Langenbecks Arch Surg (2011) 396:217–222 DOI 10.1007/s00423-010-0677-3
ORIGINAL ARTICLE
Clinicopathological features of adenosquamous pancreatic cancer Paolo Regi & Giovanni Butturini & Giuseppe Malleo & Federica Pedica & Mirko D’Onofrio & Claudio Bassi
Received: 6 April 2010 / Accepted: 23 June 2010 / Published online: 9 July 2010 # Springer-Verlag 2010
Abstract Purpose Adenosquamous pancreatic cancer represents 0.9–4.4% of exocrine pancreatic neoplasms and is generally thought to be associated with a worse prognosis than the more common ductal adenocarcinoma. The aim of the current study is to describe the outcome of patients with adenosquamous pancreatic cancer in our institution who were managed in a multidisciplinary environment. Methods In a retrospective analysis between February 1990 and February 2010, we identified from our database of 890 pancreatic lesions resected for malignancy six cases (0.67%) of adenosquamous cancer. We assessed the demographics, clinical and radiological features, surgical approach, histological details and follow-up data. Results All patients underwent pylorus-preserving pancreatoduodenectomy. Two patients, one male and one female, died in the preoperative period due to sepsis and myocardial infarction, respectively. The remaining four patients received adjuvant chemotherapy. One male patient died with local recurrence after 13 months; however, one female and two male patients are still P. Regi (*) : G. Butturini : G. Malleo : C. Bassi Surgical and Gastroenterological Department, University of Verona, Policlinico Borgo Roma, Piazzale LA Scuro #10, 37134 Verona, Italy e-mail:
[email protected] F. Pedica Pathological Department, University of Verona, Policlinico Borgo Roma, Piazzale LA Scuro #10, 37134 Verona, Italy M. D’Onofrio Radiological Department, University of Verona, Policlinico Borgo Roma, Piazzale LA Scuro #10, 37134 Verona, Italy
alive with Karnofsky status of 80–90% at 15, 14 and 39 months after the operation, respectively. Conclusions The prognosis of adenosquamous pancreatic cancer remains very poor, apparently worse than ductal pancreatic cancer. Nevertheless, our report and the review of literature seem to show that “curative” surgical resection associated with adjuvant treatment may offer the best results with a similar survival rate than ductal pancreatic cancer. Keywords Adenosquamous cancer . Squamous cell carcinoma . Pancreatic neoplasms . Surgery
Introduction Adenosquamous cancer (ASCa) was described in the literature for the first time by Herxheimer in 1907 who named this new entity “cancroide” [1]. Histologically, ASCa is characterised by cellular mixture of both adenomatous and squamous subtype in the same tumour, and thus, many authors have used differing definitions, including “adenoacanthoma, mixed squamous and adenocarcinoma, or mucoepidermoid carcinoma”. Within nonendocrine pancreatic neoplasms, ASCa is a rare subtype, ranging from 0.9% to 4.4% of overall malignancies [2–4]. According to the World Health Organization, the presence of the squamous cell carcinoma differentiation for at least 30% of the neoplasm is needed for diagnosis [5]. Usually, clinical, radiological and macroscopical aspects simulate completely a common ductal pancreatic cancer (DPC) [4, 6]. At the time of presentation, the stage of disease is generally advanced, and this contributes to the poor prognosis, but when potentially curative resection is combined with adjuvant chemoradiation, overall survival
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rate can be improved [6–9]. Various therapeutic approaches, including palliative external-beam radiotherapy along with chemotherapy, intraoperative radiation therapy (IORT) for unresectable tumours or surgical resection (alone or in conjunction with locoregional chemotherapy), have been also described, but the studies are small and survival rates are controversial for clinical conclusions [10–12]. The aim of the present study is to report our institution's experience of six cases, including a review of the international literature of this disease (Medline: 1980–2009).
