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Laparoscopic peritoneal cytology in the staging of pancreatic and periampullary cancer
HPB 1999
Volume I, Number I, 13- 20
Laparoscopic peritoneal cytology in the staging of pancreatic and periampullary cancer TG John ' , E McGoogan2, 5J Wigmore l , 5 Paterson-Brown I, DC Carter l and OJ Garden l
of Surgery, University of Edinburgh, The Royal Infirmary, Lauriston Place, Edinburgh, UK 2Department of Pathology, University of Edinburgh, Teviot Place, Edinburgh, UK I Department
Background
peritoneal cytology results were obtained in 39 patients,
Peritoneal cytology may be useful in the preoperative
13 of whom were deemed to have resectable tumours.The
assessment of patients with pancreatic cancer.
median cumulative survival at 6 months was 8% for
Method A prospective study was undertaken to evaluate the contribution of peritoneal cytology performed during staging
patients with positive cytology, compared with 71 % for those with negative cytology.
Discussion
laparoscopy in 46 patients with pancreatic or peri-
Positive peritoneal washings are an indicator of advanced
ampullary cancer.
disease and may be a useful adjunct to staging laparoscopy
Results Laparoscopic peritoneal cytology was positive for the
in the detection of patients with unresectable tumours.
Keywords
presence of malignant cells in seven patients (15%). All
pancreatic cancer, peritoneal cytology, laparoscopy, meta-
seven patients with positive peritoneal cytology had
stasis.
laparoscopic evidence of tumour unresectability. Negative
Introduction It has been suggested that peritoneal cytology may be useful in the preoperative assessment of patients with pancreatic cancer, both as an index of tumour resectability, and as a determinant of prognosis [1,2]. An association between positive peritoneal cytology and preceding operative tumour manipulation [2] or needle biopsy [1] has also been reported, implicating these manoeuvres in the dissemination of malignant cells. However, more recent studies have failed to reproduce these findings [3-6], and the role of peritoneal cytology in patients with pancreatic and periampullary malignacy remains unclear [7].
A prospective study was therefore performed to evaluate the contribution of peritoneal cytology, performed exclusively during staging laparoscopy, for pancreatic or periampullary cancer. The aims of the study were to evaluate the incidence of positive peritoneal cytology in this group of patients, to investigate patterns of tumour-spread associated with positive peritoneal cytology and to assess the implications of positive peritoneal cytology for survival. The reproducibility of results from the routine hospital cytopathology service was also assessed.
Patients and methods
If cytological analysis of peritoneal washings is to be useful in the preoperative staging of patients with pancreatic and periampullary cancer, then its value should be demon-
Patient details
strated in the context of staging laparoscopy. However, with the exception of the work on laparoscopic peritoneal cytol-
years; range 42-78). All underwent staging laparoscopy with laparoscopic ultrasonography during the 25 month period between March 1993 and April 1995. Eight patients
ogy reported by Fernandez-del Castillo et al. [5], previous investigators relied on the retrieval of some or all of the cytology samples during exploratory laparotomy [1-4,6] .
Correspondence to: Professor OJ Garden, Un iver sity Department of Surgery, University of Edinburgh, The Royal Infi rmary, Lauriston Place, Edinburgh, EH3 9YW, UK
Forty six patients with carcinoma of the pancreas or periampullary region were studied (29 men; median age 61
were classified as having periampullary tumours; endoscopic, operative and pathological findings indicated the carci-
© 1999 Isis Medical Media Ltd,
13
TG John et of. noma to have arisen within the peripapillary region. There was one patient with mucinous cystadenocarcinoma, one squamous cell carcinoma, one pleomorphic giant cell carcinoma and one periampullary small cell carcinoma, while the remaining 42 patients had ductal adenocarcinoma of the pancreas, or adenocarcinoma arising from the periampullary region. Cytologic analysis of peritoneal washings or ascitic fluid retrieved during the procedure was performed in each case. Histological confirmation of pancreatic or periampullary carcinoma was obtained in 38 patients by percutaneous (n=4) or operative (n=10) needle biopsy of the pancreas, laparoscopic (n= 13) or operative (n= 1) biopsy of metastatic lesions in the liver, serosal surfaces or regional lymph nodes, histopathological examination of the pancreatic resection specimen (n= 13) and/or endoluminal biopsy of periampullary lesions (n=10). No histological diagnosis was obtained in six other patients, although a pancreatic mass lesion was documented by imaging investigations and death from carcinomatosis was observed in each case [crude mean survival 34 weeks (range 12-67 weeks)]. The primary tumour was situated in the pancreatic head (32 patients), pancreatic body (five patients), pancreatic head and body (one patient) and periampullary region (eight patients). A biliary stent had been inserted in 30 patients (65%) by the endoscopic (22 patients) or percutaneous route (eight patients), and a cholecyst jejunostomy had previously been performed in one patient at a referring hospital.
Technique
of laparoscopic peritoneal cytology
spread peritoneal carcinomatosis and laparo copic ultrasonography was performed 'blind' via the ame port. Where present, a sample of free ascitic fluid was aspirated using a 16 FG nasogastric tube (Vygon , 95440 Ecouen, France) inserted via a 5 mm reducing sleeve and attached to a 30 ml catheter-tipped syringe. Otherwise, 300-500 ml of normal saline at room temperature was instilled into the subhepatic space early in the examination and an 80 ml sample of lavage fluid was retrieved, following completion of laparoscopic ultrasonography. Biopsy of susp icious serosal or liver lesions, or of the pancreas, was always deferred until after the aspiration of lavage fluid, to minimise its contamination with tumour cells or blood. Peritoneal lavage specimens were centrifuged at 2 000 rpm for 10 min, and the supernatant was discarded. The sediment was re-suspended in Glasgow's medium containing 0.25% heparin and cytospin preparations were made using 200 ~L aliquots of the suspension, spun at 500 rpm for four min. The cytospin preparations were fixed immediately in 95% methyl alcohol for 10 min. In instances of heavy blood-staining of the sample, additional cytospin samples were prepared and lysed in 6% acetic acid in 95% methyl alcohol. Slides were stained using the Papanicolaou method and, when appropriate, additional stains for mucin and / or cell-marker studies were performed. All cytological examinations were performed initially as part of the routine hospital service, by several duty cytopathologists, and were later reviewed independently, by a defined cytologist (EMcG) who was both experienced in the technique and blinded to patient details.
