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| Journal of the New Zealand Medical Association,
21-November-2003, Vol 116 No 1186
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Small-cell carcinoma of the ampulla of Vater and a
paraneoplastic syndrome
Ali Ghahreman, Michael Booth, Richard Cutfield and Cheryl
Wright
Small-cell (oat-cell) carcinoma of the ampulla of Vater is
rare. To our knowledge, no paraneoplastic syndromes have been associated with
small-cell carcinoma at this anatomical location. In this report the clinical,
pathological and biochemical findings in a patient with small-cell carcinoma of
ampulla, associated with syndrome of inappropriate antidiuretic hormone (SIADH),
are presented.
Case reportA 68-year-old woman presented with a
three-week history of jaundice, pruritis, dyspepsia and lethargy. She had a
background of cholecystectomy, appendectomy and tubal ligation. She was a
nonsmoker and did not consume alcohol. She was on no regular medications.
Clinical examination revealed jaundice. Abdominal examination was unremarkable.
The liver function tests revealed an obstructive pattern (Table 1). Coagulation
studies were normal. Ultrasonography revealed intra- and extra-hepatic bile duct
dilatation but no obvious cause. Chest X-ray (CXR) was normal. Endoscopic
retrograde cholangiopancreatography showed an ampulla abnormal in appearance and
irregular stricturing of the distal bile duct and pancreatic duct with proximal
dilatation. Ampullary biopsies were taken and an Amsterdam biliary stent placed.
Histology of the biopsies revealed mixed small-cell and non-small-cell
carcinoma. Computed tomography (CT) of chest, abdomen and pelvis was performed
and revealed no evidence of pancreatic mass, lymphadenopathy or metastatic
disease. On the day prior to surgery, the patient was found to be hyponatraemic
with a serum sodium concentration of 118 mmol/l and serum osmolality of 251
mosmol/kg. There were no identifiable respiratory, cardiac, renal or
pharmaceutical causes for her hyponatraemia.
Table 1. Hepatic function tests prior to
stenting
A pylorus-preserving pancreatico-duodenectomy was performed.
A firm, nodular tumour measuring 2 cm in size was found, which involved the
ampulla and part of the pancreatic head. There was no lymphadenopathy and no
evidence of hepatic metastases.
Intra-operative fluids consisted of 4.5 litres of
crystalloids (Plasmolyte 148 4 l, and normal saline (0.9% sodium chloride
solution) 500 ml), 1 litre of colloid (Gelofusin, with sodium content of 77
mmol/500 ml) and 5 units of packed red cells.
Post-operatively, Plasmolyte 148 was supplemented with
colloids (Gelofusin) and packed red cells (3 units). The post-operative course
was uneventful. Clear oral fluids were commenced on the fifth post-operative
day. The nasogastric tube was removed on the sixth post-operative day. Free oral
fluids were commenced on the seventh post-operative day. A light diet was
started on Day 8. The patient’s hyponatraemia showed significant
improvement following resection of the primary tumour. The patient was
discharged on Day 10. The peri-operative electrolyte results are summarised in
Table 2.
Table 2: Peri-operative changes in serum and urinary
electrolytes
The tumour arose in the ampulla, with invasion into the
pancreatic head. Sheets of malignant cells with small to intermediate nuclei
showed typical features of small-cell (oat-cell) carcinoma, including nuclear
moulding, finely granulated chromatin and absence of nucleoli. There were
frequent mitoses, and numerous small areas of necrosis. Cytoplasm was scant.
Scattered small foci of cells showing squamous differentiation were also
present. This minor component of squamous cells had much larger and pleomorphic
nuclei, and showed cytoplasmic keratinisation. Immunohistochemical stains
confirmed the neuroendocrine nature of the small malignant cells, which were
positive for chromogranin and NSE (neuron-specific enolase). Both the small-cell
and squamous-cell components labelled with keratin markers. There was extensive
lymphatic invasion, and metastatic tumour in three of twelve lymph nodes. The
metastases contained both the small-cell and squamous-cell components. The
resection margins were clear of tumour.
The patient was readmitted to the hospital two weeks
following discharge with progressive lethargy, weakness, anorexia, confusion and
urinary frequency. On examination, she appeared dehydrated. Blood pressure was
normal and there was no significant orthostatic drop. There were occasional
fine, bibasal crackles on auscultation of the lungs. The abdomen was soft and
not tender.
The initial investigations consisted of a normal full blood
count but profound hyponatraemia (serum sodium 114 mmol/l), potassium 2.9
mmol/l, creatinine 0.04 mmol/l, and urea 1.4 mmol/l. Serum albumin and amylase
were normal. Fasting glucose was normal. The results of serial serum and urinary
biochemistry have been summarised in Table 3. CXR showed mild linear atelectasis
in the left base. Elsewhere the lungs and pleural spaces were clear. The
cardiomediastinal contours were normal. Abdominal X-ray was
unremarkable.