Materials and methods A retrospective analysis of our database was performed between the dates February 1990 and February 2010, searching for patients with cytological or histological diagnosis of ASCa. While no patients were identified within the cytological specimens obtained by fine-needle aspiration (N=734), we found six cases from 890 pancreatic lesions resected for malignancy (0.67%). For each case, we analysed patient demographics, presenting symptoms, biochemical and haematological investigations, radiological features, type of surgical resection, histological characteristics and follow-up data. Furthermore, we performed an extensive review of the available literature utilising Medline, including the search terms “adenosquamous cancer” and “adenosquamous pancreatic carcinoma”.
Results Four patients were male and two were female (2:1), with a mean age at presentation of 63.5 years (range, 47–77). The presenting symptoms in order of frequency were jaundice (4/6), upper abdominal pain (2/6), weight loss (2/6), anorexia (2/6), recurrent fever (1/6) and diarrhoea (1/6). For one female patient, diagnosis was an incidental finding during follow-up examination after radiotherapy for lymphoma. In one case, recurrent acute pancreatitis occurred 3 months following diagnosis. Three patients were heavy smokers (20 cig/day); however, there was no family history of malignant pancreatic neoplasms or diabetes. Ca-19.9 was elevated in five patients (in three cases associated with concomitant jaundice), while carcinoembryonic antigen (CEA) was elevated in one patient. Preoperative radiological investigations (enhanced ultrasound (US) and computed tomography (CT) scan) revealed that the tumours were always localised to the pancreatic head with a radiological pattern similar to DPC (solid mass with irregular borders and possible central areas of colliquation). However, in one case, imaging revealed a huge solid macrocystic mass demonstrating increased
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uptake during both contrast-enhanced US and CT scan and simulating a mucinous cystic neoplasm. The main biliary duct was enlarged in four cases (diameters ranged from 0.9 to 1.3 cm) and the duct of Wirsung in a single case (0.5 cm) (Fig. 1). Radiological investigations did not reveal major vascular involvement or evidence of systemic metastases (Table 1). All patients underwent pyloruspreserving pancreaticoduodenectomy with a mean duration of 420 min (ranging from 390 to 450): During the operation, two patients received blood transfusion. One male patient developed stump pancreatitis with haemoperitoneum in the preoperative period and died as a result of sepsis following an early reoperation (total pancreatectomy with splenectomy was performed). Another male patient required early reoperation for acute haemoperitoneum, which was successfully managed by simple haemostasis. For the other patients, neither abdominal nor general complications were reported. Histopathological analyses of the specimens revealed two R0, three R1 and one R2 resections (all N1–M0). Details of histological features for each patient are reported in Table 2 (Figs. 2, 3, 4, and 5). According to the UICC classification, five tumours were stage III (T2-N1-M0) and one was stage IVA (T3-N1-M0) with significant infiltration of the superior mesenteric vein, which necessitated the surgeon to perform an R2 resection. Long-term follow-up was available for four patients as one female patient (R2-r) died at 20 days as a result of a myocardial infarction following an uneventful postoperative period with a regular discharge on the seventh postoperative day. All patients received adjuvant chemotherapy: One male patient (R0-r) who received six courses of 5-fluorouracil (5-FU) is still alive with a “disease free” status 39 months post-resection (Karnofsky status, 90%). Two patients (both R1-r), one male and one female,
Fig. 1 Adenosquamous pancreatic cancer involving the head of the pancreas with a solid slight hypodense appearance at contrastenhanced CT scan in the pancreatic phase (white arrow)