Staging laparoscopy with laparoscopic ultrasonography was performed under general anaesthesia, with muscle relax-
Validation
ation, as a separate procedure from any planned laparotomy. Details of this technique in the assessment of the pancreatic malignancy have been described in detail elsewhere
The decision regarding suitability for pancreatic tumour resection with curative intent, was defined as an end-point of the study. Unresectability was based upon the presence
[8,9]. Briefly, two 10 mm diameter laparoscopic ports (Endopath, Ethicon, Edinburgh, UK) were inserted at the
of distant metastases, or locoregional tumour invasion, with reference to the UICC TNM classification of pancreatic cancer stage [10]. At laparotomy, intra-operative ultra-
of tumour resectability
umbilicus and right flank, and a systematic inspection of the peritoneal cavity was performed using a 30° telescope. Laparoscopic ultrasonography was performed using a rigid 7.5 MHz linear array probe, via alternate ports (Aloka,
sonography was performed using a linear array 7.5 MHz T probe (Aloka, KeyMed Ltd, Southend-on-Sea, UK; or Tetrad, Englewood, CO, USA) to examine the liver and
KeyMed, Southend-on-Sea, UK; or Tetrad, Englewood,
pancreas. Trial dissection of the pancreas was perfonIied by
CO, USA), paying particular attention to the liver for intrahepatic metastases and examining the primary tumour
an experienced pancreatic surgeon (DCC, 0JG or SPB) using a standard technique [11], paying particular attention to the relationship between the tumour and the major
and its relationship with the peripancreatic vasculature and retroperitoneal soft tissues. A single port only was utilised in two patients in whom initiallaparoscopy revealed wide-
14
blood vessels such as the portal vein, superior mesenteric vein and artery. Microscopic involvement of the peripan-
Laparoscopic peritoneal cytology in the staging of pancreatic and periampullary cancer creatic lymph nodes and the clearance of the resection margins from tumour infiltration was sought during histopathological examination of resection specimens. Validation of tumour resectability was by laparoscopic biopsy of intra-abdominal metastases to distant sites, or to regional lymph nodes. Evidence of local tumour invasion of the major peripancreatic blood vessels, or soft tissues, was defined by trial dissection during laparotomy, by histopathological examination of the resection specimen with regard to tumour involvement of the planes of transection and lymph nodes, or by the corroborating findings of trans-abdominal ultrasonography, dynamic contrastenhanced CT, laparoscopy with laparoscopic ultrasonography and selective visceral angiography. Measures of diagnostic accuracy were calculated using two-by-two contingency table analysis; pred ictive values for positive and negative peritoneal cytology in determining tumour umesectability and resectability respectively were obtained [12]. Life-table analys is was used to calculate actuarial survival from the time of staging laparoscopy and Kap lan-Meier plots were constructed.
Results Patient outcome The decision regarding tumour resectability and the treatment received by the 46 patients in whom laparoscopic peritoneal cytology was performed are shown in Table 1. For the purposes of th is study, 13 patients (28%) were
Table I. Outcome for 46 patients with pancreatic or peri-
ampul/ary carcinoma in whom laparoscopic peritoneal cytology was performed Outcome Resectable Whipple operation Transduodenal local resection Biliary bypass ± gastroenterostomy Un resectable MI I N I No operation Whipple operation Total pancreatectomy Biliary by-pass and gast roenterostomy Un resectable T 2_ J No operation Distal pancreatectomy Laparotomy and biopsy Biliary by-pass and gastroenterostomy Gastroenterostomy alone Biliary by-pass alone
Number 13 7 3
3 17 14
16
5
5 2 2
patients and malignant regional lymphadenopathy in two patients. Sixteen patients were shown to h ave locally-umesectable tumour, of wh om nine underwen t palliative biliary and/or duodenal bypass surgery. Three patien ts who underwent pancreatic resection were subsequently reclassified as having umesectable disease, due to histopathological evidence of retroperitoneal tumour invasion (n = 1) and overt regional lymph node metastases (n=2). One patient with
deemed to have resectable disease, as confirmed at laparo-
previously unsuspected malignant infiltration of the poste-
tomy and histopathological examination of resection specimens. Three patients were considered during exploratory
rior stomach wall from carcinoma of th e pancreatic body underwent laparotomy and biopsy.
laparotomy to have potentially-resectable tumours, although pancreatoduodenectomy was considered inappropriate for reasons not related to tumour extent. Of these, two patients with cardiorespiratory risk factors were submitted to laparotomy, with the intention of performing
Peritoneal cytology T he results of independent review of the cytology specimens concurred with those reported by the routine hospital service in all cases. Laparoscopic peritoneal cytology was
transduodenal local resections for periampullary carcinomas. In each case, the tumour was found to have infiltrated the pancreatic h ead such that palliative biliary bypass sur-
positive for the presence of malignant cells in seven patients (15%). Review of the laparoscopic peritoneal cytology preparations revealed the following additional
gery was preferred, rather than pancreaticoduodenectomy which would have been required to achieve curative resection. The other patient, with known card iac disease, devel-
observations: a blood-stained sample was reported in 36 cases (78%); the preparations contained scan ty mesothelial cells, making satisfactory interpretation difficult in six cases
oped intraoperative hypotension and resectional surgery was abandoned in view of the risk of myocardial failure. Thirty-three patients were considered to have umesectable tumours (72%). Laparoscopic biopsy demonstrated
(13%); and degenerative mesothelial cells were present in 11 cases (24%). Large amounts of an amorph ous material, which was presumed to represent a fibrinous or mucoid exudate, was present in 23 patien-ts (50%). In 27 patients
distant metastases to the liver and/or peritoneum in 13
(59%), inflammatory or reactive mesothelial cells were
15
TG John et 01. observed in large numbers, the interpretation of which required particular care to avoid confusion with malignant cells. However, no instances of a false positive result were identified under these circumstances.
Table 3. Results oflaparoscopic peritoneal cytology in 46 patients with pancreatic or periampullary carcinoma in relation to the tumour site and stage; the presence of ascitic ffuid; and preceding percutaneous needle biopsy
All seven patients with positive peritoneal cytology had laparoscopic evidence of tumour unresectability due to extrapancreatic dissemination of malignancy (lymph node metastases in one patient, peritoneal metastases in four and/or liver metastases in four, i.e. Stage III-IV disease). Negative peritoneal cytology results were obtained in 39 patients, 13 of wh om were deemed to h ave resectable tumours (i.e. predictive value 33%). These results are expressed in terms of summary measures of diagnostic accuracy in Table 2. Positive peritoneal cytology was observed more frequently in patients with carcinoma involving the pancreatic body [three out of six patients (50%)] than in those with tumour in the pancreatic head [four out of 32 patients (13%)], or periampullary region (none) (Table 3). Malignant peritoneal cytology was also observed in three of the four patients (75%) in whom prev ious percutaneous pancreatic needle biopsy had been performed and in four out of 42 patients who had no previous biopsy (10%) (Table 3) . Twelve patients were found to have clinically undetectable free ascitic fluid during laparoscopy. Positive peritoneal cytology was recorded in six (50%) of these patients, compared with one out of 34 patients without ascites (3%) (see Table 3). One patief!.t with a periampullary carcinoma underwent pancreatoduodenectomy with curative intent and with histologically-negative resection margins, following the discovery of cytology-negative ascites at laparoscopy. This patient was alive and weill year later with no clinical or radiological evidence of tumour recurrence . Of the 13 patients with proven distant metastases to the liver (11 patients) and/or serosal surfaces (eight patients), peritoneal cytology was negative in seven (54%)
Number of patients Tumour site Periampullary Pancreatic head Pancreatic head and body Pancreatic body Previous biopsy Yes No Ascites Yes No Intra-abdominal metastases I liver Serosal Nodes Cancer stage grouping [10]
Positive 7
Result Negative
3
8 28 I 2
3 4
38
4
6
7 4 4
1111 III IV
39
6 33 10
7 4 3
30 3 6
7
ISix patients had intra-abdominal metastases in more than one site.
and positive in six (46%) (see Table 3). Negative peritoneal cytology was obtained in all 16 patients in whom local tumour invasion (Le. Stage T Z_3 unresectable) was the sole contraindication to tumour resection. The cumulative survival of patients found to have positive laparoscopic peritoneal cytology was less than that of patients with negative peritoneal cytology (Figure 1). The median cumulative survival at 3 and 6 months was 17% and 8% for patients with positive cytology, compared with 87% and 71 % respectively for those with negative cytology.
Table 2. Diagnostic accuracy of laparoscopic peritoneal cytology in the staging of 46 patients with pancreatic or periampullary carcinoma
Outcome Resectable Un resectable
Laparoscopic peritoneal cytology Negative Positive 13
26
7
Sensitivity = 7/33 = 21%; specificity = 13/1 3 = 100%; positive predictive value (PPV) = 7/7 = 100%; negative predictive value (NPV) = 13/39 = 33%.
