metastatic neuroendocrine carcinoma consistent with
his previous diagnosis. Immunohistochemical stains were positive for chromogranin,
synaptophysin, CD56, pan-cytokeratin, and focally weakly positive for gastrin.
One week later, the patient reported waking up with weakness in bilateral LEs and
an
inability to stand or walk. Motor examination demonstrated normal upper extremity
strength bilaterally. Strength 3/5 was demonstrated in hip and knee flexion and knee
extension bilaterally, and 4/5 in plantar flexion and dorsiflexion and extensor
hallucis longus bilaterally. Sensation was intact to light touch, pinprick, and
proprioception throughout; although the patient reported altered sensation below
level of T4 and in left fingers. Reflexes were 3+ throughout.
Computed tomographic myelogram showed a complete myelographic block at T3 with a
large destructive mass involving the T3 vertebral body with lateral extension into
the posterior pleural space and posterior extension resulting in near complete
compression of the spinal cord. Due to the metastatic lesion and spinal cord
compression at T3, the patient underwent T1–T3 laminectomy, revision of hardware,
and T3 bilateral transpedicular and circumferential spinal cord decompression.
Pathological examination again revealed metastatic neuroendocrine carcinoma,
infiltrating the bone with fibrous reaction and associated necrosis. Comparison of
the T3 paraspinous mass was made to the recently resected cervical spine mass and
both tumors showed identical histological features.
It is now 8 years after initial diagnosis and it has been 12 months since the most
recent surgery. He is able to ambulate with assistance, though is experiencing
functional decline due to progression of disease.
DISCUSSION
In general, up to 40% of patients with cancer will develop skeletal metastases, of
which the spine is the most frequent location [12], [13].
The most commonly affected location is the thoracic spine (up to 70% of cases),
followed by the lumbar and cervical spine [12].
Of all patients who develop spinal metastases, only 5%–10% develop an epidural spinal
cord compression, of which only 10%–20% will become symptomatic [12], [14]. The treatment of spinal metastases remains primarily
palliative [12]. The goals of surgery are to prevent or
reverse neurological deterioration and to relieve pain [12], [15]. Indications for surgery include intractable pain, radiotherapy
failure, deformity, spinal instability, and neural compression secondary to
retropulsed bone or tumor mass [12], [16], [17].
Determination of surgical objective, timing, and technique must consider mortality
and morbidity risks, the location and extent of metastatic disease, the rate of
neurological decline, the patient’s ability to tolerate the procedure and their
overall estimated life expectancy [10], [12].
Pancreatic endocrine tumors (PETs) can vary in regards to their malignant potential,
tumor location [1], and rate of progression. Excluding
insulinomas, metastases develop in 50%–90% of PET cases and most commonly involve
the lymph nodes and liver but can also spread to distant sites, such as the spine
and pelvis [1], [2], [18], [19]. In gastrinomas specifically,
75% of cases arise sporadically while the other 25% of tumors are associated with
MEN-1[6]. Gastrinomas are typically found in the
pancreas or duodenum, although they are rarely found in extrapancreatic sites, like
the heart and ovary [6]. Up to 30% of pancreatic
gastrinomas and 10% of duodenal gastrinomas have already metastasized at the time
of
initial diagnosis [6, 20]. Even in malignant cases, gastrinomas typically follow a
relatively indolent disease course [1].
In the past the main cause of morbidity and mortality in ZES was related to
complications of fulminant peptic ulcer disease; total gastrectomy was the only
treatment effective at preventing acid hypersecretion [21]. With the recent advancements in acid suppression therapy, like H2
antagonists and proton pump inhibitors, this is no longer the case [22]. Metastatic tumor spread is now the most common cause
of morbidity and mortality in patients with gastrinoma [23]. Currently, complete surgical tumor resection is the only potential
means of curing patients with PETs [1]. Even when
complete resection is not possible, debulking surgery can help alleviate symptoms
in
many patients [1]. While surgery is promising, it is not
likely to be successful in patients with diffuse metastatic disease, or in those who
are medically unstable or unable to tolerate the procedure [1]. In cases of gastrinoma due to ZES, the only surgical candidates are
those patients with the sporadic form [1], [4], [24], [25].
Like other PETs, the liver is the major metastatic site for gastrinomas [6], [11], [20]. The second most common location is bone, of
which the spine and sacrum are the most likely sites, especially later in the
disease course. Bone metastases occur in 7% of all patients with gastrinoma, and
occur in 31% of those same patients with existing liver metastases [10], [11], [23], [26]. Thus, it is important that patients with
PET with metastases to the liver are carefully evaluated for bone metastases since
detection of these lesions will change the patients’ overall management and affect
their prognosis [10]. Somatostatin receptor scintigraphy
and magnetic resonance imaging are the best tests to detect these lesions, although
the former is preferred because of its ability to image the entire body and detect
the extra-axial lesions that can potentially arise [1], [6], [27].
Identifying bone metastases in patients with ZES is critical to ensure they receive
the appropriate treatment plan. One study [10] showed
that the detection of bone metastases in patients with gastrinoma lead to an
alteration in the chemotherapy regimen or initiation of chemotherapy in 50% of
patients, or in 62% of patients, an initiation of radiation therapy or other
therapies in an attempt to address their bone pain. Changes in other antitumor
treatments may also occur in patients with both metastases and slow-growing tumors;
for example, the use of interferon or somatostatin analogs is commonly delayed until
aggressive tumor growth is suspected [10]. In addition,
once patients with ZES are identified as having bone metastases, they are no longer
a candidate for other common therapeutic options, such as curative tumor resection,
cytoreductive surgery, liver transplantation, or chemoembolization [10]. However, few effective therapies currently exist for
patients with ZES with bony metastases or inoperable tumors, but current trials
assessing novel treatments, like peptide receptor radiation therapy with a
radiolabeled somatostatin analogue are promising [6], [28].
CONCLUSION
Surgical management remains the strongest option in patients with spine metastases
and neurological compromise. While spinal decompressive surgery in patients with
metastatic neuroendocrine tumors is not curative, it can be effective in relieving
radicular pain, weakness and numbness; thus greatly improving quality of life.
COMMENTARY
Author Jean-Paul Wolinsky
Institution Department of Neurosurgery, The Johns Hopkins Hospital, Baltimore,
MD, USA
Crabtree et al present the case of a 43-year-old man with metastatic gastrinoma
and the surgical treatment that he underwent for spinal disease. The authors
provide a review of the natural history and treatment options for gastrinoma.
This case report illustrates the indolent nature of the disease and the need to
be vigilant in treating this patient population for epidural involvement and
spinal cord compression. Unlike patients with metastatic tumors, the life
expectancy of those with metastatic gastrinoma can be long; therefore treatment
has to be individualized.
The patient underwent four different spinal operations on different sites of
spinal cord compression and neurological dysfunction. In other disease states,
this might be considered ultra-aggressive but as the authors describe this
strategy has allowed their patient to be alive and functional for 8 years since
his diagnosis and 1 year since his last surgical decompression. As is emphasized
in this article, and also described in other papers, surgical treatment for
metastatic spinal cord compression can result in a beneficial outcome in quality
of life and preservation of neurological function [1], [2].