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Table 1 Radiological features in our series Case Tumour Tumour size localisation (enhanced US and enhanced CT scan)
Radiological behaviour
MPD vs MBD Mesenteric axis dilatation or portal vein (enhanced US vs involvement enhanced CT scan)
Systemic metastases
1
e-US, 2.3 cm
e-US, solid mass with some colliquated areas and hypoechogenic behaviour during enhancement
US, none
US, none
e-CT scan, 2.2 cm
e-CT scan, similar characteristics, hypodense during enhancement e-US, solid mass with some colliquated areas and hypoechogenic behaviour during enhancement
US MPD, normal MBD, 1.3 cm CT scan Idem US MPD, normal MBD, normal CT scan Idem
CT scan, none
CT scan, none
US, none
US, none
CT scan, none
CT scan, none
2
3
4
Head
Head
Head
Head
e-US, 2.6 cm
e-CT scan, 2.5 cm
e-CT scan, similar characteristics, hypodense during enhancement
e-US, 2 cm
e-US, solid mass with hypoechogenic behaviour during enhancement
US MPD, normal MBD, 1 cm
US, none
e-CT scan, 2 cm
e-CT scan, similar characteristics, hypodense during enhancement
CT scan MPD, 0.5 cm
CT scan, none
US, some enlarged nodes at hepatic hilum CT scan, none
US, none
US, none
CT scan, none
CT scan, none
US, none
US, none
CT scan, none
CT scan, none
US, none
US, none
CT scan, none
CT scan, none
e-US, 2.5 cm
e-CT scan, 2.5 cm 5
Head
e-US, 2 cm
e-CT scan, 2.2 cm 6
Head
e-US, 5 cm
e-CT scan, 5.2 cm
MBD, 1 cm US MPD, normal MBD, 1.1 cm e-CT scan, similar characteristics, CT scan hypodense during enhancement Idem e-US, solid mass with hypoechogenic US behaviour during enhancement MPD, normal MBD, 0.9 cm e-CT scan, similar characteristics, CT scan hypodense during enhancement Idem e-US, huge cystic mass with many septi US and solid internal node fairly hypodense MPD, normal during enhancement MBD, normal e-CT scan, huge solid-cystic tumour, fairly CT scan hyperdense during enhancement Idem e-US, solid mass with hypoechogenic behaviour during enhancement
MPD main pancreatic duct, MBD main biliary duct, US ultrasonography, e-US enhanced US, CT computed tomography
respectively had gemcitabine (five courses) and gemcitabine plus oxaliplatin (five courses) administered. They remain alive at 14 and 15 months following resection with liver metastases (Karnofsky status, 80% for both patients). One patient succumbed to local recurrence after 13 months following surgical resection and adjuvant administration of gemcitabine (five courses), but unfortunately, autopsy was not performed. The median overall survival rate of our series was 14.5 months (min 13, max 39).
Discussion Generally, ASCa shows male prevalence (1.5:1), mean age at presentation of 62.5 years, presenting symptoms such as weight
of loss, jaundice and non-specific abdominal pain. It shares similar characteristics to DPC including genetic alterations, most prevalent location being the pancreatic head, as well as radiological features and a frequent CEA and Ca 19.9 expression, which may suggest local or systemic invasion [4, 6, 8, 11, 13]. Diagnostic confirmation can be obtained by both histological examination of the resection specimen and also by fine-needle aspiration preoperatively. Moreover, the latter can discern the epidermoid “atypical” cells (which are also evident in those undergoing endoscopic biliary stent placement and patients with chronic pancreatitis) from a squamous cell cancer of the pancreas, but requires an experienced cytopathologist to accurately interpret the sample [14, 15]. Biological behaviour seems more aggressive and the prognosis worse than for DPC, with early metastatic involvement of
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Table 2 Pathological details of specimens in our series Case
Macroscopic features
MBD +
DUO+
RMR+
MA+
VmI+
PAT+
EVE
PE+
N-Inv
Squamous component (%)
Type of resection
1
2.5 cm—solid and trabecular organisation
Yes
No
Yes
No
Yes
Yes
Yes
Yes
75
R1
2
2.5 cm—solid and trabecular organisation
No
No
No
Yes
Yes
Yes