16
All patients with positive peritoneal cytology had died by 9 months, wh ereas 45% of those with negative cytology were still alive. Malignant cutaneous seeding at the umbilical port site was diagnosed in one patient 6 weeks after laparoscopy. This patient had carcinoma of the pancreatic body and had undergone CTguided percutaneous n eedle biopsy of the pancreas 2 weeks before laparoscopy, with a negative yield. Peritoneal carcinomatos is, multifocal superficial liver metastases and positive peritoneal cytology had been revealed at laparoscopy. Otherwise, there were no instances
Laparoscopic peritoneal cytology in the staging of pancreatic and periampul/ary cancer
g 1>0 C
'> .~
=39) Positive cytology (n =7)
100
Negative cytology (n
80
'"c 60 0 .., I...
0
0-
0
0-
40
., OJ
.>
'"
:; E
interpretation is a highly observer-dependent technique and prone to inter-observer variation, it was reassuring that independent retrospective review of the specimens by a specialist cytologist validated the accuracy of the routine hospital cytology service. Despite h aving deferred laparoscop ic biopsies until after retrieval of peritoneal washings,
::J
I...
lial cells showing inflammatory changes. As cytological
significant blood-staining was present microscopically in 78% of samples. This finding may reflect minor bleeding, associated with trocar and port insertion; minor trauma,
20
::J
U
0 0
3
6
9
12
15
18
Months
Figure I. Cumulative survival of 46 patients with pancreatic or periampullary carcinoma following laparoscopic peritoneal cytology.
of postoperative morbidity attributable to the performance of staging laparoscopy, with laparoscopic ultrasonography and laparoscopic peritoneal cytology.
Discussion
associated with the performance of laparoscopic ultrason ography; and/or a direct effect of the underlying malignancy. However, blood-staining did not prevent cytological diagnosis in any case. Degenerative mesothelial cells were observed in 24% of samples, perhaps reflecting an imperfect choice of collecting fluid. Furthermore, the adequacy of the laparoscopic periton eal cytology technique could be questioned in the six patients (13 %) in whom scanty mesothelial cells were present in the sample. This result highligh ts the importance of utilising the maximum 'dwell time' that is practicable and supports the practice of altering the posi-
The incidence of positive peritoneal cytology in the present study (15 %) was less than that recorded (25-30%) by Martin and Goellner [2] and Warsh aw [1]. This difference could be
tion of the operating table, to ensure 'agitation' of the
due to our inclusion of eight patients with periampullary cancer, none of whom yielded malignant peritoneal cytology.
and colleagues to retrieve peritoneal washings laparoscop ically in 18% of patients, due to the presence of adhesions, was not experienced in our study. The observation of large
Nevertheless, the apparent scarcity of positive peritoneal cytology in patients with pancreatic malignancy is supported by the findings of recent studies, in which the incidence of positive cytology was 7-13% [3,4,6] (Table 4). Furthermore, Warshaw's group's recent update of their experience indicated that the incidence of positive peritoneal cytology had fallen to 17% [5], compared with 30% in their earlier report [1], while their overall resectability rate of 32% was not dissimilar to ours (28%). It is pertinent to note that (as in the present study) fluid samples for peritoneal cytology were obtained exclusively at laparoscopy, thus facilitating an evaluation of its specific contribution to the preoperative staging process. However, there is no obvious reason why the inci-
intraperitoneal fluid, manoeuvres which were not routinely performed in this study. N everthless, the failure of Leach
quantities of an amorphous substance in h alf the samples was a new finding which does not appear to h ave been reported before. Its relevance is unclear. Although laparoscopic peritoneal cytology was found to have been insensitive (21 %) in identifying patients with umesectable tumours, the predictive value of a positive result was 100% and was associated with tumour umesectability due to metastatic disease in all seven cases. However, laparoscopic peritoneal cytology contributed no additional staging information, all seven patients with positive results having been shown to h ave metastases within
dence of positive peritoneal cytology should be influenced by the method of retrieval of peritoneal washings, providing
the peritoneal cavity by laparoscopy and biopsy. These observations concur with those of Martin and Goellner [2] and Lei et al. [4], who also reported positive peritoneal
that the sample is removed before the tumour is mobilised or traumatised in any way.
cytology exclusively in the context of intra-abdominal metastases. Leach et al. documented distant metastatic dis-
As with any staging investigation, the avoidance of 'false positive' results is of paramount importance and accu-
ease at a median of 4.8 months after diagnosis in the four patients with positive cytology in their study [6]. These findings are at variance with those initially reported by Warshaw during 1985-1990 [1], who observed that of 12
rate interpretation of the cytological samples is critical, given that most lavage samples contained many mesothe-
17
TG John et 0/.
Table 4. Summary
of studies of peritoneal cytology in
assessment
of patients with
pancreatic
or periampu/lary carcinoma
Author and year
Positive peritoneal cytology (mode of retrieval)
Resectability rate
Martin and Goellner 1986 [2]
5/20
=25% (all laparotomy)
2/20
Warshaw 1991 [I]
12/40 = 30% (Iaparoscopy 27) (laparotomy 13)
14/35
Lei et 0/. 1994 [4]
3/36
=8% (all laparotomy)
17/36
Zerbi et 0/. 1994 [3]
2/ 15
= 13% (all laparotomy)
5/ 15=33%
Fernandez-del Castillo et 0/. 1995 [5]
16/94 = 17% (all laparoscopy)
30/94
= 32%
n = 15 (4115)
N/A
Leach et 0/. 1995 [6]
4/60
=7% (laparoscopy 29) (laparotomy 3 I)
42/60
= 70%
n =49
Sensitivity = 22% Specificity = 100% PPV = 100% NPV = 75%
7/46= 15%
13/46
Present study
Staging information
N/A2
Sensitivity = 28% Specificity = I00% PPV = 100% NPV = 13%
=40%
n=8 (6/8)
Sensitivity = 43% Specificity =93% PPV =90% NPV =52%
=47%
N/A
Sensitivity = 18% Specificity = 100% PPV = 100% NPV =48%
n=2
N/A
= 10%
N/A
(3/49)
(all laparoscopy)
I PPC
Prior biopsy (PPC ' )
=28%
n=4 (3/4)
Sensitivity = 21 % Specificity = 100% PPV = 100% NPV =33%
=number of patients with prior percutaneous needle biopsy/aspiration cytology who had positive peritoneal cytology.
2N/A not available. PPY
=positive predictive value.
NPY = negative predictive value.