Table 3. Results of serum and urinary biochemistry and
fluid balance after readmission to hospital
Comments: Day
16: Hyponatraemia acutely treated with normal saline 1.8%; Day 20:
Fludrocotisone commenced and continued for three days; Day 23: Demeclocycline
commenced
*measurement in mmol/kg; †measurement in kg She had normal serum electrophoresis. Serum cortisol (09:00
hours sample) was within the reference range (1041 nmol/l). She had a normal
short synacthen (Tetracosactrin) test with basal cortisol of 565 nmol/l and peak
level of 947 nmol/l. Thyroid function tests were normal. An assay for tissue
autoantibodies was negative and complement studies were normal.
In addition, 24-hour urinary biochemistry revealed a volume
of 3.77 litres on the twelfth day following admission with sodium 460 mmol/day,
potassium 113 mmol/day, urea 95 mmol/day, creatinine 4.1 mmol/day, and
osmolality 332 mosmol/kg.
CT of the head was normal. Chest CT did not reveal any
evidence of pulmonary or mediastinal lesions. Ultrasound of the abdomen showed
multiple hepatic metastases in addition to intra-abdominal lymphadenopathy in
the para-aortic region and porta hepatis.
Initially, salt-losing nephropathy was thought to be the
prominent mechanism. The patient was rehydrated aggressively (with normal saline
with added potassium, initially via a jejunostomy tube and later parenterally).
Her response to this treatment was only partial and transient. Treatment with
9-alpha-fludrocortisone did not result in any improvement in this
patient’s biochemical abnormalities.
In view of her clinical and biochemical picture, SIADH was
then thought to be the primary underlying factor for this patient’s
hyponatremia. Response to fluid restriction therapy was slow and inconsistent.
Demeclocycline 900 mg daily in three divided doses was commenced with a prompt
improvement in the patient’s hyponatraemia.
She was discharged to the palliative care services and died
soon afterwards.
Arginine vasopressin level was subsequently found to be 14.5
pmol (reference range <5 pmol/l).
DiscussionIn the absence of iatrogenic causes
for hyponatraemia, and following exclusion of other causes of hyponatraemia
including other endocrinopathies and salt-losing nephropathy, SIADH is
considered to be the cause of this patient’s hyponatraemia. The serum and
urinary electrolytes and the arginine vasopressin level further support a
diagnosis of SIADH. The changes in the severity of the hyponatraemia parallel
the changes in the overall tumour volume. After the initial resection of the
primary tumour there was significant improvement in the severity of
hyponatraemia. At this time there was no macroscopic evidence of tumour spread.
However, there was significant worsening in the severity of hyponatraemia at the
time of presentation with metastatic disease. The correlation between overall
tumour mass and the severity of SIADH provides further evidence for the tumour
as the source of the aberrant hormone production.
To our knowledge, only 11 cases of small-cell carcinoma of
the ampulla have been reported.1–8
Patients affected by ampullary small-cell carcinoma have been reported to be
between 53 and 86 years of age, with the majority being males. Prognosis is
generally poor.
Macroscopically, ampullary small-cell carcinomas may be
polypoid or ulcerated. In three cases these carcinomas have been associated with
an overlying villous adenoma with an abrupt transition from adenoma to
carcinoma.4,6
The presence of variably sized islands of large cells
admixed with the small-cell component is common with extrapulmonary small-cell
carcinoma.9 The presence of these larger cells
are considered acceptable as long as the overall pattern fits that of small-cell
carcinoma. It can be postulated that both components are derived from epithelial
stem cells expressing both neuroendocrine and epithelial
characteristics.
Although these tumours illustrate neuroendocrine features,
no paraneoplastic syndromes have been reported to be associated with this
clinical entity. There have, however, been reports of SIADH occurring in
association with pancreatic tumours, including a case of SIADH in association
with adenocarcinoma of the pancreas,10 a case
of SIADH associated with endocrine pancreatic
carcinoma,11 and ectopic ACTH secretion from
small-cell carcinoma of the pancreas in association with
SIADH.12
Immunocytochemical studies have failed to demonstrate
specific peptides in most cases of ampullary small-cell carcinoma. One case
demonstrated the production of vasoactive intestinal peptide by the tumour.
However, this was not associated with clinical
endocrinopathy.8
The case presented in this paper is the first reported case
of small-cell carcinoma of the ampulla associated with a paraneoplastic
syndrome.
Author information:
Ali Ghahreman, Basic Surgical Trainee; Michael WC Booth, Upper GI, General
Surgeon and Endoscopist, Department of General Surgery; Richard G Cutfield,
Endocrine Physician; Cheryl L Wright, Pathologist, Surgical Pathology Unit,
North Shore Hospital, Waitemata District Health Board, Auckland
Correspondence: Mr
Michael WC Booth, Department of General Surgery, 8th Floor, North Shore
Hospital, Private Bag 93505, Takapuna, Auckland. Fax: (09) 488 4621; email: boothmi@whl.co.nz
References:
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