–
Yes
50
R2
3
2.3 cm—solid and trabecular organisation
Yes
No
No
No
Yes
–
Yes
Yes
65
RO
4
3 cm—solid and trabecular organisation
Yes
Yes
No
No
Yes
Yes
Yes
Yes
40
RO
5
2 cm—solid and trabecular organisation
Yes
No
Yes
No
Yes
Yes
Yes
Yes
40
R1
6
Huge mass with small cysts and haemorrhagic patterns
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
4/14, posterior pancreatoduodenal nodes 7/12, SMA nodes Overall resected nodes, 35 1/2, posterior pancreatoduodenal nodes Overall resected nodes, 1 3/6 Overall resected nodes, 12 1/3, pancreato-duodenal nodes Overall resected nodes, 25 2/2, pancreato-duodenal nodes Overall resected nodes, 25 3/3, SMA nodes 4/7, retroperitoneal nodes Overall resected nodes, 20
70
R1
MBD main biliary duct, MBD+main biliary duct infiltration, DUO+duodenal infiltration, RMR+retroperitoneal margin of resection infiltration, MA+mesenteric axis infiltration, VmI+vascular micro-infiltration “ab-estrinseco”, PAT+peripancreatic adipous tissue infiltration, EVE endolymphatic vascular embolisation, PE+peri-endoneural invasion, N-Inv node involvement, SMV superior mesenteric vein, SMA superior mesenteric artery
not only local or distant lymph nodes but also other solid organs (liver, lung, adrenal, brain, stomach, kidney, oesophagus and peritoneum) [6, 8, 16]. It seems that adenomatous elements are more invasive and responsible of systemic progression, while squamous cellular line shows faster and more aggressive vascular and lymphatic invasion [6, 8, 17, 18]. Different theories have been suggested to explain the pathological origin of ASCa, but the most widely accepted hypothesis is that of focal adenomatous pancreatic cancer metaplasia vs squamous histotype, supported by three principal observations: 1. A cytological spectrum from ductal hyperplasia to carcinoma in situ is frequently present just into adenomatous foci whereas squamous line does not show any cellular heterogeneity [6, 19]. 2. KRAS2 gene mutations are quite constant in ASCa (more similar than DPC) even within tumours that present squamous predominance [6, 20]. 3. Squamous cells are arranged principally “on the periphery” of adenomatous foci, without an identifiable transitional mixture [6]. ASCa still remains a severe clinical problem for physicians. In most cases, “curative” surgical approach is not possible because of local or systemic dissemination at
diagnosis, and the mean overall survival for these patients remains exceptionally poor, indeed worse than DPC, amounting to 4.5 months [6, 8, 11, 16, 21]. In the series of Kardon et al. [6], the survival rate of patients with advanced ASCa (12 not treated, one received only chemotherapy and six underwent palliative surgery) ranged between 3.0 and 7.0 months (mean, 5.0). As for DPC, when feasible, surgical resection along with adjuvant therapy would appear to represent the best therapeutic approach. In a recent retrospective study, Voong et al. [9] reported their long-term follow-up experience of 38 patients who underwent pancreatic resection for ASCa (the largest series available to date). This study identified a statistically significant improvement in survival for those patients who received adjuvant chemoradiation (5-FU or gemcitabine or capecitabine plus 5,040 Gy) compared with simple resection of the primary lesion (median, 13.6 and 8.6 months respectively; P=0.05). The 1-, 2- and 5-year overall survival rates reported were 34%, 11% and 5%, respectively. Curiously, other established prognostic factors associated with DPC including T stage, nodal involvement, residual microscopic tumour and operative blood loss were not significant prognostic factors for ASCa. In the study by of Smoot et al. [8], on the contrary, the completeness of resection influenced the survival rate, with a mean survival
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Fig. 2 Adenosquamous carcinoma of the pancreas eliciting a desmoplastic reaction. The squamous component shows loss of cohesion of tumour cells Fig. 3 Squamous component at higher magnification (original magnification, ×200) Fig. 4 Immunostaining of p63 confirms squamous differentiation Fig. 5 Immunostaining of ck5 confirms squamous differentiation