out of 40 patients with positive peritoneal cytology, only one was associated with a visible surface tumour implant. A ll 12 patients with positive cytology in the latter study were found to h ave locally-advanced tumour, while all six patients with liver metastases had yielded negat ive peritoneal cytology [1] . T hese disparate results were not reproduced in subsequent work from the same cen tre, which showed a significant association between pos it ive peritoneal cytology and visible intra-abdominal tumour spread (45%, versus 8% in patients without metastases) [5]. It is pertin ent to note that none of the 49 patients found to h ave malignant peri toneal cytology in seven stud-
18
ies [1-6] (including the seven patients in the present study) have undergone potentially curative pancreatoduodenectomy, alth ough a palliative resection, with grossly positive resection margins, was performed in one patient in Warshaw's series [1]. If transcoelomic spread of exfoliated can cer cells is accepted as th e likely mechanism whereby peritoneal tumour seedlings become established, then th e fai lure to detect malignan t ce lls in four of eight patients with serosal dissemination was surprising and may indicate the need for better methods of retrieval or more sensit ive analytical methods, such as immunocytology [13]. Nevertheless, peri-
Laparoscopic peritoneal cytology in the staging
of pancreatic and periampu/lary cancer
toneal cytology must be undertaken, utilising existing hospital resources, if it is to become useful as a routine staging investigation and it is within this context that these results
reported positive cytology in 52 out of 92 patients (57%)
should be interpreted. Alternatively, based on the assumption that there were no false negative results in this or other
present study suggest that patients who are found to have small quantities of ascitic fluid on laparoscopy should not necessarily be considered as having a poor prognosis and this conclusion concurs with the views of others [1,4]. Indeed,
studies, the observation that peritoneal carcinomatosis is not always associated with cytologically-demonstrable malignant cells within the peritoneal cavity supports an alternative hypothesis, that peritoneal dissemination of malignancy is established by the haematogenous or lymphatic route. Suggestions that needle biopsy [1] or surgical mobilisation of the pancreas [4,14] may be implicated in the dissemination of cancer cells into the peritoneal cavity, thereby establishing tumour unresectability, stimulated recommendations that injudicious percutaneous or transduodenal biopsy of potentially resectable pancreatic tumours be avoided [1,7]. However, preoperative percutaneous needle biopsy of the pancreas was performed too infrequently in the present study to allow definite conclusions regarding its association with malignant perironeal cytology, or tumour dissemination. Nevertheless, three out of four such patients were found to be unresectable, with cytologically-malignant ascites, although all had presented with advanced
with clinically-evident malignant ascites, associated with a variety of intra-abdominal tumours [15]. The results of the
five out of nine such patients proved to be peritoneal-cytology negative, one of whom, with a localised periampullary carcinoma, was found to be suitable for tumour resection with curative intent. The case of malignant port-site seeding in the present study gives cause for concern. There have been two other case reports of malignant seeding to the parietes following laparoscopy in patients with pancreatic cancer [1 6,1 7], one instance of needle-track seeding of pancreatic cancer following percutaneous FNA biopsy [18] and another of cutaneous seeding following percutaneous transhepatic biliary drainage and stenting [19]. The patient reported here had presented with malignant ascites and peritoneal carcinomarosis following a recent, albeit negative, percutaneous needle biopsy of a carcinoma of the pancreatic body and was clearly at increased risk of such an occurrence. Although there has been increasing concern regarding the
tumours, three of which were situated in the pancreatic body. The possibility that such advanced and unresectable tumours were the source of positive peritoneal cytology,
risks of port-site seeding fo llowing laparoscopy in patients with a variety of intra-abdominal malignancies, most reported cases have been in the context of therapeutic
irrespective of subsequent biopsy, is a .confounding factor which cannot be excluded. A similar criticism can be made of Warshaw's original report [1], and it is noteworthy that
laparoscopy in patients with gall-bladder or colorectal cancers [20]. Although the benefits of staging laparoscopy in
further work in the same institut ion subsequently revealed no significant difference between patients with positive laparoscopic peritoneal cytology who had undergone biopsy (27%) and those who had not (15%) [5]. The association between positive peritoneal cytology, unresectability and prior percutaneous fine-needle aspiration (FNA) biopsy has also been refuted by Leach and colleagues [6] who reported a series of 60 patients with pancreatic cancer, of whom 49 (82%) had previously undergone biopsy. When these were compared with 11 patients in whom no biopsy had been attempted, they found no significant differences in the incidence of positive peritoneal cytology (6% versus 9%), 'eventual peritoneal failure' (10% versus 18%) or disease-free survival [6]. Malignant peritoneal cytology has previously been detected in 9% [4] and 50% [1] of patients with pancreaticcancer associated ascites, while Garrison and colleagues
the evaluation of selected patients with pancreatic cancer appear to outweigh such potential risks [5,8,21-23], it would also seem prudent to recommend that laparoscopic biopsy, or manipulation of potentially resectable tumours, be avoided. The incidence and mechanisms of malignant seeding in the context of laparoscopy require furth er attention. The grave prognosis associated with positive laparoscopic peritoneal cytology in the present study concurs with the find ings of others [1,2,4,6], that positive peritoneal washings are an indicator of advanced disease, characterised by unresectability, early metastasis and sh ort survival. Nevertheless, the results of the present study do not support the adoption of routine peritoneal cytology as a useful adjunct to staging laparoscopy in the detection of patients with unresectable tumours. The available information suggests that th ose patients with positive peritoneal cytology have an appalling prognosis, irrespective of
19
TG John et of. tumour stage . The identification of this subgroup of patients, with a short life-expectancy, may therefore aid clinical decision-making, such as the appropriateness of adjuvant therapy or palliative surgical intervention and, arguably, could be incorporated into future staging class ifications.
References Warsh aw A L. Implications of peritoneal cytology for staging of early pancreatic cancer. Am] Surg 1991 ;161:26-30. 2 Martin JK, Goellner JR. Abdominal fluid cytology in patients with gastro intestinal malignant lesions. Mayo Clin Proc 1986; 61:467-71. 3 Zerbi A , Balzano G, Bottura R, Di Carlo V. Reliability of pancreatic cancer staging classifications. Int] PancreatoI1 994;15: 13-1 8. 4 Lei S, Kini J, Kim K, Howard JM. Pancreatic can cer. Cytologic study of peritoneal washings. Arch Surg 1994;12 9: 639-42. 5 Fernandez-del Castillo C, Rattner DW, Warsh aw AL. Further experience with laparoscopy and peritoneal cytology in the staging of pancreatic cancer. Br ] Surg 1995;82:11 27- 9. 6 Leach SD, Rose JA, Lowy AM et al. Significance of peritoneal cytology in patients with potentially resectable adenocarcinoma of the pancreatic head . Surgery 1995;118:472-8. 7 van Heerden JA . Invited commentary: Lei et al. Pancreatic cancer. Cytologic study of peritoneal washings. Arch Surg 1994;129:642. 8 John TG, G reig JD, Carter DC, Garden OJ. Carcinoma of the pancreatic head and periampullary region : turuor staging with laparoscopy and laparoscopic ultrasonography. Ann Surg 1995 ; 221:1 56-64. 9 John TG , G arden OJ. Intraoperative and laparoscop ic ultrasound of the pancreas. Garden OJ, editor. Intraoperative and laparoscopic ultrasonography. Oxford: Blackwell Science, 1995: 77-1 08. 10 Hermanek P, Sobin LH. UICC : TNM classification of malignant tumors. Berlin: Springer-Verlag, 1992.
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11 Trede M. Approaches to the pancreas and abdominal explorat ion. In: Trede M and Carter DC, editors. Surgery of the pancreas. Ed inburgh: Churchill Livingstone, 1993 :141-5. 12 Freedman LS. Evaluating and comparing imaging techniques: a rev iew and class ification of study designs. Br] Radiol 1987; 60:107 1-8 1. 13 Juhl H , Strizel M, Wroblewski A et al. Immunocytological detect ion of micrometastatic cells: comparative evaluation of findings in the peritoneal cavity and the bone marrow of gastrlc, colorectal and pan cr eatlc can cer patien ts. In t ] Cance-r 1994;57:330-5. 14 Weiss SM, Skibber JM, Mohiudd in M, Rosato FE. Rapid intra-abdominal spread of pancreatic cancer. Arch Surg 1985; 120:415-16. 15 Garrison RN, Kael in LD, Heuser LS, Galloway RH . Malignant asc ites. C linical and experimental observations. Ann Surg 1986;203: 644-5 1. 16 Siriwardena A, Samarji WN. Cutaneous tumour seeding from a previously undiagnosed pancreatic carcinoma after laparoscopic cholecystectomy. Ann R Col Surg Eng 1993 ;75: 199-200. 17 Jorgensen JO, McCall JL, Morris DL. Porr site seeding aft er laparoscopic ultrasonographic staging of pancreatic carcinoma. Surgery 1995;117:11 8-19. 18 Rashleigh-Belcher HJC, Russell RCG, Lees WR. Cutaneous seeding of pancreatic carcinoma by fin e- needle asp iration biopsy. Br] RadioI1 986;59:182-3. 19 Doctor N, Dafnios N, Dick R, Dav idson BR. Peritoneal seeding of pancreatic head carcinoma following percutaneous transh epatic drainage and stenting. Br ] Surg 1997;84:197 . 20 Nduka CC, Monson JRT, Menzies-Gow N, Darzi A. Abdominal wall metastas is fo llowing laparoscopy. Br ] Surg 1994;81: 648-52. 21 Warsh aw A L, Gu ZY, Wittenberg J, Waltman A C. Preoperative stag ing and assessment of resectab ility of pancreatic cancer. Arch Surg 1990; 125 :230-3. 22 Cuschieri A. Laparoscopy for pancreatic cancer: does it benefit the patient? Eur] SurgOncoI1 988; 14:41- 4. 23 Bemelman WA, de Wit LT, van Delden OM et al. Diagnostic laparoscopy combined with laparoscopic ultrasonography in staging cancer of the pancreatic head region . Br ] Surg 1995 ; 82:820-4.
Volume I, Number I, 13- 20
Laparoscopic peritoneal cytology in the staging of pancreatic and periampullary cancer TG John ' , E McGoogan2, 5J Wigmore l , 5 Paterson-Brown I, DC Carter l and OJ Garden l
of Surgery, University of Edinburgh, The Royal Infirmary, Lauriston Place, Edinburgh, UK 2Department of Pathology, University of Edinburgh, Teviot Place, Edinburgh, UK I Department
Background
peritoneal cytology results were obtained in 39 patients,
Peritoneal cytology may be useful in the preoperative
13 of whom were deemed to have resectable tumours.The
assessment of patients with pancreatic cancer.
median cumulative survival at 6 months was 8% for
Method A prospective study was undertaken to evaluate the contribution of peritoneal cytology performed during staging
patients with positive cytology, compared with 71 % for those with negative cytology.
Discussion
laparoscopy in 46 patients with pancreatic or peri-
Positive peritoneal washings are an indicator of advanced
ampullary cancer.
disease and may be a useful adjunct to staging laparoscopy
Results Laparoscopic peritoneal cytology was positive for the
in the detection of patients with unresectable tumours.
Keywords
presence of malignant cells in seven patients (15%). All
pancreatic cancer, peritoneal cytology, laparoscopy, meta-
seven patients with positive peritoneal cytology had
stasis.
laparoscopic evidence of tumour unresectability. Negative
Introduction It has been suggested that peritoneal cytology may be useful in the preoperative assessment of patients with pancreatic cancer, both as an index of tumour resectability, and as a determinant of prognosis [1,2]. An association between positive peritoneal cytology and preceding operative tumour manipulation [2] or needle biopsy [1] has also been reported, implicating these manoeuvres in the dissemination of malignant cells. However, more recent studies have failed to reproduce these findings [3-6], and the role of peritoneal cytology in patients with pancreatic and periampullary malignacy remains unclear [7].
A prospective study was therefore performed to evaluate the contribution of peritoneal cytology, performed exclusively during staging laparoscopy, for pancreatic or periampullary cancer. The aims of the study were to evaluate the incidence of positive peritoneal cytology in this group of patients, to investigate patterns of tumour-spread associated with positive peritoneal cytology and to assess the implications of positive peritoneal cytology for survival. The reproducibility of results from the routine hospital cytopathology service was also assessed.
Patients and methods
If cytological analysis of peritoneal washings is to be useful in the preoperative staging of patients with pancreatic and periampullary cancer, then its value should be demon-
Patient details
strated in the context of staging laparoscopy. However, with the exception of the work on laparoscopic peritoneal cytol-
years; range 42-78). All underwent staging laparoscopy with laparoscopic ultrasonography during the 25 month period between March 1993 and April 1995. Eight patients
ogy reported by Fernandez-del Castillo et al. [5], previous investigators relied on the retrieval of some or all of the cytology samples during exploratory laparotomy [1-4,6] .
Correspondence to: Professor OJ Garden, Un iver sity Department of Surgery, University of Edinburgh, The Royal Infi rmary, Lauriston Place, Edinburgh, EH3 9YW, UK
Forty six patients with carcinoma of the pancreas or periampullary region were studied (29 men; median age 61
were classified as having periampullary tumours; endoscopic, operative and pathological findings indicated the carci-
© 1999 Isis Medical Media Ltd,
13
TG John et of. noma to have arisen within the peripapillary region. There was one patient with mucinous cystadenocarcinoma, one squamous cell carcinoma, one pleomorphic giant cell carcinoma and one periampullary small cell carcinoma, while the remaining 42 patients had ductal adenocarcinoma of the pancreas, or adenocarcinoma arising from the periampullary region. Cytologic analysis of peritoneal washings or ascitic fluid retrieved during the procedure was performed in each case. Histological confirmation of pancreatic or periampullary carcinoma was obtained in 38 patients by percutaneous (n=4) or operative (n=10) needle biopsy of the pancreas, laparoscopic (n= 13) or operative (n= 1) biopsy of metastatic lesions in the liver, serosal surfaces or regional lymph nodes, histopathological examination of the pancreatic resection specimen (n= 13) and/or endoluminal biopsy of periampullary lesions (n=10). No histological diagnosis was obtained in six other patients, although a pancreatic mass lesion was documented by imaging investigations and death from carcinomatosis was observed in each case [crude mean survival 34 weeks (range 12-67 weeks)]. The primary tumour was situated in the pancreatic head (32 patients), pancreatic body (five patients), pancreatic head and body (one patient) and periampullary region (eight patients). A biliary stent had been inserted in 30 patients (65%) by the endoscopic (22 patients) or percutaneous route (eight patients), and a cholecyst jejunostomy had previously been performed in one patient at a referring hospital.
Technique
of laparoscopic peritoneal cytology
spread peritoneal carcinomatosis and laparo copic ultrasonography was performed 'blind' via the ame port. Where present, a sample of free ascitic fluid was aspirated using a 16 FG nasogastric tube (Vygon , 95440 Ecouen, France) inserted via a 5 mm reducing sleeve and attached to a 30 ml catheter-tipped syringe. Otherwise, 300-500 ml of normal saline at room temperature was instilled into the subhepatic space early in the examination and an 80 ml sample of lavage fluid was retrieved, following completion of laparoscopic ultrasonography. Biopsy of susp icious serosal or liver lesions, or of the pancreas, was always deferred until after the aspiration of lavage fluid, to minimise its contamination with tumour cells or blood. Peritoneal lavage specimens were centrifuged at 2 000 rpm for 10 min, and the supernatant was discarded. The sediment was re-suspended in Glasgow's medium containing 0.25% heparin and cytospin preparations were made using 200 ~L aliquots of the suspension, spun at 500 rpm for four min. The cytospin preparations were fixed immediately in 95% methyl alcohol for 10 min. In instances of heavy blood-staining of the sample, additional cytospin samples were prepared and lysed in 6% acetic acid in 95% methyl alcohol. Slides were stained using the Papanicolaou method and, when appropriate, additional stains for mucin and / or cell-marker studies were performed. All cytological examinations were performed initially as part of the routine hospital service, by several duty cytopathologists, and were later reviewed independently, by a defined cytologist (EMcG) who was both experienced in the technique and blinded to patient details.