of 8 months for R1 resections and 14.4 months for R0 resections. Data from the present study would appear to follow this trend (13.5 and 27 months for R1 and R0 resection, respectively) (Table 3). Furthermore, other kinds of treatment have been proposed with controversial results. Hsu et al. [11] reported two male patients, a 63- and a 78year-old, with very large masses in the head (60 mm) and tail (80 mm) of pancreas, respectively. They underwent both open tumoural biopsy and IORT (1,800 and 2,000 cGy), and the 78-year-old patient also received palliative chemotherapy with gemcitabine with a reported survival of 22.4 and 5.4 months, respectively. Moreover, Yamaue et al. [10] reported the longest survival rate (40 months) for an ASCa after an extensive surgical
2
3
4
5
resection along with IORT and locoregional chemotherapy. The main series in the literature comparing adjuvant chemotherapy with standard resection have been unable to detect any differences in the overall survival rate (mean of 8.8 and 7.5 months, respectively) [4, 6, 8, 9, 11, 16, 22]. Probably, this has been due to the lack, in most of these reports, of homogeneous samples and details about the status of margin infiltration and the TNM stage. In our series, the four patients who underwent surgical resection with “curative intent” and adjuvant chemotherapy showed a median overall survival rate of 14.5 months (three of them are still alive), a rate that is considerably better than previously reported in literature. Moreover, this result is comparable with the median overall survival rate described by Voong et al. in
Table 3 Principal characteristics and mean overall survival rate of patient underwent surgical resection of ASCa in main series reported in literature (Pts≥6) Author
Year
Pts
Age (M/Med)
Tumour size (M/Med)
Pancreatic localisation (He/Bo/Ta)
Yamaguchi [22] Madura [4] Kardon [6] Rahemtullah [16] Smoot [8] Hsu [11] Voong [9]
1991 1999 2003 2003 2008 2008 2010
8 6 25 14 23 12 38
55.7 (M) 63.5 (M) 65.4 (M) 69.7 (M) 67 (M) 66.3 (M) 68 (Med)
NA 42 mm 63 mm 37 mm 45 mm 63 mm 50 mm
6/1/1 4/2 17/4/9 6/3/4 NA 5/5/4 21/15/2
Pts patients, He/Bo/Ta head/body/tail, M mean, Med median
(M) (M) (M) (M) (M) (Med)
Surgical resection
Patient survival (mean)
8 6 8 1 10 7 38
6 5 13.4 13 13.1 6.6 17.9
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his series for those patients who underwent surgical resection and adjuvant chemoradiation (13.6 months).
Conclusion ASCa still remains a clinical problem for physicians because of its poor prognosis, reportedly worse than DPC. Currently, surgical resection along with adjuvant chemoradiation appears to offer the best outcome for patients with ASCa. Nevertheless, the role of adjuvant chemotherapy is still unclear. The largest series from the literature did not demonstrate benefit from this treatment; however, these studies failed to include a number of prognostic factors, including residual microscopic tumour and the TNM stage. Even though our report would seem to show that adjuvant chemotherapy following surgical resection with “curative intent” can offer good results, unfortunately, this cannot at the moment be stated because the sample is too small to allow firm conclusions to be drawn. Thus, in the absence of further evidences, we strongly recommend, when feasible, radical resection of the primary tumour plus adjuvant chemoradiation. Further multi-institutional trials with complete and clear clinical information are required to improve our knowledge about this unusual and aggressive neoplasm, and evaluate the efficacy of alternative therapeutic approaches. Informed consent All patients gave the informed consent prior to their inclusion in the study. Role of the funding source its realisation.
This study had no sponsors involved for
Conflicts of interest None.
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