Staging laparoscopy with laparoscopic ultrasonography was performed under general anaesthesia, with muscle relax-
Validation
ation, as a separate procedure from any planned laparotomy. Details of this technique in the assessment of the pancreatic malignancy have been described in detail elsewhere
The decision regarding suitability for pancreatic tumour resection with curative intent, was defined as an end-point of the study. Unresectability was based upon the presence
[8,9]. Briefly, two 10 mm diameter laparoscopic ports (Endopath, Ethicon, Edinburgh, UK) were inserted at the
of distant metastases, or locoregional tumour invasion, with reference to the UICC TNM classification of pancreatic cancer stage [10]. At laparotomy, intra-operative ultra-
of tumour resectability
umbilicus and right flank, and a systematic inspection of the peritoneal cavity was performed using a 30° telescope. Laparoscopic ultrasonography was performed using a rigid 7.5 MHz linear array probe, via alternate ports (Aloka,
sonography was performed using a linear array 7.5 MHz T probe (Aloka, KeyMed Ltd, Southend-on-Sea, UK; or Tetrad, Englewood, CO, USA) to examine the liver and
KeyMed, Southend-on-Sea, UK; or Tetrad, Englewood,
pancreas. Trial dissection of the pancreas was perfonIied by
CO, USA), paying particular attention to the liver for intrahepatic metastases and examining the primary tumour
an experienced pancreatic surgeon (DCC, 0JG or SPB) using a standard technique [11], paying particular attention to the relationship between the tumour and the major
and its relationship with the peripancreatic vasculature and retroperitoneal soft tissues. A single port only was utilised in two patients in whom initiallaparoscopy revealed wide-
14
blood vessels such as the portal vein, superior mesenteric vein and artery. Microscopic involvement of the peripan-
Laparoscopic peritoneal cytology in the staging of pancreatic and periampullary cancer creatic lymph nodes and the clearance of the resection margins from tumour infiltration was sought during histopathological examination of resection specimens. Validation of tumour resectability was by laparoscopic biopsy of intra-abdominal metastases to distant sites, or to regional lymph nodes. Evidence of local tumour invasion of the major peripancreatic blood vessels, or soft tissues, was defined by trial dissection during laparotomy, by histopathological examination of the resection specimen with regard to tumour involvement of the planes of transection and lymph nodes, or by the corroborating findings of trans-abdominal ultrasonography, dynamic contrastenhanced CT, laparoscopy with laparoscopic ultrasonography and selective visceral angiography. Measures of diagnostic accuracy were calculated using two-by-two contingency table analysis; pred ictive values for positive and negative peritoneal cytology in determining tumour umesectability and resectability respectively were obtained [12]. Life-table analys is was used to calculate actuarial survival from the time of staging laparoscopy and Kap lan-Meier plots were constructed.
Results Patient outcome The decision regarding tumour resectability and the treatment received by the 46 patients in whom laparoscopic peritoneal cytology was performed are shown in Table 1. For the purposes of th is study, 13 patients (28%) were
Table I. Outcome for 46 patients with pancreatic or peri-
ampul/ary carcinoma in whom laparoscopic peritoneal cytology was performed Outcome Resectable Whipple operation Transduodenal local resection Biliary bypass ± gastroenterostomy Un resectable MI I N I No operation Whipple operation Total pancreatectomy Biliary by-pass and gast roenterostomy Un resectable T 2_ J No operation Distal pancreatectomy Laparotomy and biopsy Biliary by-pass and gastroenterostomy Gastroenterostomy alone Biliary by-pass alone
Number 13 7 3
3 17 14
16
5
5 2 2
patients and malignant regional lymphadenopathy in two patients. Sixteen patients were shown to h ave locally-umesectable tumour, of wh om nine underwen t palliative biliary and/or duodenal bypass surgery. Three patien ts who underwent pancreatic resection were subsequently reclassified as having umesectable disease, due to histopathological evidence of retroperitoneal tumour invasion (n = 1) and overt regional lymph node metastases (n=2). One patient with
deemed to have resectable disease, as confirmed at laparo-
previously unsuspected malignant infiltration of the poste-
tomy and histopathological examination of resection specimens. Three patients were considered during exploratory
rior stomach wall from carcinoma of th e pancreatic body underwent laparotomy and biopsy.
laparotomy to have potentially-resectable tumours, although pancreatoduodenectomy was considered inappropriate for reasons not related to tumour extent. Of these, two patients with cardiorespiratory risk factors were submitted to laparotomy, with the intention of performing
Peritoneal cytology T he results of independent review of the cytology specimens concurred with those reported by the routine hospital service in all cases. Laparoscopic peritoneal cytology was
transduodenal local resections for periampullary carcinomas. In each case, the tumour was found to have infiltrated the pancreatic h ead such that palliative biliary bypass sur-
positive for the presence of malignant cells in seven patients (15%). Review of the laparoscopic peritoneal cytology preparations revealed the following additional
gery was preferred, rather than pancreaticoduodenectomy which would have been required to achieve curative resection. The other patient, with known card iac disease, devel-
observations: a blood-stained sample was reported in 36 cases (78%); the preparations contained scan ty mesothelial cells, making satisfactory interpretation difficult in six cases
oped intraoperative hypotension and resectional surgery was abandoned in view of the risk of myocardial failure. Thirty-three patients were considered to have umesectable tumours (72%). Laparoscopic biopsy demonstrated
(13%); and degenerative mesothelial cells were present in 11 cases (24%). Large amounts of an amorph ous material, which was presumed to represent a fibrinous or mucoid exudate, was present in 23 patien-ts (50%). In 27 patients
distant metastases to the liver and/or peritoneum in 13
(59%), inflammatory or reactive mesothelial cells were
15
TG John et 01. observed in large numbers, the interpretation of which required particular care to avoid confusion with malignant cells. However, no instances of a false positive result were identified under these circumstances.
Table 3. Results oflaparoscopic peritoneal cytology in 46 patients with pancreatic or periampullary carcinoma in relation to the tumour site and stage; the presence of ascitic ffuid; and preceding percutaneous needle biopsy
All seven patients with positive peritoneal cytology had laparoscopic evidence of tumour unresectability due to extrapancreatic dissemination of malignancy (lymph node metastases in one patient, peritoneal metastases in four and/or liver metastases in four, i.e. Stage III-IV disease). Negative peritoneal cytology results were obtained in 39 patients, 13 of wh om were deemed to h ave resectable tumours (i.e. predictive value 33%). These results are expressed in terms of summary measures of diagnostic accuracy in Table 2. Positive peritoneal cytology was observed more frequently in patients with carcinoma involving the pancreatic body [three out of six patients (50%)] than in those with tumour in the pancreatic head [four out of 32 patients (13%)], or periampullary region (none) (Table 3). Malignant peritoneal cytology was also observed in three of the four patients (75%) in whom prev ious percutaneous pancreatic needle biopsy had been performed and in four out of 42 patients who had no previous biopsy (10%) (Table 3) . Twelve patients were found to have clinically undetectable free ascitic fluid during laparoscopy. Positive peritoneal cytology was recorded in six (50%) of these patients, compared with one out of 34 patients without ascites (3%) (see Table 3). One patief!.t with a periampullary carcinoma underwent pancreatoduodenectomy with curative intent and with histologically-negative resection margins, following the discovery of cytology-negative ascites at laparoscopy. This patient was alive and weill year later with no clinical or radiological evidence of tumour recurrence . Of the 13 patients with proven distant metastases to the liver (11 patients) and/or serosal surfaces (eight patients), peritoneal cytology was negative in seven (54%)
Number of patients Tumour site Periampullary Pancreatic head Pancreatic head and body Pancreatic body Previous biopsy Yes No Ascites Yes No Intra-abdominal metastases I liver Serosal Nodes Cancer stage grouping [10]
Positive 7
Result Negative
3
8 28 I 2
3 4
38
4
6
7 4 4
1111 III IV
39
6 33 10
7 4 3
30 3 6
7
ISix patients had intra-abdominal metastases in more than one site.
and positive in six (46%) (see Table 3). Negative peritoneal cytology was obtained in all 16 patients in whom local tumour invasion (Le. Stage T Z_3 unresectable) was the sole contraindication to tumour resection. The cumulative survival of patients found to have positive laparoscopic peritoneal cytology was less than that of patients with negative peritoneal cytology (Figure 1). The median cumulative survival at 3 and 6 months was 17% and 8% for patients with positive cytology, compared with 87% and 71 % respectively for those with negative cytology.
Table 2. Diagnostic accuracy of laparoscopic peritoneal cytology in the staging of 46 patients with pancreatic or periampullary carcinoma
Outcome Resectable Un resectable
Laparoscopic peritoneal cytology Negative Positive 13
26
7
Sensitivity = 7/33 = 21%; specificity = 13/1 3 = 100%; positive predictive value (PPV) = 7/7 = 100%; negative predictive value (NPV) = 13/39 = 33%.
16
All patients with positive peritoneal cytology had died by 9 months, wh ereas 45% of those with negative cytology were still alive. Malignant cutaneous seeding at the umbilical port site was diagnosed in one patient 6 weeks after laparoscopy. This patient had carcinoma of the pancreatic body and had undergone CTguided percutaneous n eedle biopsy of the pancreas 2 weeks before laparoscopy, with a negative yield. Peritoneal carcinomatos is, multifocal superficial liver metastases and positive peritoneal cytology had been revealed at laparoscopy. Otherwise, there were no instances
Laparoscopic peritoneal cytology in the staging of pancreatic and periampul/ary cancer
g 1>0 C
'> .~
=39) Positive cytology (n =7)
100
Negative cytology (n
80
'"c 60 0 .., I...
0
0-
0
0-
40
., OJ
.>
'"
:; E
interpretation is a highly observer-dependent technique and prone to inter-observer variation, it was reassuring that independent retrospective review of the specimens by a specialist cytologist validated the accuracy of the routine hospital cytology service. Despite h aving deferred laparoscop ic biopsies until after retrieval of peritoneal washings,
::J
I...
lial cells showing inflammatory changes. As cytological
significant blood-staining was present microscopically in 78% of samples. This finding may reflect minor bleeding, associated with trocar and port insertion; minor trauma,
20
::J
U
0 0
3
6
9
12
15
18
Months
Figure I. Cumulative survival of 46 patients with pancreatic or periampullary carcinoma following laparoscopic peritoneal cytology.
of postoperative morbidity attributable to the performance of staging laparoscopy, with laparoscopic ultrasonography and laparoscopic peritoneal cytology.
Discussion
associated with the performance of laparoscopic ultrason ography; and/or a direct effect of the underlying malignancy. However, blood-staining did not prevent cytological diagnosis in any case. Degenerative mesothelial cells were observed in 24% of samples, perhaps reflecting an imperfect choice of collecting fluid. Furthermore, the adequacy of the laparoscopic periton eal cytology technique could be questioned in the six patients (13 %) in whom scanty mesothelial cells were present in the sample. This result highligh ts the importance of utilising the maximum 'dwell time' that is practicable and supports the practice of altering the posi-
The incidence of positive peritoneal cytology in the present study (15 %) was less than that recorded (25-30%) by Martin and Goellner [2] and Warsh aw [1]. This difference could be
tion of the operating table, to ensure 'agitation' of the
due to our inclusion of eight patients with periampullary cancer, none of whom yielded malignant peritoneal cytology.
and colleagues to retrieve peritoneal washings laparoscop ically in 18% of patients, due to the presence of adhesions, was not experienced in our study. The observation of large
Nevertheless, the apparent scarcity of positive peritoneal cytology in patients with pancreatic malignancy is supported by the findings of recent studies, in which the incidence of positive cytology was 7-13% [3,4,6] (Table 4). Furthermore, Warshaw's group's recent update of their experience indicated that the incidence of positive peritoneal cytology had fallen to 17% [5], compared with 30% in their earlier report [1], while their overall resectability rate of 32% was not dissimilar to ours (28%). It is pertinent to note that (as in the present study) fluid samples for peritoneal cytology were obtained exclusively at laparoscopy, thus facilitating an evaluation of its specific contribution to the preoperative staging process. However, there is no obvious reason why the inci-
intraperitoneal fluid, manoeuvres which were not routinely performed in this study. N everthless, the failure of Leach
quantities of an amorphous substance in h alf the samples was a new finding which does not appear to h ave been reported before. Its relevance is unclear. Although laparoscopic peritoneal cytology was found to have been insensitive (21 %) in identifying patients with umesectable tumours, the predictive value of a positive result was 100% and was associated with tumour umesectability due to metastatic disease in all seven cases. However, laparoscopic peritoneal cytology contributed no additional staging information, all seven patients with positive results having been shown to h ave metastases within
dence of positive peritoneal cytology should be influenced by the method of retrieval of peritoneal washings, providing
the peritoneal cavity by laparoscopy and biopsy. These observations concur with those of Martin and Goellner [2] and Lei et al. [4], who also reported positive peritoneal
that the sample is removed before the tumour is mobilised or traumatised in any way.
cytology exclusively in the context of intra-abdominal metastases. Leach et al. documented distant metastatic dis-
As with any staging investigation, the avoidance of 'false positive' results is of paramount importance and accu-
ease at a median of 4.8 months after diagnosis in the four patients with positive cytology in their study [6]. These findings are at variance with those initially reported by Warshaw during 1985-1990 [1], who observed that of 12
rate interpretation of the cytological samples is critical, given that most lavage samples contained many mesothe-
17
TG John et 0/.
Table 4. Summary
of studies of peritoneal cytology in
assessment
of patients with
pancreatic
or periampu/lary carcinoma
Author and year
Positive peritoneal cytology (mode of retrieval)
Resectability rate
Martin and Goellner 1986 [2]
5/20
=25% (all laparotomy)
2/20
Warshaw 1991 [I]
12/40 = 30% (Iaparoscopy 27) (laparotomy 13)
14/35
Lei et 0/. 1994 [4]
3/36
=8% (all laparotomy)
17/36
Zerbi et 0/. 1994 [3]
2/ 15
= 13% (all laparotomy)
5/ 15=33%
Fernandez-del Castillo et 0/. 1995 [5]
16/94 = 17% (all laparoscopy)
30/94
= 32%
n = 15 (4115)
N/A
Leach et 0/. 1995 [6]
4/60
=7% (laparoscopy 29) (laparotomy 3 I)
42/60
= 70%
n =49
Sensitivity = 22% Specificity = 100% PPV = 100% NPV = 75%
7/46= 15%
13/46
Present study
Staging information
N/A2
Sensitivity = 28% Specificity = I00% PPV = 100% NPV = 13%
=40%
n=8 (6/8)
Sensitivity = 43% Specificity =93% PPV =90% NPV =52%
=47%
N/A
Sensitivity = 18% Specificity = 100% PPV = 100% NPV =48%
n=2
N/A
= 10%
N/A
(3/49)
(all laparoscopy)
I PPC
Prior biopsy (PPC ' )
=28%
n=4 (3/4)
Sensitivity = 21 % Specificity = 100% PPV = 100% NPV =33%
=number of patients with prior percutaneous needle biopsy/aspiration cytology who had positive peritoneal cytology.
2N/A not available. PPY
=positive predictive value.
NPY = negative predictive value.
out of 40 patients with positive peritoneal cytology, only one was associated with a visible surface tumour implant. A ll 12 patients with positive cytology in the latter study were found to h ave locally-advanced tumour, while all six patients with liver metastases had yielded negat ive peritoneal cytology [1] . T hese disparate results were not reproduced in subsequent work from the same cen tre, which showed a significant association between pos it ive peritoneal cytology and visible intra-abdominal tumour spread (45%, versus 8% in patients without metastases) [5]. It is pertin ent to note that none of the 49 patients found to h ave malignant peri toneal cytology in seven stud-
18
ies [1-6] (including the seven patients in the present study) have undergone potentially curative pancreatoduodenectomy, alth ough a palliative resection, with grossly positive resection margins, was performed in one patient in Warshaw's series [1]. If transcoelomic spread of exfoliated can cer cells is accepted as th e likely mechanism whereby peritoneal tumour seedlings become established, then th e fai lure to detect malignan t ce lls in four of eight patients with serosal dissemination was surprising and may indicate the need for better methods of retrieval or more sensit ive analytical methods, such as immunocytology [13]. Nevertheless, peri-
Laparoscopic peritoneal cytology in the staging
of pancreatic and periampu/lary cancer
toneal cytology must be undertaken, utilising existing hospital resources, if it is to become useful as a routine staging investigation and it is within this context that these results
reported positive cytology in 52 out of 92 patients (57%)
should be interpreted. Alternatively, based on the assumption that there were no false negative results in this or other
present study suggest that patients who are found to have small quantities of ascitic fluid on laparoscopy should not necessarily be considered as having a poor prognosis and this conclusion concurs with the views of others [1,4]. Indeed,
studies, the observation that peritoneal carcinomatosis is not always associated with cytologically-demonstrable malignant cells within the peritoneal cavity supports an alternative hypothesis, that peritoneal dissemination of malignancy is established by the haematogenous or lymphatic route. Suggestions that needle biopsy [1] or surgical mobilisation of the pancreas [4,14] may be implicated in the dissemination of cancer cells into the peritoneal cavity, thereby establishing tumour unresectability, stimulated recommendations that injudicious percutaneous or transduodenal biopsy of potentially resectable pancreatic tumours be avoided [1,7]. However, preoperative percutaneous needle biopsy of the pancreas was performed too infrequently in the present study to allow definite conclusions regarding its association with malignant perironeal cytology, or tumour dissemination. Nevertheless, three out of four such patients were found to be unresectable, with cytologically-malignant ascites, although all had presented with advanced
with clinically-evident malignant ascites, associated with a variety of intra-abdominal tumours [15]. The results of the
five out of nine such patients proved to be peritoneal-cytology negative, one of whom, with a localised periampullary carcinoma, was found to be suitable for tumour resection with curative intent. The case of malignant port-site seeding in the present study gives cause for concern. There have been two other case reports of malignant seeding to the parietes following laparoscopy in patients with pancreatic cancer [1 6,1 7], one instance of needle-track seeding of pancreatic cancer following percutaneous FNA biopsy [18] and another of cutaneous seeding following percutaneous transhepatic biliary drainage and stenting [19]. The patient reported here had presented with malignant ascites and peritoneal carcinomarosis following a recent, albeit negative, percutaneous needle biopsy of a carcinoma of the pancreatic body and was clearly at increased risk of such an occurrence. Although there has been increasing concern regarding the
tumours, three of which were situated in the pancreatic body. The possibility that such advanced and unresectable tumours were the source of positive peritoneal cytology,
risks of port-site seeding fo llowing laparoscopy in patients with a variety of intra-abdominal malignancies, most reported cases have been in the context of therapeutic
irrespective of subsequent biopsy, is a .confounding factor which cannot be excluded. A similar criticism can be made of Warshaw's original report [1], and it is noteworthy that
laparoscopy in patients with gall-bladder or colorectal cancers [20]. Although the benefits of staging laparoscopy in
further work in the same institut ion subsequently revealed no significant difference between patients with positive laparoscopic peritoneal cytology who had undergone biopsy (27%) and those who had not (15%) [5]. The association between positive peritoneal cytology, unresectability and prior percutaneous fine-needle aspiration (FNA) biopsy has also been refuted by Leach and colleagues [6] who reported a series of 60 patients with pancreatic cancer, of whom 49 (82%) had previously undergone biopsy. When these were compared with 11 patients in whom no biopsy had been attempted, they found no significant differences in the incidence of positive peritoneal cytology (6% versus 9%), 'eventual peritoneal failure' (10% versus 18%) or disease-free survival [6]. Malignant peritoneal cytology has previously been detected in 9% [4] and 50% [1] of patients with pancreaticcancer associated ascites, while Garrison and colleagues
the evaluation of selected patients with pancreatic cancer appear to outweigh such potential risks [5,8,21-23], it would also seem prudent to recommend that laparoscopic biopsy, or manipulation of potentially resectable tumours, be avoided. The incidence and mechanisms of malignant seeding in the context of laparoscopy require furth er attention. The grave prognosis associated with positive laparoscopic peritoneal cytology in the present study concurs with the find ings of others [1,2,4,6], that positive peritoneal washings are an indicator of advanced disease, characterised by unresectability, early metastasis and sh ort survival. Nevertheless, the results of the present study do not support the adoption of routine peritoneal cytology as a useful adjunct to staging laparoscopy in the detection of patients with unresectable tumours. The available information suggests that th ose patients with positive peritoneal cytology have an appalling prognosis, irrespective of
19
TG John et of. tumour stage . The identification of this subgroup of patients, with a short life-expectancy, may therefore aid clinical decision-making, such as the appropriateness of adjuvant therapy or palliative surgical intervention and, arguably, could be incorporated into future staging class ifications.
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11 Trede M. Approaches to the pancreas and abdominal explorat ion. In: Trede M and Carter DC, editors. Surgery of the pancreas. Ed inburgh: Churchill Livingstone, 1993 :141-5. 12 Freedman LS. Evaluating and comparing imaging techniques: a rev iew and class ification of study designs. Br] Radiol 1987; 60:107 1-8 1. 13 Juhl H , Strizel M, Wroblewski A et al. Immunocytological detect ion of micrometastatic cells: comparative evaluation of findings in the peritoneal cavity and the bone marrow of gastrlc, colorectal and pan cr eatlc can cer patien ts. In t ] Cance-r 1994;57:330-5. 14 Weiss SM, Skibber JM, Mohiudd in M, Rosato FE. Rapid intra-abdominal spread of pancreatic cancer. Arch Surg 1985; 120:415-16. 15 Garrison RN, Kael in LD, Heuser LS, Galloway RH . Malignant asc ites. C linical and experimental observations. Ann Surg 1986;203: 644-5 1. 16 Siriwardena A, Samarji WN. Cutaneous tumour seeding from a previously undiagnosed pancreatic carcinoma after laparoscopic cholecystectomy. Ann R Col Surg Eng 1993 ;75: 199-200. 17 Jorgensen JO, McCall JL, Morris DL. Porr site seeding aft er laparoscopic ultrasonographic staging of pancreatic carcinoma. Surgery 1995;117:11 8-19. 18 Rashleigh-Belcher HJC, Russell RCG, Lees WR. Cutaneous seeding of pancreatic carcinoma by fin e- needle asp iration biopsy. Br] RadioI1 986;59:182-3. 19 Doctor N, Dafnios N, Dick R, Dav idson BR. Peritoneal seeding of pancreatic head carcinoma following percutaneous transh epatic drainage and stenting. Br ] Surg 1997;84:197 . 20 Nduka CC, Monson JRT, Menzies-Gow N, Darzi A. Abdominal wall metastas is fo llowing laparoscopy. Br ] Surg 1994;81: 648-52. 21 Warsh aw A L, Gu ZY, Wittenberg J, Waltman A C. Preoperative stag ing and assessment of resectab ility of pancreatic cancer. Arch Surg 1990; 125 :230-3. 22 Cuschieri A. Laparoscopy for pancreatic cancer: does it benefit the patient? Eur] SurgOncoI1 988; 14:41- 4. 23 Bemelman WA, de Wit LT, van Delden OM et al. Diagnostic laparoscopy combined with laparoscopic ultrasonography in staging cancer of the pancreatic head region . Br ] Surg 1995 ; 82:820-4.